Clinical and Experimental Pharmacology and Physiology (2014) 41, 381–391

doi: 10.1111/1440-1681.12236

SPECIAL ARTICLE

The Florey turns 50 John P Coghlan Office of the Dean of Medicine Dentistry and Health Science, The University of Melbourne, Melbourne, Victoria, Australia

SUMMARY The origins of the Howard Florey Laboratories of Experimental Physiology, Department of Physiology, The University of Melbourne, are tied to the ground-breaking clinical work of Derek A Denton in 1947 and to the investigations of the initial scientific team into the control of salt and water balance in health and disease over the period 1947–1963 were Professor RD Wright, Drs JR Goding, IR McDonald, John P Coghlan, E Marelyn Wintour and John R Blair-West. An Act of Parliament in 1971 by the Victorian State Government formally established the Institute named after Howard Florey, the Australian Nobel Prize winner who isolated penicillin. The Howard Florey Laboratories/Institute quickly became an international leader in the scientific areas of the physiological control of body fluids and electrolyte balance, especially sodium regulation and the regulation of the secretion of aldosterone, the adrenal salt-retaining hormone; the micro measurement of hormones, in particular steroids and peptides; instinctive ingestive behaviour; fetal fluid regulation; hybridization histochemistry, and the hormone relaxin. Subsequently, the senior staff included, inter alia, Bruce Scoggins, Richard Weisinger, John McDougall, Brian Oldfield, Michael McKinley, Robin McAllen, Hugh Niall, Geoff Tregear and Felix Beck. During the 1990s, an explosion occurred in neuroscience and, in 1997, the Board made the strategic decision to change the focus of the Institute to brain disorders. From 1997 to 2007, Fred Mendelsohn steered the Florey to become one of Australia’s premier brain research institutes and, under the current director (the eminent clinician and neuroscientist Geoffrey Donnan), this reputation has been further enhanced. Key words: aldosterone, angiotensin, Howard Florey institute, hybridization histochemistry, hypertension, instinctive behaviour, relaxin, sodium appetite, testosterone.

INTRODUCTION August 2013 was the 50th Anniversary of the dedication of the Howard Florey Laboratories for Experimental Physiology at The University of Melbourne. The anniversary may have properly been celebrated in 1997, but that was an opportunity missed: the 50th Correspondence: John P Coghlan, AO, Faculty Medicine Dentistry Health Science, Level 3766, Elizabeth St., The University of Melbourne, Parkville, Victoria 3010, Australia. Email: [email protected] Received 21 November 2013; revision 11 March 2014; accepted 17 March 2014. © 2014 Wiley Publishing Asia Pty Ltd

Anniversary of Sir Howard Florey’s, later Lord Florey’s gracious acceptance that his name be used for the group and building. The Florey is an interesting story of the successful symbiotic interaction between town and gown; between private sector philanthropists and philanthropic bodies; between State and Commonwealth Governments; between the Department of Physiology and The University of Melbourne; and medical research support agencies, namely the National Health and Medical Research Council of Australia (NHMRC) and the US National Institutes of Health (NIH), only more so because the integrated outcome is interesting beyond the composite strands. The outcomes reported here were linked to internationally competitive science that the supporters, both government and private, found compelling. The history has many salient features before 1963. A summary of the history of the group (with a series of name changes and key personnel) is given below. 1947–63: The Ionic Research Unit, Department of Physiology; Professor RD Wright (Chair), Drs Victor Wynn (until 1949), IR McDonald, DA Denton and JR Goding (part-time). 1963–71: Howard Florey Laboratories of Experimental Physiology (HFLEP), Department of Physiology; Head, Professor RD Wright; Chief Scientist, Dr DA Denton. 1971–2007: Howard Florey Institute of Experimental Physiology and Medicine (HFIEPM); Directors: Professor DA Denton (1971–1989), Professor JP Coghlan (1990–1996), Professor FO Mendelsohn (1997–2007). 2007–12: Florey Neuroscience Institutes (FNI); Director, Professor GA Donnan (2007–12). 2012–: Florey Institute of Neuroscience and Mental Health (FINMH); Director, Professor GA Donnan (2012–). To place these developments into perspective, we need to focus on the beginnings.

PROLOGUE (1947–63) This critical period is presented in some detail as befits establishing something from nothing. Of necessity, the detail diminishes as the story unfolds. This history gives a thumbnail overview of the parallel strands, each internally in chronological order. In contrast, the account by Hewat,1 rich in detail as it is, focuses on personalities and the time line is blurred, except for those then present and involved. Strand 1: Patients and sodium measurement (1947–49) Fons et origo [the origin and the source] Picture the scene, the Royal Melbourne Hospital in 1947: a young resident doctor, aged 22, newly graduated from the short

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medical course introduced in war time, was on rotation on the surgical ward. Resident training in those days consisted of rotation through the specialties and disciplines. The resident training was patient focused, much more than learning to navigate bureaucratic rules and management of multiple forms, and was more an apprenticeship. This young man had the care of a patient with tragic postoperative complications following a radical gastrectomy. The surgeon was Sir Albert Coates who, even after World War II (WWII), still enjoyed revered status. With much bravery and at huge personal risk, Coates had organized health care and medical treatment of his fellow prisoners of war of the Japanese on the notorious Burma–Thai railroad. 1947 was the era of ‘heroic surgery’, especially for cancer that had metastasized. The postoperative problem of this patient was a duodenal fistula that caused the fluid normally secreted by the pancreas into the duodenum to leak out of the body instead of into the gut. This lost secretion was largely alkaline (sodium bicarbonate), pushing the patient into both extreme sodium depletion and acidosis. The rather obvious answer to give sodium bicarbonate back was not possible because sterile sodium bicarbonate solution suitable for intravenous use did not become available until 1948, and then only in limited supply; alternative measures had to be used. On top of this, nothing about this patient fitted with the current clinical lexicon, and even less with the internationally accepted dogma concerning kidney function. Despite valiant efforts and treatment (but travelling in uncharted waters), the patient died. During this treatment period, there had been much discussion about the patient with Professor R Douglas (Pansy) Wright, the renowned Professor of Physiology who, coincidentally, was a patient himself at the Royal Melbourne Hospital for a bout of acute food poisoning complicated by a severe reaction to penicillin. His life may have been saved by Macfarlane Burnet, who recognized the problem. One wonders as to the possibility of an earlier accidental sensitization of Wright to penicillin in Oxford? The young resident was Dr Derek Denton and his intuitive understanding and rigorous pursuit of the underlying science earned him a paper in Nature2 and later a report in the Medical Journal of Australia,3 an auspicious start to a future career in science. Denton moved on to research studies with Macfarlane Burnet at the Walter and Eliza Hall Institute. Even so, another surgeon (Mr Douglas Leslie) approached Denton because he had another patient with duodenal fistula. Denton’s sterling work with the first patient had not gone unnoticed in the hospital. Denton was not alone this time, having made contact with Dr Victor Wynn, reflecting their shared interest in ballet (or perhaps more so in ballerinas: both Derek Denton and Alan Wynn married ballerinas). Alan was Victor’s twin brother and subsequently a leading physician at Prince Henry’s Hospital. By coincidence, Victor Wynn was studying for a doctoral degree in Professor Wright’s Physiology Department, struggling with the intricacies of metabolic regulation, at this time a totally new area of medicine in which he was an almost lone pioneer. In the metabolic sense, almost nothing of immediate relevance to patient care could be measured in the appropriate time. The Leslie patient, with Denton in attendance, was the touchstone for an instant collaboration between the young men. Denton’s entrepreneurial spirit did not find favour with Macfarlane Burnet, so he departed the Walter and Eliza Hall Institute

for a position as an NHMRC junior research fellow with Professor Wright in the Department of Physiology. Here, under Wright, he joined Victor Wynn, Ian McDonald and Jim Goding (who was part-time), in the Ionic Research Unit of the Physiology Department. This was, in effect, a life-changing event. Wynn had heard of a newfangled instrument called a Beckman flame photometer that could measure the key plasma components sodium and potassium almost instantly. Professor Wright obtained a grant to purchase the instrument from the Rockefeller Foundation in New York. The cost was £2000, which, in those days, was a princely sum and an unheard of amount for equipment for a physiology laboratory. Professor Wright knew of the munificence of Rockefeller from his time with Howard Florey, who had been the beneficiary of their generosity in working up the production of penicillin. Even so, the air freight was a crippling £1000. The instrument was designed to measure sodium and potassium (as well as lithium) in soil or food, so the sample preparation for plasma and urine had to be developed post-haste.4 After 90 days, the patient was discharged. Both the first and second cases are recorded in extenso in a monograph in Acta Medica Scandinavica.5 During this period, Wynn and Denton acted as a clinical flying squad trying to resuscitate patients with extreme electrolyte disturbances. These frequently resulted from infection following botched ‘backyard’ abortions. These interventions were unquestionably the template for the much more sophisticated intensive care of today. Strand 2: Sheep, transplanted adrenal, cross circulation (1948–63) For further development of the fundamental questions raised by these patients, an experimental animal was needed because there was no way ethically acceptable experiments could be devised on humans. The involvement of Wynn in a sheep health issue with the CSIRO opened the door. While exploring the possibility of replicating the patients’ duodenal and pancreatic fistula in the sheep, the copious continuous flow of parotid saliva was noticed as a particular problem during anaesthesia. It was observed that this saliva was extremely alkaline and its loss could meet the experimental purpose and duplicate the patient problem. Denton performed the first surgical exteriorization of the parotid papilla. Critical to this move into using a large experimental animal was animal care. The first technical appointment was Mr Ben Dyzenhaus, a survivor of Auschwitz, whose medical course had been interrupted by WWII. Ben was widely recognized as a hero of the Warsaw ghetto. His contribution was also vital to the survival of the fledgling Ionic Research Unit. The parotid fistula successfully contrived for the sheep to lose several litres of sodium-based alkaline saliva a day. Sadly, this preparation allowed saliva to drip down the sheep’s face and neck and make the collection of clean samples difficult and sheep hygiene a major concern. Although salivary loss was the initial aim and clean samples were not a priority, uncontaminated salivary collection rapidly became an imperative. But by then Wright, using plastic surgical techniques, had modelled the exteriorized papilla into a teat so that the saliva dripped free and was easily collected for analysis: the ‘Wright fistula’. Thus, sheep were chosen because they were an excellent model. However, the

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Howard Florey Institute: 50th Anniversary infrastructure for using a large animal that had to be surgically prepared was a formidable challenge, but was created over time. In 1949, Wynn had flown off for ‘further training’ at St Mary’s Hospital, London, never to return. In fact, reflecting his experience in Melbourne, the roles were reversed and he became the teacher. In early experiments it was noticed that, as the sodium depletion progressed and the sodium loss mounted, the sodium content of the saliva was replaced, somewhat unexpectedly, by potassium. The term used in much of the subsequent work was coined: the ‘the Na/K ratio’ (180/3 mmol/L = 60 in a normal sheep, falling to 30/180 = 0.17 during sodium depletion).6 Subsequently, it was shown that this change in ratio was dependent on the adrenal glands. The change in ratio could be restored by the replacement of sodium or the administration of deoxycorticosterone (succinate or acetate), the only synthetic steroid with mineralocorticoid properties available at the time.7,8 Although deoxycorticosterone is a naturally occurring product of the adrenal gland, it was thought that the Na/K ratio was probably altered by secretion of the newly discovered steroid aldosterone. So, here was an experimental animal in which not only the sodium balance could be manipulated easily, but the animal also had an inbuilt bioassay to monitor what was happening to aldosterone secretion (e.g. when sodium was rapidly restored).8,9 Nevertheless, bioassays had inherent disadvantages because there was a significant response time. In this particular situation, secretion was out of phase with the measured response and the bioassay was thus not particularly sensitive. Autotransplantation of the adrenal to the neck of the sheep to allow access to adrenal blood in the conscious undisturbed animal became one of the hallmarks of the group.10 The first of these animals was created in 1954, largely due to the surgical skill of Goding and McDonald, but especially the dexterity of Wright, who performed the surgical anastomosis. The idea of the adrenal transplant was unquestionably raised by Denton, but the use of surgery to allow access to deep-seated organs was a common approach of experimental physiology. These unique experimental animals with a parotid fistula and adrenal transplant allowed the cross-circulation experiments described by Denton et al. in 1958.11,12 These experiments were complex, sophisticated and attracted international interest when presented by Denton at several overseas venues, but in particular at University College London in November 1958.11,12 Parenthetically, it should be noted that there was a heavy dependence on the surgical skills of Professor Wright because the various experimental sheep, and later fetal preparations, had to be prepared serially over many months. Professor Wright had a succession plan as early as 1971 and Dr Ken Hardy, later Professor of Surgery at the Austin Hospital, was brought in as an associate. Hardy was a great contributor and the linchpin of the fetal program. Later, when Professor Wright stepped aside from this role, Hardy took over the adrenal transplant surgery with the same dexterity as the old master. Many of the routine surgical procedures were very ably done, under supervision, by Mr Rod Paterson, who had been trained to take on this role, which he filled very capably. Strand 3: Measurement of adrenal steroids (1959–63) In the papers on the cross-circulation and the putative new hormone some desiderata, modified from Starling, are set out,11,12

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including: ‘The chemical assay of the venous effluent must be developed until it detects quantitatively each substance known to be active to the biological indicator and overall effect of these substances must correspond quantitatively to the entire venous effluent’. In the present world, where a huge spectrum of unbelievably sophisticated methods is available to measure hormones in blood, it may be hard for the reader to imagine that in 1959 very few hormones could be measured. Some insensitive colorimetric assays were used for blood cortisol and urinary steroids. In early 1959, Coghlan reported reading that a new, complex, technically tedious and demanding method to measure aldosterone had been introduced in the US.13 The method was announced as a short abstract and used two reasonably safe radioactive isotopes. The method had been introduced during the discovery of aldosterone, but was restricted by the lack of effective radioactive counting equipment.13 The method required complex and very expensive equipment by the standard of the day (£10 000) for an automatic liquid scintillation spectrometer to measure radioactivity as well as other expensive infrastructure. One internal isotopically labelled steroid was added at the start of a very complex and tedious purification process, the other used as a labelling reagent to measure the amount. The methodology was too new for experienced people to be available for recruitment, even if it could be afforded.14 Ken Myer, the leading Melbourne businessman and philanthropist, in his well-known style, saw that for the group that this was a must. He funded the whole project, the liquid scintillation spectrometer, the isotopes and other equipment. Coghlan was sent to the US in September 1959 to gain experience with the methodology and to learn at the Packard Instrument Factory how to assemble, install and service the machine; because at the outset there was no local service available. The direct assay was up and running by 1961. Our experience with our modified method over 6 years has been set out elsewhere.15 At the start we did not use the assay as originally described, but a double isotope dilution derivative procedure. Dilution meant that the recovery markers were added at the outset, not later. This is much more user friendly and the assay could be run production-line style. By the end of 1961, we had a measurement method established that met the original criteria. Because salivary secretion was monitored continuously, the chemical method had to pass this continuous surveillance. In 1962, Sylvia and Jim Tait,16 who had discovered, isolated and determined the structure of aldosterone in 1953, visited the Ionic Research Unit from the Worcester Foundation for Biological Research at Shrewsbury in Massachusetts on a 3 month study leave. This project, funded by the NIH at their end, was to exploit the unique opportunity of in vivo biosynthetic studies of adrenal steroid synthesis, in particular aldosterone using the adrenal transplant. These joint studies continued for 7 years. The Taits were not surprised at the sophistication of the steroid laboratory and its achievements. Pincus had advised them of this and it was a critical factor in their decision to collaborate. Such was the quality control between the two laboratories that the results from either laboratory were within a few percent of each other. Later in 1962, Denton had been invited to the Laurentian Hormone Conference to present a paper on the Control of Aldosterone Secretion. Such an invitation is one of the pinnacles of achievement in the endocrine world. This visit led to lifelong

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friendship and collaboration with the Taits, especially with John Coghlan and Marelyn Wintour Coghlan.

encouraged funding from both the public and private sectors, as set out below and elsewhere.1

Strand 4: Support from the National Institutes Of Health USA (1958–1971)

Strand 5: The Howard Florey Laboratories (1956–63)

During his 1958 lecture tour detailing the all-important and unique cross-circulation experiments, Denton made contacts of cardinal importance for the future. The results from these experiments had raised the real possibility of a new hormone regulating aldosterone secretion. The vital role of aldosterone was still being unravelled. The role of aldosterone in maintaining correct total body sodium, its impact on blood volume and high blood pressure and on the heart and vascular system were compelling questions (and, it should be noted, still are). These studies were regarded as a potential major contribution to health. One critical contact was with Dr Robert Berliner, Chief of the Laboratory of Kidney and Electrolyte Metabolism in the National Heart Institute of the NIH. Berliner was fascinated by the results in Denton’s presentation and aware of the singular achievement in a conscious, non-traumatized large animal. To him, these were compelling findings and he suggested that the Department of Physiology group apply for an NIH grant. At this time (1960– 61), an NIH grant was a major and rare achievement in terms of medical research support. The long-term philosophy at the NIH has been that top medical research should be supported anywhere as long as it benefited the American public, provided the work could not be done by an American group. Most national bodies supporting medical research were less generous and much more parochial, not supporting work outside their national boundaries. Much of the next history must be compressed into a few lines at this point. In the event, a grant was submitted. Two site visits were conducted by the NIH in 1961. One included Dr Gregory Pincus,17 of contraceptive pill fame and Director of the celebrated Worcester Foundation of Experimental Biology (WFEB). Pincus was astonished at the effectiveness of the adrenal transplant and the opportunities it opened up and wondered aloud whether the ovary could be transplanted? This was achieved by Goding, but later. Pincus was also impressed that Coghlan, virtually single handed, had accomplished so much in getting the steroid laboratory up and running. Although introduced by the Taits during the isolation and identification of aldosterone, this new steroid measurement methodology had not been established yet at the WFEB. A separate visit from Dr RT Hill, Secretary of the Endocrinology Study Section, NIH, was all important because he had a crucial influence. His remit was to establish that the group had adequate infrastructure to carry a large infusion of funds. Hill was a Southern gentleman, said to be austere and tough. Pansy Wright’s bucolic humour was a worry, but they hit it off immediately and soon showed great rapport. Both visits awarded us a big tick. The integrated scientific development was important in obtaining a grant from the NIH that demonstrated the acceptance of the Ionic Research Unit of the Department of Physiology on the world stage. In the end, starting in 1962, £700 000 was awarded over 5 years. One of the stumbling blocks was concern at the US end that this sum would disturb the research funding ecology of Australia, reflecting more on the gross inadequacy of the total NHMRC funding than anything else. This grant, in turn,

Simultaneously, and in parallel with the above developments, interest in the group from the private sector gained momentum. Denton’s tennis acquaintances, Ken and Baillieu Myer, and others in the group developed a natural curiosity about what Denton did. They were told of the continuing accomplishments and eventually visited the run-down, vermin-infested, ramshackle laboratories in the old Physiology Department. They were amazed that such internationally competitive outcomes could come from this dilapidated infrastructure; it is true to say that they left shocked. Support had already come from this quarter: air-conditioning for the operating theatre, the new animal house and the establishment of isotopic steroid measurement. It may be of interest that I recall a familiarization with two textbooks was de rigueur, both volumes of the Textbook of Physiology by Schafer (1898) for Professor Wright and the Study of Instinct by Tinbergen (1951, Oxford) for Dr Denton. A landmark dinner party was hosted by Professor Wright and included inter alia the Myers, Ian Potter (a leading stockbroker and another tennis connection), Nugget Coombs (Governor of the Reserve Bank) and Denton. After some discussion, the concept of a new laboratory was canvassed. Professor Wright and Dr Coombs were no strangers to such a concept, because they had been part of the founding group of the John Curtin School of Medical Research at The Australian National University (ANU). The outcome of these discussions was that Ken and Baillieu Myer, together with Ian Potter, agreed to underwrite a new laboratory for the work with The University of Melbourne, up to £150 000. This proposal to underwrite a new building was without precedent and typical of this forward-thinking group. Parenthetically, it should be noted that the wives, Pamela and Sarah Myer, were strong supporters, as were Meriel Wilmot (later Mrs/ Lady Wright), executive officer of the Myer Foundation. Margaret Scott, Denton’s wife (later Dame Margaret), was a key connection to the Arts. A high achiever herself, Dame Margaret was the Founding Director of the Australian Ballet School. There were now two major issues: (i) to convince the University and for them to make space available that was not in the Master Plan of the day; and (ii) to obtain full funding for infrastructure and operation. The first issue was fraught because there was strong opposition within the Department of Physiology and the Faculty of Medicine. The new laboratory would be an extension of the Department of Physiology and thus created a ‘conflict’ with the proposed new Department of Physiology that was now on the planning horizon. For this and other reasons,the University itself was lukewarm. Much of the opposition was ill-founded: on envy, ultraconservatism and a perception of threatened interests. Professor Wright had written ‘Academies are not lotus gardens of mutual adulation. Academic behaviour would often scare Daniel even after his biblical experiences’.18 In this case Professor Wright was certainly on the receiving end of his own portent. The whole University negotiation really totally depended on Wright until the closing stages when the ‘town and gown’

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Howard Florey Institute: 50th Anniversary influences of the private sector donors could be brought to bear. The Vice Chancellor made supportive noises to them, but even so a site was offered with what was expected to be an unacceptable footprint: 40 9 90 ft east of the proposed new Department of Physiology. This size problem was brilliantly overcome by an attractive design by the award-winning architect Barry Patton, who had designed the Sidney Myer Music Bowl and was a friend of Ken Myer. A complication to the design was the University’s demand that provision be made for later connection to the eastern face of the proposed new Physiology Department. In the event, a change of plans that included physiology in the tri-radiate medical building made this connection impracticable. The funding saga and the ramifications of the initial shortfall on the building design are set out in extenso by Hewat.1 A compressed version follows. Although the Myer connection brought in Ian Potter, he and Professor Wright were old acquaintances, having shared a house in Eaglemont in the early 1930s. They had a healthy respect for each other and had good rapport with Robert Menzies, the Prime Minister. This connection was reinforced by Denton’s friendship with Harold Holt, the Treasurer. A sum of £100 000 was injected from the Federal Government and £50 000 from the Rockefeller Foundation (which had already donated the flame spectrometer). Wright had connections at the Rockefeller Foundation, but the grant followed directly from a visit by Denton there in 1958. A sum of £45 000 from the University of Melbourne was later substantially increased. Meanwhile, the under writing of £150 000 by Myer and Potter was supported by other benefactors. The sum available enabled the University to commission the building: occupation began in Easter 1963 and the formal dedication took place in August 1963. It was instantly nick-named the ‘Sheep Hilton’ by friend and foe because of the air-conditioned chemical laboratories, sheep housing and excellent large animal facilities in general. The accommodation for the animals was better in some ways than staff amenities. The latter, however, were excellent, with a Danish and Mediterranean influence, open and light, in contrast with the old-style academic architecture (drab, utilitarian and generally aesthetically unappealing). As facilities in the campus buildings improved, the Sheep Hilton became an anachronism to be replaced by the Florey, now imbedded in the formal title of the Institute. The HFLEP won some well-earned architectural design awards. The HFLEP was unquestionably the most aesthetically appealing modern building on the campus for many years, and it remains a fine-looking building even after sensitive extensions (Figs 1 and 2). Every successful endeavour has many fathers, but failure is an orphan. The successful outcome of the establishment of the HFLEP was based on the significant contributions of many people. Professor Wright had the key formative role, the founding father. His foresight was in supporting the group whose only academic credentials at the time were an impressive track record with substantial grant income but no higher degrees, no academic appointments and no postgraduate students. Marelyn Wintour was a Research Associate in the HFLEP and held the junior academic post of Demonstrator in the Department of Physiology. Professor Wright’s influence in persuading the University to expand his department was a vital issue. All this was consistent with Professor Wright’s major contribution to medical research as a creator and builder.19,20

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Fig. 1 The Howard Florey Institute of Experimental Physiology and Medicine University of Melbourne, 1986, after the first extension. At the rear is the Medical Centre of the University.

Fig. 2 Dr Derek Denton (left), Dr James Goding, Marelyn Wintour and John Coghlan in discussion at the time of the first occupancy of the new Howard Florey Institute.

TRANSITION FROM LABORATORIES TO INSTITUTE (1963–71) In 1963, the HFLEP group, the rebadged Ionic Research Unit, was still part of the Department of Physiology where Professor Wright was head. Dr Denton was given the appropriate but courtesy title of Chief Scientist. In any case, in contemporary jargon, he was the Principal Investigator (PI) on the NHMRC grant. The Ionic Research Unit was a close-knit team, where Derek Denton was the unanimously accepted leader; the opinion of this small

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group having been canvassed by Professor Wright. Although the operation was harmonious and collegiate, issues occasionally arose where Professor Wright had to exercise his position as Head. For example, all matters relating to postgraduate students were dealt with by the Department of Physiology. The formal separation of Dr Jim Goding from the HFLEP and the Department of Physiology, to pursue further studies using the ovarian transplant that he had developed, was arbitrated personally by Wright. There were those in the University, presumably with nothing better to do, who spent an inordinate amount of time opposing Denton’s appointment. Claims were made about lack of teaching experience, postgraduate supervision and even formal research training, which overlooked the many other positive issues that impressed Wright. During this period (1963–71) the scientific work of the group continued on its international upward trajectory. A vignette of the work over that period may be set down where a key paper has been selected as representative of a series: ● ● ●

● ●

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very significant change in sensitivity to aldosterone response during sodium deficiency21 systematic studies of instinctive behaviour were expanded, especially sodium appetite22 development of double isotope dilution derivative procedures for aldosterone, particularly in peripheral blood, as a routine procedure23 the first chemical assay for testosterone in peripheral blood24 the important discovery that the angiotensin (Ang) II hexapeptide ‘metabolite’ is equipotent on aldosterone secretion as its parent AngII25 the first workable routine chemical assay for AngII in blood established with Kevin Catt26 exquisite sensitivity of aldosterone secretion to increased plasma potassium demonstrated27 systematic study of renovascular hypertension in progress28 ground-breaking studies showing that adrenocorticotrophic hormone (ACTH) causes hypertension in the sheep and study of the roles of specific steroids29 broad-based studies of the comparative endocrinology of native and introduced species begin30

Professor Wright said at the time ‘the Florey grew so well and gained such fame in the world that it became a place which excited envy, the less-than-avuncular interests of other departments’.1 There were University staff who, instead of spending their time on academic matters and research, preferred to indulge in academic politics, however irrational and ill informed. The Florey became an even closer-knit group because there is nothing better to encourage group solidarity than a ‘common enemy’. Coghlan became a very effective and articulate advocate in defence of the group and some senior academics bore the scars of a public joust with him, especially in defence of Denton and their success. During this period, reinforced by the continued scientific achievement, the idea of independence of the Howard Florey group from the Department and the University was floated by Dr Coombs and supported by Wright, even though he was giving up one of the signature groups in his department. One rationale, among several, was the need for the unfettered ability to raise funds. Later, falling gold reserves in the US had a flow-on effect

on foreign grants, thus putting renewal of the NIH grant in jeopardy. In addition, towards the end of this period, Professor Wright’s guiding and protective hand was about to be removed because of his early retirement. Professor Wright bore the brunt of the very difficult University negotiations for which there was no precedent. Many of the same arguments emerged in opposition to the institute that had plagued negotiations over the HFLEP. Furthermore, there were academics who did not wish to see a sizeable piece of University property and infrastructure with its resource platforms removed from their domain, albeit covered by a lease. Independence was impossible if the University did not back the idea. The Deputy Chancellor had a negative input to the Vice Chancellor Professor David Derham who, after a meeting with the NHMRC, was himself also less than enthusiastic. Professor Wright was able to convince the senior members of the Faculty of Medicine and Dentistry to support the principle of independence for very successful and self-sustaining research groups, a group including the very influential Dean of Medicine Professor Sidney Sunderland. The Chancellor Sir Robert Menzies was a supporter of the original laboratories and, after an approach, this time by Denton, agreed in principle to separation. A series of negotiations with the State Government involving several people took place with Professor Wright making the final presentation to Henry Bolte, the State Premier. As a farmer, Bolte shared Pansy’s bucolic sense of humour and was quickly on side, even presenting the Bill to Parliament himself but stumbling through the scientific prose. It is not insignificant that the first of Coghlan’s contributions to the larger University came with Jack Best, when they put childcare for staff and students on a proper basis; although a big plus later, it was not so at the time. All the multiple complex issues are encapsulated nicely by Poynter and Rasmussen:31 The unclear [continuing] relationship the Howard Florey Laboratories to the University’s structure was about to be defined by the extraordinary device of creating an Institute by Act of Parliament, evidence yet again of the public power of the Florey’s stellar governing body, tenaciously led by Mr K.B. Myer and Sir Ian Potter. Denton was made a member of the Board, usually denied to paid employees by the conventions and/or regulations of the day. But the Act went beyond this, making Denton an originating member, in effect on the Board for life. Regrettably, this final form of the Act establishing the HFIEPM soured relationships with the Vice Chancellor Professor David Derham:31 . . .who did not like the idea of such legislation and who took strong objection to its drafting; allegedly based on the Harvard [College] precedent, it entrenched too completely, in his view, the right of the Board to determine its own future membership. In the end the Act was a pastiche of the old Harvard College governance and membership required by several stakeholders. This potentially created a worrying divisive issue of two classes of board members. As Chairman, Ken Myer handled this adroitly by an inclusive management style that was not sustained after his

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Howard Florey Institute: 50th Anniversary untimely death in 1991. What was not aired at the time of the drafting of the Act was that years ago Harvard College had modified this form of governance with its life time term and self perpetuation as anachronistic for the 20th century. Dr Denton was appointed the first Director of the HFIEPM. The initial board of HFIEPM, especially the Chairman Ken Myer, rightly ignored the pressures that demanded that this appointment follow an international search by advertisement. Myer cited the independence of the HFIEPM board from slavishly following University procedures and the obvious special circumstances and other positive factors in favour of Denton. These are self-evident, as set out in the developments above. The first business manager was Mr Norman Geschke, later the first Ombudsman of Victoria. Mr Geschke had a stellar career in the RAAF and there was some future shock associated with his plunge into academic life. No stranger to bureaucratic thickets, he oversaw the separation from the University with patience, persistence and goodwill on both sides. Even so, this separation was not finalized administratively until 1973. The HFIEPM now existed, but other academics, disgruntled from the outset about this development, were very ungracious in defeat and continued to snipe from the side lines for years afterwards. In a spiteful and petty reaction they effectively blocked Denton’s appointment as Professor until 1977 when the new Dean, Professor Sir Lance Townsend, put his weight behind the appointment.

THE HOWARD FLOREY INSTITUTE (1971–2007) To detail the work of HFIEPM until the repeal of the Act of Establishment in 1997 could take a whole book. What follows is a snapshot of the years between 1971 and 1997 and then the rebadging, amalgamations and start-up of the Florey Neuroscience Institutes that quickly morphed into the Florey Institutes of Neuroscience and Mental Health. Key issues, achievements and people are selected in what must be inevitably a personal preference, but with every effort to be even handed. In 1973, the NHMRC invited an application for and awarded an institutional block grant to the HFI of the type awarded earlier to the Walter and Eliza Hall Institute. Part of the conditions of the NHMRC block funding was that the NHMRC would conduct an independent review of the whole institute every 5 years, the quinquennial review (QQR). The first QQR was in 1979; there were two international reviewers as well as senior members of the NHMRC. The two international reviewers were Dr Robert Berliner, formerly Deputy Director for Science at the NIH Cardiovascular Renal Institute but then Dean of Yale University Medical School, and Dr Roger Guillemin, Chief of Neuroendocrinology, Salk Institute and later Nobel Laureate. The review had an excellent outcome and recommended increased funding within the capacity of NHMRC to do so. Aware of the newness of the block funding concept, locally or anywhere else in the world, the reviewers wrote separately from the formal review report to NHMRC saying: The facilities, of the Howard Florey Institute, with its original use over the past 20 years of the sheep as an experimental animal, are unique, not only in Australia but in the world. The Florey Institute has placed Australian experi-

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mental medicine at the forefront of anything of quality anywhere in the world.1 This was reassuring for the NHMRC, which had drawn flak over its decision to award a block grant, and for the staff who were likewise under the pump. About this time, Dr Ralph Reader, one of the Institute’s strongest supporters and the remarkable first director of the National Heart Foundation, when challenged about his continuing support, said ‘there is nothing wrong with their science which is compelling but I must say they are a flamboyant bloody bunch’. Because the previous submission and the review outcome were central documents for the incoming reviewers for subsequent reviews, they continued with the precedent of a letter to the NHMRC from the international reviewers as well as the formal report. The QQR took place in 1979, 1985, 1991 and 1997. On each occasion the programs and achievements of the Institute were highly praised and the letter of the international members highly laudatory. This independent international peer review process was critical in sustaining the research of the Howard Florey Institute at the cutting edge of international endeavour. The 1991 review was especially important in that there had been a change of Directors, Denton stepping down and Coghlan being appointed in 1990. There was a new focus on organization in response to increasing pressures about accountability and a consolidation of programs that continued to develop as the science changed. At this time the work was structured into overlapping divisions that had evolved from the original sodium input, sodium output paradigm: Integrated Physiology, Cardiovascular Physiology, Fetal Physiology, Neurobiology including Ingestive Behaviour, Reproductive Biology, Developmental Biology and Research and Development. The review inter alia stated: . . .the committee considers the Institute to be at the forefront of medical science internationally. Research continues to be of the highest standard and the Institute remains competitive across a wide range of endeavours. Much of the work is pioneering and at the leading edge of scientific knowledge. This portfolio of interests may seem diverse, but there is a clear historic thread of development and the interests of our scientific groups have determined the multidisciplinary character of our investigations. Our early interest was in the renal response to profuse loss of sodium from the body. This led to investigation of hormonal responses to alterations of body fluid composition caused by the loss, and to the study of the instinctive appetitive drives resulting from the loss. Many of the hormones involved had not even been recognized let alone discovered when we started out on these investigations. From these beginnings, a broad investigation of the control of hormone secretion developed. There was early recognition of the overarching role of the brain in every aspect. There was a logical progression into molecular biology. The introduction of the molecular idiom and its remarkable technologies into our traditional areas of physiological research has opened up many new and exciting avenues. Up until the time of major reorganization into Neuroscience, the Howard Florey Institute was a ‘lean machine’ noted for its collegiate structure. In the scientific area, the absence of rigid

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departmentalization provided for very effective use of all shared resources and eliminated duplication of facilities, which is a common feature of divisions and departments. The flexibility achieved allowed the free interchange of personnel, supplies and equipment between projects. Although there were administrative functions attached to each senior scientific position, the major responsibility was leadership of a team engaged in research activities and day-to-day experimentation. An important hallmark of the Institute was the willingness of senior staff to serve on peer review committees, both local and international. These bodies included NHMRC committees, where a succession of staff did major reviews and held the highest offices, the National Heart Foundation Advisory Committee, the Anticancer Council (Vic.), the Cancer Council (NSW) and other philanthropic bodies (e.g. ANZ and Perpetual). Professor Denton was notably on the jury for Basic and Clinical Medical Research Awards of the Albert and Mary Lasker Foundation (NY). The staff monthly wine tasting club, the Friday Club founded by John Funder and Bruce Scoggins, both PhD students, had quite a well-earned reputation. Very complete records and minutes, including wine labels, were kept meticulously from 1964 to 1996 and are a notable historical record of the changing times and fortunes of students and junior staff. Premier cru French

wines were relatively more affordable then than now. Formal dinners for donors and supporters, catered by the staff, were a hallmark of the Institute. Both these features were part of the distinctive ‘Florey’ brand. Institute staff had a notable role in the Australian Society for Medical Research (ASMR). John Coghlan, as the inaugural Chairman of the ASMR Public Affairs Committee, together with John Funder had major successes over more than a decade as lobbyists for medical research funding. Florey staff served on the Councils of the Endocrine Society of Australia, the International Endocrine Society, The High Blood Pressure Research Council of Australia, The Australasian Society of Nephrology, Australian Society of Physiology and Pharmacology, The Royal College of Physicians, The Royal College of Surgeons and the Annual Victorian Medical Research Week. Sometimes staff was in a supportive role, but in others a founding presence and involvement at the highest level. Florey staff were also critical in the foundation of Clinical and Experimental Pharmacology and Physiology.32 Some developments that fall outside the logical extension of the programs or are relevant to the image of the Institute are listed in Appendix S1, available as Supplementary Material to this paper. Of necessity this is not exhaustive. Some future career

Fig. 3 Diagram of scientific organization of the Howard Florey Institute.

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Howard Florey Institute: 50th Anniversary trajectories of Howard Florey post graduate scholars or postdoctoral fellows (alumni), with a couple of exceptions, ‘beyond’ the Institute are noteworthy (Appendix S2). The international standing of the ‘old Institute’ is vividly affirmed and reflected in awards to the first director, Professor Derek Denton AC, LLD(Hon), Foreign Member of the Royal Swedish Academy of Science, Fellow of the Australian Academy of Science, Fellow Royal Society London, Fellow National Academy of Science USA, Fellow of the Academy of Science of the Institute of France and Fellow of the American Academy of Arts and Sciences. This whole precis is drawn from the annual reports of HFIEPM and later FNI/FINMH, which were also used as a memory check. This annual reporting set a new national standard for transparency and conformity with statutory provisions. The Institute received several Gold and Silver awards from the Australian Institute of Management. Therein is the fine detail of every scientific program, the administrative and financial particulars, local and international collaborations as well as extensive lists of national and international visitors, invitations to staff to present their work at the leading meetings in their fields and postgraduate scholars and postdoctoral fellows. Recognition must be given to the series of business managers, each a paragon with special expertise appropriate for the moment:

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Mr Norman Geschke, Mr Jim Carroll, Mr Bob Hookham, Mr Jerry de la Harpe, Mr Graeme Chandler and Mr Gary Gray, now styled COO. The Laboratory Managers were no less impressive: Mr Conrad Rabl and Mr Ruston Barlow. Special mention must be made of the contribution of Dr John McDougall (Research and Resources Manager) at a time of critical change when accountability in all matters became sharply defined and the operating lexicon suddenly contained performance evaluation, milestones, time lines, outcomes and citation scores. From the initial research profile, the research groups evolved; each of these areas was supported by a team and these groups continually had an internationally competitive output and outcome. These programs are set out schematically in Fig. 3 Change began in 1997 with the appointment of the third Director, Professor Fred Mendelsohn. The established culture and ethos had to change of necessity. Professor Mendelsohn brought in a large group steeped in another culture; there was ‘future’ shock on both sides. The long-standing board directive that staff size should be limited to 100 was set aside. The old culture and ethos was hard to sustain with increased numbers. The termination by NHMRC of the block grant program meant that the friendly sibling rivalry of the old and united front was replaced by real competition between groups for funds. The increasing size and subsequent split campuses did have an impact on the

Fig. 4 Diagram of Scientific organization of the Florey Institute of Neuroscience and Mental Health. Ten major themes are being pursued, using techniques that range from molecular biology, genetics, biophysics, population studies, peptide chemistry, cell and tissue investigations, clinical studies, investigation of brain structure and function using magnetic resonance imaging and other forms of neuroimaging, and clinical trials.

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old modus operandi; however, one of the keys to survival is adaptability to a change in environment. The Florey Institute of Neuroscience and Mental Health was created from the amalgamation of the Brain Research Institute, the Howard Florey Institute and the National Stroke Research Institute with an ongoing affiliation with the Mental Health Institute in July 2007. Each organization has brought individual strengths to the partnership: The Howard Florey Institute is recognized as a leader in basic science, the Brain Research Institute specializes in imaging development and epilepsy and the expertise of the National Stroke Research Institute is in stroke, public health, epidemiology and clinical trials.33,34 The creation of the Florey represents a powerful step forward in collaboration and productivity, drawing together leading neuroscientists from many areas to create an intense buzz of ideas on which new research thrives.33,34 The Florey Institute of Neuroscience and Mental Health has more than 300 scientists researching basic and clinical neuroscience areas aimed at developing better treatments for a range of neurological and psychiatric conditions. Sharing infrastructure and support services has also streamlined operational costs, ensuring our researchers have maximum access to the expensive and cutting-edge equipment and expertise they need.33,34 In 2012, with the formal amalgamation of the Mental Health Research Institute and the Florey Neuroscience Institutes, the Florey Institute of Neuroscience and Mental Health (FINMH) was formed. A thumbnail presentation of the current research is shown in Fig. 4. The continuing amalgamation has created one of the largest and best neuroscience research organizations in the world. In the international rankings of brain research institutions the FINMH already has a high score, with major basic contributions and in the clinical areas listed above. Although there was risk with the changes of direction, the amalgamation of the two campuses is almost completed with remarkably successful outcome. Who can predict what the future holds? The major potential risk, that FINMH would be a ‘research hotel’ housing specialized non-communicating quasiindependent research silos, has been skilfully avoided. A biological allegory seems appropriate: metamorphosis. First the caterpillar, the Ionic Research Unit; second, the juvenile form defining the shape of the adult, The Howard Florey Institute; and third, a beautiful butterfly emerges, the FINMH. It would be a marvellous outcome if the future continues to recapitulate the past.

ACKNOWLEDGEMENTS The author gratefully acknowledges the very willing assistance received from a wide spectrum of staff, but in particular Professor Judy Whitworth, Dr John McDougall and Professor Marelyn Wintour Coghlan. The author also sincerely thanks the CEPP editorial staff, in particular Ass. Professor Roger Evans, and Profes-

sor John Funder and Professor Trefor Morgan for their constructive contribution. Mark Farrelly Photography (Melbourne, Australia) provided invaluable assistance.

REFERENCES 1. Hewat T. The Florey. The Story of the Sheep Hilton. Angus and Robertson, Sydney. 1990. 2. Denton DA. Renal regulation of the extracellular fluid. Nature 1948; 162: 618. 3. Denton DA. Renal regulation of the extracellular fluid: A study of homoeostasis in a patient with a duodenal fistula. Med. J. Aust. 1949; 2: 521–8. 4. Wynn V, Simon S, Morris RJ, McDonald IR, Denton DA. The clinical significance of sodium and potassium analyses of biological fluids: Their estimation by flame spectrophotometry. Med. J. Aust. 1950; 1: 821–35. 5. Denton DA, Wynn V, McDonald IR, Simon S. Renal regulation of the extracellular fluid. II. Renal physiology in electrolyte subtraction. Acta med. scand. Suppl. 1951; 261: 1–202. 6. Denton DA. The effect of Na+ depletion on the Na+ to K+ ratio of the parotid saliva of the sheep. J. Physiol. 1956; 131: 516–25. 7. Goding JR, Denton DA. Adrenal cortex and the parotid secretion of sodium-depleted sheep. Science 1956; 123: 986–7. 8. Denton DA, McDonald IR. The effect of a rapid change of Na balance on the Na/K ratio of the parotid saliva of Na-depleted sheep. J. Physiol. 1957; 138: 44–62. 9. Goding JR, Denton DA. The effects of adrenal insufficiency and overdosage with DOCA on bilaterally adrenalectomized sheep. Aust. J. Exp. Biol. Med. Sci. 1957; 35: 301–20. 10. McDonald IR, Goding JR, Wright RD. Transplantation of the adrenal gland of the sheep to provide access to its blood supply. Aust. J. Exp. Biol. Med. Sci. 1958; 36: 83–95. 11. Denton DA, Goding JR, Wright RD. Control of adrenal secretion of electrolyte-active steroids. I. BMJ 1959; 2: 447–56. 12. Denton DA, Goding JR, Wright RD. Control of adrenal secretion of electrolyte-active steroids: Adrenal stimulation by cross-circulation experiments in conscious sheep. BMJ 1959; 2: 522–30. 13. Avivi R, Simpson SAS, Tait JF, Whitehead JF. The use of 3H and 14 C labelled acetic anhydride as analytical reagents in micro biochemistry. In: Johnston JF (ed). Proceedings of 2nd Radio Isotope Conference. Butterworth, London. 1954; 312–24. 14. Kliman B, Peterson RE. Double isotope derivative assay of aldosterone in biological extracts. J. Biol. Chem. 1960; 235: 1639–48. 15. Coghlan JP, Wintour M, Scoggins BA. The measurement of corticosteroids in adrenal vein blood of sheep. Aust. J. Exp. Biol. Med. Sci. 1966; 44: 639–63. 16. Tait SAS, Tait JF. A Quartet of Unlikely Discoveries. Athena Press, London. 2004. 17. Speroff L. A Good Man: Gregory Goodwin Pincus. Arnica Publishing, Portland, OR. 2009. 18. Wright RD. The academy and its freedoms. Meanjin Quarterly 1958; September: 284–91. 19. Best J. Sir Roy Douglas Wright. Portraits in Australian Health. MacLennan and Petty, Sydney. 1988; Ch. 6. 20. McPhee P. Pansy: A Life of Roy Douglas Wright. Melbourne University Press, Melbourne. 1999. 21. Blair-west JR, Coghlan JP, Denton DA, Goding JR, Wright RD. The effect of aldosterone, cortisol and corticosterone upon the sodium potassium content of sheep’s parotid saliva. J. Clin. Invest 1963; 42: 484–96. 22. Beilharz S, Denton DA, Sabine JR. The effect of concurrent deficiency of water and sodium on the sodium appetite of sheep. J. Physiol. 1962; 163: 378–90.

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Howard Florey Institute: 50th Anniversary 23. Coghlan JP, Scoggins BA. Measurement of aldosterone in peripheral blood of man and sheep. J. Clin. Endocrinol. Metab. 1967; 27: 1470–86. 24. Dulmanis A, Coghlan JP, Wintour M, Hudson B. The estimation of testosterone in biological fluids. Aust. J. Exp. Biol. Med. Sci. 1964; 42: 384–400. 25. Blair-west JR, Coghlan JP, Denton DA, Funder JW, Scoggins BA, Wright RD. The effect of the heptapeptide (2–8) and hexapeptide (3–8) fragments of angiotensin II on aldosterone secretion. J. Clin. Endocrinol. Metab. 1971; 32: 575–8. 26. Catt KJ, Cran E, Zimmett PZ, Best JB, Cain MD, Coghlan JP. Angiotensin II blood-levels in human hypertension. Lancet 1971; 1: 459–64. 27. Funder JW, Blair-West JR, Coghlan JP, Denton DA, Scoggins BA, Wright RD. Effect of (K+) on the secretion of aldosterone. Endocrinology 1969; 5: 381–4. 28. Funder JW, Blair-west JR, Cain MC et al. Circulatory and humoral changes in the reversal of renovascular hypertension in sheep by unclipping the renal artery. Circ. Res. 1970; 27: 249–58.

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29. Fan JS, Coghlan JP, Denton DA, Oddie CJ, Scoggins BA, Shulkes AA. Effect of intravenous infusion of corticosteroids on blood pressure, electrolytes, and water metabolism in sheep. Am. J. Physiol. 1975; 228: 1695–701. 30. Coghlan JP, Scoggins BA. The measurement of aldosterone, cortisol and corticosterone in the blood of the wombat (Vombatus hirsutus Perry) and the kangaroo (Macropus giganteus). J. Endocrinol. 1967; 39: 445–8. 31. Poynter J, Rasmussen C. A Place Apart. Melbourne University Press, Melbourne. 1996. 32. Coghlan JP. Clinical and Experimental Pharmacology and Physiology: The formative years. Clin. Exp. Pharmacol. Physiol. 2009; 36: 1137–8. 33. Florey Institute of Neuroscience and Mental Health. 2013. Available from: http://www.wikipedia.org/wiki/Florey_Institute_of_Neuroscience_and_Mental_Health (accessed 2 December 2013). 34. Florey Institute of Neuroscience and Mental Health. 2012. Available from: http://www.florey.edu.au (accessed 2 December 2013).

SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Appendix S1. Special milestones. Appendix S2. Career trajectories of Florey postgraduate students and postdoctoral fellows.

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