Medical history

Without advance knowledge of the virulence and behaviour of a novel pathogen, pandemic response planning is difficult. Australia’s ability to manage future pandemics will depend not only on robust scientific and health care systems but also on fostering public trust and resilience

Matthew Brown · Alan W Hampson · John Gerrard

The diaries of captive Australian medical officer Major Kennedy Burnside reveal the role of pathology in the medical infrastructure of Changi prisoner of war camp during the Second World War

Kate Ariotti · Elizabeth Roberts‐Pedersen

The nationwide use of insulin began 100 years ago with experiments in an Adelaide laboratory

Sophie Templer

The Australian Government ’s offshoring policy for hospital care of Christmas Island residents classified as “Asian” contradicted the spirit of the United Nations multilateral convention against racial discrimination

Simon Barraclough · Alison Hughes · John Oldroyd

The evolution of treatment for a distinctly Australian affliction

Alon Taylor · Hannah North · Narinder P Singh · Paul A Fagan

The psittacosis epidemic of 1929–1930, spread by the Australian budgie, provides lessons for the COVID- 19 pandemic

Robert M Kaplan

Medicine in the pre‐antibiotic era offers lessons still relevant today, particularly regarding the prudent use of valuable medications The handwritten line on an archived envelope stored in a safe in The Children's Hospital at Westmead undercroft — “The first child in Australia to have ‘Penicillin’ therapy” (Box 1) — understates the remarkable story of how an experimental drug was requested, approved and delivered in secrecy during the Second World War for one child. The “Penicillin Papers”, rediscovered in 2018 by the Heritage Committee of The Children's Hospital at Westmead, highlight important questions of ongoing relevance. The story of the fortuitous discovery of penicillin by Alexander Fleming in 1928 has entered popular consciousness. What is less well known is how penicillin, which dramatically changed the course of medicine, came to be given to patients. The patient: a small boy in wartime Sydney On 17 June 1943, Peter, almost 7 years old, was admitted to the Royal Alexandra Hospital for Children with fever and increasing drowsiness. During the following 24 hours he reported headache, and a lumbar puncture found turbid cerebrospinal fluid (CSF) with an “uncountable number of leucocytes”, and Streptococcus pneumoniae “type 18” was cultured, a serotype that frequently caused meningitis.1 Sulfonamide drugs were manufactured in Australia in the 1940s, but between 1942 and 1945 stocks were strictly controlled, being reserved almost exclusively for military campaigns in New Guinea.2 Peter, diagnosed with pneumococcal meningitis, was treated with intravenous sulfapyridine for four days, and his fever resolved (Box 2); daily lumbar punctures showed CSF clearing. Treatment switched to oral sulfapyridine, but his fever and vomiting returned. Further intravenous sulfapyridine for one day was followed by extremely painful subcutaneous sulfadiazine infusions for 18 days, then by oral sulfathiazole for four days. Sulfadiazine was obtained from the 118th General Hospital of the United States Army, based in Herne Bay (now Riverwood) and staffed by health professionals from the Johns Hopkins University Hospital in Baltimore. Access to the restricted sulfa drugs was granted by Major McPherson Brown (1906–1989), a professor at the Johns Hopkins, suggesting early involvement of the US Army. By 10 July, however, Peter's CSF was again culture‐positive for S. pneumoniae and the outlook was “grave”. In 1943, penicillin was a highly experimental drug; clinical trials in US troops in Sicily were underway, and only two scientific articles on its clinical use had been published.3,4 In the US, the unenviable task of rationing the small supply for civilian use fell to Chester Keefer, professor of medicine at Boston University Hospital and chairman of the National Research Council Committee on Chemotherapy. Keefer personally vetted each penicillin request, restricting its use to cases in which all other treatments had failed.5 To better understand its potential and limitations, he collected detailed information on all patients given penicillin. Fortunately for Peter, his father was Lieutenant Commander Leo Harrison, a Navy surgeon working as a base medical officer in Sydney in 1943. It is likely that his father's connections with US Army doctors helped secure access to the treatment that ultimately saved his life. On the morning of Saturday, 10 July, Sir Alan Newton, chairman of the Medical Equipment Control Committee, cabled Washington to request urgent supply of penicillin for Peter. At 4:30 pm, one million units (600 mg) were despatched from Washington to San Francisco, together with documents stipulating that the penicillin was for research purposes only, and on the understanding that clinical notes would be provided to the National Research Council following treatment. The penicillin was transported by Liberator bomber from San Francisco to Hawaii, and from there via Brisbane to Sydney, arriving at the Royal Alexandra Hospital at midnight on Thursday, 15 July. The first dose was administered to Peter intramuscularly at 12:18 am on 16 July. Over ten days he received 15 000 units (9 mg) penicillin intramuscularly every four hours, and 10 000 units (6 mg) intrathecally. Today, 5 million units intravenous benzylpenicillin per day would be recommended for a boy of Peter's weight (almost 22 kg). Although Peter's condition improved dramatically, waking from “a stupor” to eat a full breakfast within 48 hours, the dose and treatment duration were inadequate. By 21 July, Peter was again febrile and CSF cultures were positive. Regretting that type‐specific pneumococcal antiserum had not also been requested, Newton had sent a second cable to Washington on 16 July. Rabbit anti‐pneumococcal (type 18) serum arrived and 100 000 units were administered intramuscularly each day from 23 July to 1 August, and oral sulfadiazine from 26 July to 8 August. On 18 September 1943, Peter was discharged home “cured”. Seventy‐five years later, he and his family (Box 3) were interviewed by ABC News reporter Tracy Bowden,6 after his case had been re‐discovered by The Children's Hospital at Westmead Heritage Committee. Research secrecy There are three references in the medical literature regarding this incredible case. The first was a report published in the Medical Journal of Australia in June 1944 by the treating physicians Donald Vickery and Lindsay Dey.7 The second, a short mention by Newton in a speech to the British Medical Association, was published in July 1944;2 the third, a letter by Dey's son in the MJA in August 1981,8 described his father's recounting of events that “would have made an excellent basis for a film”. The initial publication7 was delayed by the condition that details of the case be released only to the US National Research Council, effectively a non‐disclosure agreement. Discussions about research secrecy are as old as science itself.9 Proponents of openness argue that it promotes innovation and enhances productivity and efficiency of research. Openness is essential for testing hypotheses and fostering collaboration. Sharing information with the public fulfils moral obligations to provide evidence for shaping policy and to be accountable for the use of public funds. Conversely, research secrecy is often justified as protecting credit and intellectual property, shielding scientists and human research participants from stigmatisation or harassment, and minimising threats to national or international security. The financial interests of biotechnology and pharmaceutical companies further complicate the discussion. In 1943, arguments for secrecy about experimental penicillin treatments were compounded by the need to protect the limited supplies of the drug. It is pertinent here that the reverse of the envelope containing the Penicillin Papers was marked “Silence saves soldiers” (Box 1). Under the direction of Keefer, the Committee on Chemotherapy charged “accredited investigators” with assessing thousands of requests for penicillin.5 A strict allocation policy was adopted to ensure that decisions were made on clinical grounds. Only patients with severe infections caused by sulfonamide‐resistant, penicillin‐susceptible streptococci, gonococci and staphylococci, should receive penicillin, and only then if a cure could be expected. Access, compassionate and otherwise Equitable allocation of limited medical resources is a problem that often confronts clinicians and public authorities, particularly in resource‐constrained environments and during wartime, natural disasters,10 or epidemics.11 In 1943, Vickery and Dey did all they could to obtain the experimental drug penicillin for their patient. Wartime priorities in Australia did not include active control of therapeutic substances, although the National Health and Medical Research Council dealt with some medication access questions.12 In the US, the Food and Drug Administration (FDA) first addressed access to investigational drugs for therapeutic purposes in January 1963,13 three months after President Kennedy had approved the amendment of the Food, Drug, and Cosmetic Act that strengthened the FDA mandate to approve medications.14 The process of “expanded access”, the preferred FDA term for compassionate use — that is, of an unlicensed drug or device outside clinical trials — was formalised in 1987 in response to requests for access to investigational anti‐retroviral agents.13 In Australia, the Therapeutic Goods Administration (TGA) was established in 1989 as the national regulatory body; its Special Access Scheme, introduced in response to the 1991 Baume report,15 is the mechanism by which doctors can secure access to unlicensed drugs for selected patients. The 1962 American drug law amendments, passed in the wake of the thalidomide catastrophe, had the potential to make children “therapeutic orphans”, as many drugs have been tested only in adults.16 Paediatricians today regularly use medications off‐label, but the use of unlicensed drugs is less common and usually restricted to neonatal intensive care.17 Fortunately, the importance of including children in clinical trials is increasingly recognised internationally by research institutions and funding and regulatory agencies.18 Further, the FDA was empowered to provide financial incentives for including children in clinical trials and licensing applications by the 2007 Best Pharmaceuticals for Children and Pediatric Research Equity Acts.19 Lessons for the post‐antibiotic era from the pre‐antibiotic era Sulfonamides, the first effective antimicrobial agents, were available from the mid‐1930s, but drug resistance was widespread by the 1940s. One initial control on penicillin use was the requirement for demonstrated penicillin susceptibility and sulfonamide resistance: an early form of antimicrobial stewardship. As we approach the post‐antibiotic era because of rapidly increasing antimicrobial resistance, institutional, national and international antimicrobial stewardship programs are being implemented to protect the limited therapeutic options available for many infections. Multimodal programs incorporate pharmacokinetic and pharmacodynamic principles to avoid treatment failure through undertreatment, as experienced by Peter in 1943.20 In the future, strengthening these antimicrobial stewardship programs by integrating molecular technologies and high throughput screening methods will be critical. We also need to rediscover non‐antibiotic approaches to treating infections, including serotherapy21 and bacteriophage therapy.22 Both were widely and successfully employed in the early 20th century, and Peter's ultimate recovery in August 1943 appeared to require type‐specific anti‐pneumococcal serum treatment. However, our reliance on antibiotics over the past century has led to clinical and research neglect of alternative treatment modalities, although interest has revived in recent years, particularly in bacteriophage therapy.22 Greater investment in alternative treatment options is needed, as well as investigation of novel therapeutic and infection prevention strategies. Box 1 – The “Penicillin Papers”, retrieved from a safe in the basement of The Children's Hospital at Westmead in 2018, include letters and telegrams about the acquisition of penicillin from the United States and its use for treating Peter Harrison Source: The Penicillin Papers; courtesy of The Children's Hospital at Westmead. Box 2 – Details from transcribed observation charts for the first patient in Australia to be treated with penicillin, 1943 Source: The Penicillin Papers; courtesy of The Children's Hospital at Westmead. Box 3 – Peter Harrison (right), the first person in Australia to be treated with penicillin, pictured with his family in 2018, together with Bethany Robinson (second from right), the University of Sydney student who rediscovered the “Penicillin Papers”

Ameneh Khatami · Philip N Britton · Glendon Farrow · Megan Phelps · Alyson Kakakios

The institute that has investigated the “common diseases of mankind” for 100 years was established by an unlikely partnership During the First World War, two young men served with distinction on opposite sides of the battlefields in France. One, William Wilson Ingram (1888–1982) was wounded in action, “mentioned in despatches”, and awarded the Military Cross by the British government. The other, Max Rudolf Lemberg (1896–1975), was awarded the Iron Cross after being wounded in the Somme offensive of March 1918. Despite being on opposing sides of this appalling conflict, they later formed a partnership in Sydney, together laying the foundations for the Kolling Institute of Medical Research at the Royal North Shore Hospital. The Kolling, which traces its origin to the Institute of Pathological Research in 1920, is the oldest medical research organisation in NSW. In this, its centenary year, it is an opportune time to explore the contributions of its two remarkable pioneers. William Wilson Ingram (1888–1982) MC, MB, ChB, MD (Aberdeen), FRACP William Wilson Ingram graduated from the University of Aberdeen in 1912. On the declaration of war, he enlisted in the Royal Medical Corps. He served in France, where he received the Military Medal in 1915; wounded, he returned to England. In 1916, Captain Ingram resumed active service, and ultimately took command of the Pathology Services at the headquarters of the British Expeditionary Force in France.1 After the War, Ingram completed a medical degree at Aberdeen. He then accepted the post of lecturer in physiology at the University of Sydney, and also established a general medical practice. In 1921, Ingram was appointed Honorary Pathologist at the Royal North Shore Hospital (RNSH), where, in addition to supervising the routine pathology service, he founded the Institute of Pathological Research. The Institute of Pathological Research of New South Wales In 1920, a group of influential NSW citizens proposed a research institute for investigating the “common diseases of mankind”, inspired by the Lister Institute of Preventive Medicine in London. They launched an appeal for establishing the Institute of Pathological Research of New South Wales (under the Royal North Shore Hospital of Sydney Act of Incorporation, 1910).2 Initial donations were disappointingly few, but after Mr Thomas Rofe (1869–1945), member of the Hospital Board, donated £5000, the Institute was ready to proceed in 1923. These funds facilitated the appointment of G. Vincent Rudd MSc, senior biochemist, as its first fulltime research scientist in 1925. Later that year, Ingram returned to London for postgraduate study, during which he observed the clinical effects of the newly discovered insulin. On his return to RNSH, he established one of the first specialist diabetes clinics in Australia. He later collaborated with Rudd on the significant and popular text, The diagnosis and treatment of diabetes, published in 1933.3 By 1928, space at the Institute was at a premium, and as it expanded in scope and personnel, more commodious, fully equipped laboratories were urgently required.4 Ingram invited Eva Kolling, the widow of American‐born merchant, Charles Kolling (1858–1926), to tour the original hospital cottage that now served as a laboratory. Mrs Kolling was suitably impressed by the standard of clinical research carried out in extremely cramped conditions. With the opportunity to commit funds to commemorate her husband — but also because “many lives will be spared and Humanity assisted generally”5 — she donated £5000, a sum matched by the NSW government. Ingram drew up plans for the “Charles Kolling Memorial Laboratory” shortly before his departure as medical officer with Douglas Mawson and the British, Australian and New Zealand Antarctic Research Expedition (BANZARE) (Box 1). Eva Kolling laid the foundation stone for the new laboratory in 1930 (Box 2) and, after Ingram returned from his second BANZARE expedition (1931), she officially opened the new facility on 12 September 1931. After the move into the new building, which provided much needed laboratory space and a library, and to re‐emphasise its focus on research into common medical conditions, the institute was renamed the Institute of Medical Research. Ingram was appointed honorary director, a position he held until his retirement in 1974. When Rudd resigned in 1934, Ingram was unable to recruit a suitably qualified Australian‐based scientist, and extended his search overseas. Max Rudolf Lemberg (1896–1975), with a 14‐year background in biochemical research and working in Cambridge after fleeing Hitler's Germany, applied for the position. Max Rudolf Lemberg (1896–1975) Max Rudolf (Rudi) Lemberg was born in Breslau (Silesia; now Wrocław, Poland), where he graduated in science in 1916. In mid‐1917, he enlisted in the German army as a private, a gunner in the field artillery. Lemberg was wounded in action during the Somme offensive of March 1918, his bravery recognised with the Iron Cross. These experiences had a profound effect on Lemberg, who became a convinced pacifist; he later (1952) joined the Society of Friends in Sydney. In 1922, he completed a doctorate in Breslau under Heinrich Blitz, an organic chemist. Blitz strongly advised him against an academic career, citing the poor prospects for a scientist of Jewish descent in any German university.6 After a period as an industrial chemist with Boehringer in Mannheim, he returned to academic life in Heidelberg in 1926. Equipped with a Rockefeller Foundation scholarship, he moved to Cambridge to study with Sir Frederick Gowland Hopkins (1861–1947) in the Institute of Biochemistry.7 He then returned to Heidelberg, but Lemberg later recalled that “the Nazi shadows began rapidly to gather”, and in 1933 his academic career came to an abrupt halt. He realised that, despite his war service and Iron Cross, he was unlikely to escape ending in a concentration camp.6 He fled Germany and returned to Cambridge, which at the time was full of highly qualified refugees from Germany, and not all could stay. Lemberg successfully applied for the position of director of the biochemical laboratories at the RNSH, going “into the wilderness, for I did not expect inspiration from my Australian colleagues at that time.”6 After a final (and risky) visit to his ageing parents in Breslau, Lemberg and his wife arrived in Sydney on 1 October 1936. Australia must have seemed remote from his academic life in Heidelberg and Cambridge, especially as “there was little space for research and hardly any equipment”.6 Nevertheless, Ingram and Lemberg established a good partnership, Ingram as the director of the Institute of Medical Research and Lemberg later as assistant director until his retirement in 1972 (Box 3). Ingram managed the administration and provided the clinical input, while Lemberg undertook fundamental scientific research, primarily into porphyrins and tetrapyrrole metabolism, research with which the Institute developed its scientific reputation. The Institute during the Second World War During the Second World War, Ingram enlisted in the Australian Army Medical Corps and served as Lieutenant‐Colonel until 1944.8 Lemberg remained in his laboratory, contributing to the war effort with research into the metabolism of trinitrotoluene (TNT) in animals, the role of sulphonamides in bacterial metabolism, and the preparation of X‐ray contrast media, among other topics.7 Eva Kolling, who remained one of the most significant supporters of the Institute, died in 1941, and left an extraordinary bequest of £25 000 to support and expand the work of the Institute and the Charles Kolling Memorial Laboratory. The Institute of Medical Research, 1945–1974 In 1948, the RNSH became a teaching hospital of the University of Sydney; in 1950, Ingram created a Unit of Clinical Investigation within the Institute of Medical Research, under the direction of Frank Rundle (1910–1993), later founding Dean and Professor of Surgery of the University of New South Wales. A new teaching block in 1963 provided additional facilities for the Institute, and a closer relationship with the clinical school developed. In 1964, routine hospital pathology moved from the Kolling laboratories into stage I of the new hospital complex, so that the Institute of Medical Research was free, for the first time, to concentrate solely on research. Lemberg continued his basic biochemical research. In 1949 he published his monograph on Hematin compounds and bile pigments, which became a standard text in the field of tetrapyrroles and confirmed his international scientific reputation.9 In 1952, he was elected a Fellow of the Royal Society and a Foundation Fellow of the Australian Academy of Science, and in 1955 was elected the first president of the Australian Biochemical Society. His scientific output was prodigious, encompassing more than 200 scientific publications.7 After Ingram and Lemberg: the Kolling Institute of Medical Research Following the retirements of Ingram and Lemberg, David Nelson (1935–1989), clinician and researcher, was appointed the first fulltime director (1974–1989). From 1971, the Institute was commonly known as the Kolling Institute of Medical Research, and, under Nelson's direction, concentrated on the emerging discipline of clinical immunology.10 Under its third director (1994–2011), Robert Baxter, the Kolling focused on endocrinology and cell biology. In 2008, the various research laboratories were all relocated to a new purpose‐built facility on the RNSH campus. With the appointment of Jonathan Morris as its fourth director in 2012, the academic research focus of the Kolling broadened to ensure that medical research findings informed clinical practice. Carolyn Sue was appointed the fifth director in 2019. The Institute now hosts numerous research teams investigating an extensive range of medical conditions. The Kolling Institute of 2020 has thereby remained true to the original charter of the Institute of Pathological Research in 1920, investigating the “common diseases of mankind”. Box 1 – William Wilson Ingram, 1929 Source: Archive and Heritage Collection, Royal North Shore Hospital, Sydney; with kind permission. Box 2 – Eva Kolling lays the foundation stone for the new laboratory of the Institute of Medical Research, 1930 Source: Archive and Heritage Collection, Royal North Shore Hospital, Sydney; with kind permission. Box 3 – Max Rudolf Lemberg and William Wilson Ingram, 1970 Source: Archive and Heritage Collection, Royal North Shore Hospital, Sydney; with kind permission.

Catherine E Storey