THE RESEARCH ENTERPRISE THE RESEARCH ENTERPRISE Bench-to-bedside research in Australian research institutes: a snapshot

DURING THE 20TH CENTURY Australians have benefited a poll of institute directors (see Box). Their responses are immensely from improvements in their general health and life given on the following pages. What inferences can we draw expectancy. Our average life span has increased by 25 years, from this snapshot? and even in the century’s dying decade we managed to gain Firstly, it is apparent that “bench-to-bedside” research is another two years! As with many success stories, there have alive and well in Australian medical research institutes, and is been numerous contributors, but there is no doubt that basic wide-ranging in its scope. It includes public health advances medical research has played a prominent part. Indeed, the relevant to South-East Asian and Australian interplay between basic research and advances in medicine is Indigenous communities, clinical succinctly captured by the phrase “from bench to bedside” or advances in areas such as assisted repro- by the term “translational highway” — an autobahn for taking duction and cancer, and improved treat- basic research advances and transferring these into clinical ments for chronic disorders, such as practice. diabetes or visual impairment in older The powerhouses of basic research in are our people. universities and research institutes. Their financial Secondly, this research is achieved by underpinnings are the competitive grants provided by teamwork between clinician–scientists both government and non-government and scientists working together in a organisations. In 2002, for example, the collegial spirit. National Health and Medical Research Thirdly, and most importantly, it Council’s expenditure on health takes time. research and development was $276 Finally, it is apparent that our research million. Of this, the universities institutes are increasingly forging closer received $190 million (69%) and the links with industry. medical research institutes received $74 However, there is one overriding message — that success million (27%). in basic research cannot be solely developed from imposed priorities and schemes. Research is driven by human imagina- Since 1995, the Christmas issue of the Journal has regularly tion, inquisitiveness, insight and a generous sprinkling of featured Australian medical Martinresearch B Vaninstitutes, Der Weyden beginning serendipity. For, as observed by the Nobel laureate Albert with portraits of the Walter and Eliza Hall Institute in Szent-Gyorgi, “. ..research means going out into the MelbourneThe Medical and Journalthe John of Australia, Curtin StrawberryInstitute ofHills, Medical NSW. unknown with the hope of finding something new to bring Research in Canberra, and featuring most recently the Men- Martin B Van Der Weyden, Editor. home. If you know in advance what you are going to do or zies Centre for Population Health Research in Hobart in Correspondence: Dr Martin B Van Der Weyden, The Medical even to find there, then it is not research at all: then it is only 2001Journal (now ofthe Australia, Menzies Locked Research Bag 3030, Institute). Strawberry Hills,This NSW year, we a kind of honorable occupation.” sought2012. to [email protected] a different avenue. In short, basic research has two defining features: uncer- In The1998, Medical the Journalthen Ministerof Australia for ISSN: Health, 0025-729X Dr Michael1/15 tainty and surprise. As long as these twin principles are Wooldridge, empowered a prominent committee chaired by December 2003 179 11/12 603-HIDDEN treasured in our medical research institutes, meaningful Peter©The Wills, Medical then Journal Chairman of Australia of the 2003 Garvan www.mja.com.au Institute of “bench-to-bedside” research will continue to advance the MedicalThe ResearchResearch, Enterprise Sydney, to review health and medical practice of medicine. research in Australia and report on strategies for these efforts Martin B Van Der Weyden in the first decade of the 21st century. In its final report, the committee identified a number of issues including: Editor, The Medical Journal of Australia ■ the need to sustain and expand an effective health and medical research sector underpinned by innovative and Survey of Medical Research Institutes in Australia high impact basic research; ■ a greater need for research that contributes directly to the The directors of Australian medical research institutes were health of the people and the healthcare system; and contacted in September 2003 and asked : “Most Australian medical research institutes have been operative for more than 25 years and ■ the need for links between research and industry to the theme we wish to pursue is . . .what has come out of [name of capitalise on the potential commercialisation of research your institute] that has been translated into population health or findings. clinical practice; ie, what has made it from ‘bench to bedside’? We In short, the report recommended an increased emphasis want you to restrict these to two major impacts.” on “bench-to-bedside” research, focused on the health and Twenty-eight research institutes were approached and we economic wellbeing of the nation. accepted 22 submissions (Australian Capital Territory, 1; , 5; Northern Territory, 1; , 2; , 1; To gain some perspective on the vitality of this research in , 1; , 9; and , 2). Australian medical research institutes, we recently conducted

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AUSTRALIAN CAPITAL TERRITORY Funhaler: A more recent contribution from the Institute addresses a major Eradication of smallpox: In 1988 Frank Fenner problem for children with asthma, of the John Curtin School, along with Donald A who typically show poor adherence to Henderson of the Johns Hopkins University prescribed frequency and technique of School of Hygiene and Public Health and Isao inhaled medication. The Funhaler Arita, Director of the Kumamoto National (Visiomed Group Ltd, Australia), Hospital, Japan, were awarded the Japan Prize invented by the Institute’s Paul Watt, is a small volume spacer for Preventive Medicine in recognition of their device incorporating an incentive toy module. A pilot study international team effort in eliminating smallpox from the showed that the Funhaler reduced problems in giving chil- world. This feat is one of the greatest accomplishments of dren asthma medication, improved child and parental adher- modern medical science. Fenner’s work at the John Curtin ence to the medication regimen and created a more positive School on pox viruses (ectromelia, myxoma and vaccinia) attitude towards treatment. A recent grant from the US through the 1950s, 60s and 70s had uniquely qualified him to National Institutes of Health (US$700 000) supports further lead the WHO smallpox eradication team which announced to study of the device, which is due to be launched throughout the World Health Assembly in 1980 that the disease had been Australia by the end of 2003. eradicated worldwide. Fiona Stanley, Director, TICHR

Discovery of MHC restriction: In the early-to-mid 1970s, Peter Doherty and Rolf Zinkernagel, working on the response AlphaCor artificial cornea: Starting in 1990, of mice to viruses discovered a major property of the immune polymer chemistry research by Traian Chirila and system — major histocompatibility (MHC) restriction. In Celia Hicks resulted in the world’s first soft artifi- order for T lymphocytes to cial cornea, now marketed by the WA company, destroy cells infected by foreign Argus Biomedical Pty Ltd. Hundreds of novel polymers were invasion, their receptors must formulated and tested for physical characteristics, including simultaneously recognise on optical clarity, tensile strength and elasticity as well as bio- the cell’s surface a complex of compatibility in tissue culture and after implantation in foreign antigen and a self animals. Novel chemical methods were developed to create a molecule, one of the MHC porous outer rim into which human cells would grow and antigens. Their discovery revo- establish a firm bond. This porous outer rim was co-polymer- lutionised our understanding ised with the same polymer materials under differential of how the immune system conditions to create an optically clear centre via an interpene- works and won Doherty and trating network. Human trials of the novel artificial cornea Zinkernagel the 1996 Nobel started in 1997 and CE-Mark European approval was fol- Doherty and Zinkernagel with lowed in 2002 by FDA approval in the United States. their Nobel prize medals. Prize for Physiology or Medi- cine. MHC restriction has many clinical implications for organ transplantation and for the treatment of diseases involving the immune system. Peter Jeffrey, Public Affairs Manager, JCSMR

WESTERN AUSTRALIA Laser-induced surgery and central retinal vein blockage: In Folate supplementation: Perhaps the longest the early 1990s, Ian McAllister, Ian Constable and Dao-Yi Yu established and best known research from the began developing a method to bypass the outflow from blocked Institute that has had an enduring impact on retinal venous circulation, which commonly causes rapid loss health is the case–control study of neural tube of vision in older people with hypertension. After experiments defects conducted in Western Australia in the in animals, Ian McAllister realised that a very powerful laser early 1980s by Carol Bower and Fiona Stanley. This showed was required to break the structural barrier (called Bruch’s that maternal dietary and supplemental folate intake around membrane) between the retinal and overlying choroidal circu- the time of conception protected against neural tube defects lation. In addition, rupture of the obstructed retinal vein was in the offspring. Further international studies showed that required to create an anastomosis between the two circulations 70% of neural tube defects could be prevented by folate and this was best achieved with a Yag cutting laser. Further intake. Based on these findings, the Institute, in collaboration experiments and observations identified a group of patients with the WA Health Department, embarked on a health with incomplete central retinal vein occlusion for trials. Case– promotion project in 1992, the first in Australia and one of control studies showed that a successful shunt could be the first in the world. There was an increase to 30% of women achieved in about two-thirds of the target population, and that taking folic acid supplements periconceptionally, and a 29% visual acuity markedly improved as a result. This procedure has fall in neural tube defects in WA. been taken up in a number of centres around the world. A

604 MJA Vol 179 1/15 December 2003 THE RESEARCH ENTERPRISE randomised controlled clinical trial is under way in four embryo and determine its genetic status has enabled pre- Australian locations. implantation genetic diagnosis to be successfully performed Ian J Constable, Director, for fertile couples with a history of genetically based disease. Y Chromosomal defects: In 40% of infertile men the cause of the spermatogenic defect is unknown, but the observation of VICTORIA small Y chromosomes in some of these men suggests a genetic cause. Scientists from the Institute, together with Mobilising myelopoiesis: Basic re- colleagues at Charles Drew University Los Angeles, further search at WEHI and LICR has had a defined the deleted regions of the Y chromosome causing profound impact on cancer treat- azoospermia or severely reduced sperm counts. These obser- ment. Don Metcalf’s tenacious re- vations, together with others, showed that some Y chromo- search at WEHI over three decades some deletions did not completely prevent sperm production, transformed understanding of blood raising the possibility of using intracytoplasmic sperm injec- cell production and haemopoietic tion (ICSI). The Institute’s scientists, together with col- diseases. He and his colleagues, in- leagues at Monash IVF, demonstrated transmission of Y cluding Nic Nicola (WEHI) and chromosome deletions from father to son by the use of ICSI. Tony Burgess (then at WEHI, later They also developed a routine clinical test to screen men with at LICR), purified two of the hormones involved in white sperm counts less than 5 million/mL, enabling genetic coun- blood cell production. Known as colony-stimulating factors selling for couples where the man has a Y chromosomal (CSFs), these hormones (GM-CSF and G-CSF) accelerate deletion. Current estimates indicate that 3%–8% of men with white blood cell regeneration in patients undergoing chemo- idiopathic infertility have a Y chromosomal disorder. therapy or radiotherapy and have helped treat over 3.5 David M de Kretser, Director, MIRD million patients worldwide. During the first clinical trials of CSFs at the Royal Melbourne Hospital (directed by George Morstyn, LICR), Uli Duhrsen (WEHI) and the team made Noradrenaline in heart failure: In the 1980s the unexpected observation that CSFs mobilise blood stem scientists led by Murray Esler developed a cells into the bloodstream, a discovery which led to bone unique radiotracer technique for neuro- marrow transplantation being replaced by blood stem cell chemical quantification of sympathetic nervous system activ- therapy. The CSFs are now finding new applications in in- ity and measurement of the spillover of the sympathetic vitro fertilisation and treatment of Crohn’s disease. neurotransmitter, noradrenaline, from individual organs. With this advance they were able to isolate neurophysiological Suppressing autoimmunity: Ian R Mackay, Head of mechanisms in heart failure. At that time the accepted view the Clinical Research Unit at WEHI, formally was that the failing heart was functionally and anatomically defined the concept and key features of autoimmune sympathetically denervated and ␤-adrenergic blocking drugs diseases in a book co-authored by Frank Macfarlane Burnet were said to be contraindicated. An innovative series of in 1963. Despite considerable scepticism about the concept, research projects at the Baker showed that in many patients Mackay pioneered the treatment of autoimmune (lupoid) with heart failure the sym- hepatitis with the immunosuppressive drugs, azathioprine pathetic nerves of the heart and prednisolone. This approach continues to be the gold- were, in reality, stimulated standard for immunosuppression and has saved the lives of at an exceedingly high level. countless patients with autoimmune hepatitis and other A prospective study of autoimmune diseases. patients with severe heart Suzanne Cory, Director, WEHI failure showed that the car- Antony W Burgess, Director, LICR diac sympathetic tone was the strongest predictor of Concepts and conception: Alan Trounson, together death. This research pro- with Carl Wood and his colleagues from Monash Murray Esler and Gavin Lambert vided the pathophysiological performing noradrenaline spillover University Department of Obstetrics and Gynaecol- evidence for the use of ␤- ogy, pioneered studies of in-vitro fertilisation and measurements to quantify adrenergic blocking drugs in sympathetic nervous system activity other reproductive technologies for the management cardiac failure. in a patient during head-up tilting. of human infertility. Building on the work of Edwards and Steptoe in the UK, they integrated ovarian The renin–angiotensin system (RAS) in diabetes: Over the stimulation into the routine IVF protocol, providing multiple last 15 years it has become apparent that blockade of the RAS oocytes for fertilisation. When combined with the capacity to plays a central role in diabetic nephropathy, the leading cause freeze embryos these technologies contributed to improved of endstage renal disease in the developed world. Basic IVF success rates. The Monash group also developed the research, including that of Mark Cooper’s group, showed conditions necessary for oocyte donation to become a routine that, despite RAS suppression, intervention with angiotensin- procedure and extended the capacity for IVF to women converting enzyme inhibitors or angiotension II antagonists without ovaries. The ability to biopsy a blastomere from an could reduce the functional and structural manifestations of

MJA Vol 179 1/15 December 2003 605 THE RESEARCH ENTERPRISE diabetic nephropathy. Over the last decade the underlying mesenchymal molecular and cellular pathways whereby angiotensin II stem cells promotes renal injury have been unravelled and may provide (MSC) to treat new targets for further renoprotection. This basic research a non-union was the impetus for three landmark studies exploring block- fracture of the ade of the RAS in type 2 diabetic patients with incipient and ulna. This pio- overt renal disease. More recently, research has linked the neering proof- RAS to other diabetic complications involving the retina, of-principle heart and vascular system. Multicentre clinical trials are now procedure was investigating the benefits of interrupting the RAS for diabetic the first use of complications at these extrarenal sites. prospectively Garry Jennings, Director, BHRI isolated autolo- gous MSC in a Linking research with health clinical setting. outcomes: Over the past 15 years Characterising cancer: In about 5% of cancer patients, the Institute’s major achievements extensive clinical workup fails to reveal the primary carci- have involved the development of appropriate and sustainable noma. Researchers at Peter Mac are using microarray-based technologies to prevent or control infectious diseases in gene expression profiling, a method of molecular diagnostics resource-poor regions. that may assist in diagnosing and treating this kind of cancer. Immunisation programs: In the early 1990s the Institute pio- Metastatic tumours have been shown to maintain gene neered the introduction of routine hepatitis B immunisation expression patterns that are consistent with tissue of origin. in Lombok, Indonesia, and demonstrated the feasibility of Clinically plausible prediction of the origin of the metastatic implementing universal hepatitis B vaccination without dam- tumour has been made in numerous cases of carcinoma of aging other vaccine programs. This was the first demonstra- unknown primary, suggesting that the test will facilitate tion of the usefulness of hepatitis B vaccination in a clinical management. developing country’s immunisation program, and contrib- David Bowtell, Director of Research Division, PMCI uted to the models used now by Global Alliance for Vaccines and Immunization and the Gates Foundation to support In-situ gene expression: In the 1980s, universal hepatitis B immunisation in the world’s 70 poorest researchers John Coghlan, Jennifer Pen- countries. schow, Geoffrey Tregear and Hugh Niall developed the technique of hybridisation Harm reduction: Since 1989 the Institute has championed the histochemistry using oligonucleotides for application of harm-reduction approaches to mitigate the detection of in-situ gene expression in tissues. The Institute impact of HIV and hepatitis C infection, and has played a holds patents on this technique, which is now widely used for major role in driving the acceptance and implementation of the diagnosis of viral and infectious diseases and in research. these approaches, especially in South-East Asia. Fortifying bone with Forteo: A peptide comprising part of Cheap sustainable diagnostics: The Institute has led the human parathyroid hormone (PTH[1-34]) was recently development of cheap and sustainable CD4 cell assays to approved by the US Federal Drug Administration for the support the widespread implementation of antiretroviral drug treatment of osteoporosis. Marketed by Eli Lilly & Co as therapy to treat HIV infection in developing nations. It has Forteo, or teriparatide, it is the first approved agent for the also developed, and is now commercialising, new technolo- treatment of osteoporosis that stimulates new bone forma- gies for the diagnosis of hepatitis E and hepatitis A infections. tion. Hugh Niall and Geoffrey Tregear played a pivotal role in Steven L Wesselingh, Director, the discovery and development of PTH(1-34). Working initially at the Massachusetts General Hospital, Boston, and Cellular therapies: The stem then at the Howard Florey Institute in the 1970s, they were cell biology program at Peter the first in the world to isolate and sequence parathyroid Mac, a major node of the hormone. They subsequently synthesised parathyroid hor- National Stem Cell Centre, is studying fundamental properties mone fragments and established that the amino terminal 1– of stem cells in adult tissues and using their unique biological 34 region of the sequence had full biological activity. Forteo is properties in novel cellular therapies. The stem cell facility at the peptide originally designed and synthesised by Tregear. Peter Mac has good manufacturing process (GMP) accredita- Frederick A O Mendelsohn, Director, HFI tion and is licensed by the Therapeutic Goods Administration. It has been used for stem cell therapy in several patient groups, Inhibin: A major focus of the Institute has including Australia’s first clinical trial with ex-vivo expanded been reproductive endocrinology, partic- haematopoietic stem and progenitor cells for breast cancer ularly the relationship between the patients after repetitive high-dose chemotherapy. A significant hypothalamus, anterior pituitary and the reduction in neutropenia and platelet transfusion requirements gonads. The most significant outcome of this research was the was demonstrated in these patients. The Peter Mac propagated first isolation, purification and characterisation of a new

606 MJA Vol 179 1/15 December 2003 THE RESEARCH ENTERPRISE gonadal hormone, inhibin. Inhibin acts as a feedback signal by drugs that increase insulin sensitivity, including metformin regulating the secretion of follicle stimulating hormone (FSH) and the glitazones. The Institute’s intellectual property in this by the pituitary. This achievement was the result of collabora- area has been licensed to Mercury Therapeutics and Aventis, tion between scientists as Prince Henry's, Monash University, who are searching for new drugs that activate AMPK. The St Vincent's Institute of Medical Research and La Trobe pharmaceutical industry has the protein kinases as one of its University. The major impact on clinical practice came with three top targets for drug development. the finding that concentrations of inhibin were markedly Thomas W H Kay, Director, SVIMR elevated in the serum of patients with ovarian granulosa cell tumours or mucinous epithelial cancers. The marker com- monly used for ovarian cancer diagnosis and monitoring, TASMANIA CA125, is not especially helpful in these two types of ovarian tumour. Work at the Institute has shown that combining SIDS: By the 1980s sudden infant death inhibin and CA125 measurement can diagnose 95% of ovar- syndrome (SIDS) had become the com- ian cancers. Inhibin measurement is now standard practice in monest cause of death in postneonatal following up patients with ovarian granulosa cell tumours. infants in Australia and some other Research on inhibin has also clarified the mechanisms developed countries. However, little involved in the hormonal changes in women as they approach was known about its causes or prevention. As early as 1944, it the menopause, and has indirectly led to the realisation that had been proposed that placing a baby prone (on the measurements of FSH and oestrogen are of little value in the abdomen) might increase risk. Despite the gradual accumula- assessment of perimenopausal women. tion of retrospective evidence from case–control studies of an Henry G Burger, Emeritus Director, PHIMR association between prone position and SIDS, concerns about recall bias (particularly at a time when many hospitals Automating amino-acid sequences: advised prone sleeping) limited the acceptance of sleeping St Vincent’s Institute has a long position as a cause. Prospective data were needed. heritage of studying protein struc- The Menzies team reported the first prospective evidence, ture and function. The founding director, Pehr Edman obtained from the Tasmanian infant cohort, in the Lancet in (1957–1972), discovered how to sequence the order of 1991, confirming a higher risk for infants sleeping in the amino acids within proteins and ways to automate this prone position. This research work led to a rapid policy process. Protein sequencing enabled characterisation of response. A national meeting in July 1991 provided a new proteins for diagnostic (eg, radioimmunoassay) and thera- recommendation that healthy infants should not sleep prone. peutic use, as well as the unravelling of protein mutations SIDSAustralia incorporated the finding into health education in genetic diseases such as phenylketonuria and thalassae- advice to new parents. In Australia the number of SIDS mia. Salmon calcitonin, for example, was sequenced using deaths declined from 507 in 1990 to 101 in 2001 (rate, 1.93 the Beckman commercial version of Edman’s automated to 0.41) — a fall of about 80%. Similar successful campaigns sequencer by Hugh Niall (who had been a student of occurred internationally. Edman) and then synthesised by Sandoz (now Novartis) Subsequent research at the Menzies Institute has continued for widespread therapeutic use in Paget’s disease. Obtain- to inform international policy and contributed to a continued ing amino acid sequence using Edman’s technology has decline in SIDS deaths. been a necessary step in cloning many recombinant mole- Terence Dwyer, Director, MRI cules used as drugs, such as growth hormone, tissue plasminogen activator and erythropoietin. SOUTH AUSTRALIA Calcium and cancer: Jack Martin and his team discovered parathyroid hormone-related protein (PTHrP), a hormone Cause and prevention of discitis after secreted by cancers that causes the syndrome known as discography: For more than 50 years discogra- humoral hypercalcaemia of malignancy and contributes to phy has been used to confirm a diagnosis of bone metastasis. This discovery established a molecular expla- internal disc disruption and the presence of nation for this common clinical syndrome, and led to its normal discs adjacent to the level of an intended accurate diagnosis by radioimmunoassay and immunohisto- spinal fusion. Discitis following discography is a chemistry for PTHrP. A humanised monoclonal antibody serious complication and, although the presence of infection against PTHrP is now in Phase III clinical trials, having been is occasionally confirmed, numerous authors have suggested developed by Chugai as a result of proof of principle supplied that it is caused by a chemical or aseptic process. by this Institute’s research. Fraser, Osti and Vernon-Roberts showed that the injec- Protein kinases as drug targets: Bruce Kemp has made piv- tion of a single Staphylococcus epidermidis into an interverte- otal discoveries about the structure and function of protein bral disc in a sheep was sufficient to produce radiographic, kinases, particularly the amino-acid sequences used by kinases macroscopic and histological discitis, but that organisms to interact with their substrates. Most recently these have been could not be isolated from the lesion after 6 weeks. They applied to adenosine monophosphate-activated protein kinase found also that in 7 patients with discitis no bacteria were (AMPK), which Kemp and colleagues purified and sequenced. isolated from the 3 biopsied 6 weeks after discography but This is an enzyme involved in fuel metabolism that is activated bacteria were isolated in 3 of the 4 biopsied within 6 weeks.

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These findings indicated that discitis after discography is Controlling dengue in Vietnam: Brian Kay, initiated by needle-tip infection, but the causative bacteria are head of mosquito control at QIMR, realised rapidly eliminated after the inflammatory destruction of the that the copepod predator of young mosquito plate of bone separating the avascular disc from the richly larvae, Mesocyclops, had enormous potential vascular bone marrow of the vertebral body. Changing from a for dengue fever control in Asia. Mesocyclops single needle lacking a stilette to stiletted needles and a two- inhabit freshwater ponds and needle technique reduced the incidence of discitis from 2.7% lagoons, but, from surveys in Viet- to 0.7%. Combining the two-needle technique with a single nam, were also found in water stor- prophylactic dose of broad spectrum antibiotic effectively age containers (eg, concrete tanks, prevented discitis in a follow-up study. jars, wells). Barrie Vernon-Roberts, Director, In 1989, Kay began working with Institute of Medical and Veterinary Science Mesocyclops eating Vu Sinh Nam from the National Aedes aegypti larva Institute of Hygiene and Epidemiol- ogy, Hanoi, to develop community-driven programs for den- QUEENSLAND gue vector control, using new sampling technologies, key container prioritisation and Mesocyclops. Nine years later they The Institute for Molecular Bio- reported the first eradication of Aedes aegypti without insecti- science was formed in 2000 by the cide, in the 400 households of Phan Boi. By 2002 the program amalgamation of the Centre for had expanded to 6 communes (11 675 households) in 3 other Molecular and Cellular Biology (which focused on mamma- provinces. At the project’s completion, local leaders commit- lian cell and developmental biology) and the Centre for Drug ted themselves to main- Design and Development (which focused on pharmaceutical taining and expanding development), both at the University of Queensland. dengue control, sup- ported by the national Inflammation and pain: In the past 6 years researchers at the dengue budget. To date IMB have discovered three candidate molecules to treat 40 of 46 communes rheumatoid arthritis, chronic pain and neuropathic pain. (93 111 households and The first orally active small molecule C5a-receptor antago- 386544 people) are free nist (an anti-inflammatory drug which blocks an important of Ae. aegypti, and all 46 component of the complement system) was designed and have no further reports developed by David Fairlie and Steve Taylor and has pro- Brian Kay inspecting water storage tanks of dengue and dengue in central Vietnam. gressed to Phase II clinical trials for rheumatoid arthritis haemorrhagic fever. patients. The molecule was licensed to the spin-off company Promics to undertake full development. Vaccine to prevent rheumatic fever: Michael Good, Michael A molecule, CVID (a conotoxin from Conus catus, a fish- Batzloff, Colleen Olive and Sri Sriprakash have been develop- eating marine cone snail on the Great Barrier Reef), which ing a vaccine to prevent group A streptococcus (GAS, Strepto- blocks N-type voltage-gated calcium channels, was discov- coccus pyogenes) infection and its associated diseases such as ered by Paul Alewood and Richard Lewis. The molecule, rheumatic fever. GAS is a serious problem in developing which has the potential countries and in Indigenous communities of devel- to alleviate neuropathic oped countries including Australia. The vaccine is pain, was licensed to based on a conformational peptide antigen from the AMRAD and Phase I/II conserved region of the M-protein. In preclinical clinical trials have been studies the peptide was immunogenic in inbred mice. successfully completed In outbred mice, the peptide was conjugated to the in cancer patients with carrier protein, diphtheria toxoid, and formulated pain refractive to mor- with the human-compatible adjuvant alum. Mice phine treatment. immunised with this formulation had significantly Another molecule enhanced survival following challenge with several from cone snails, MrIA GAS serotypes. We have used our peptide in combin- (a conotoxin from Model of the inflammatory protein C5a and a small ation with several experimental intranasal adjuvants Conus marmoreus), was molecule C5a receptor antagonist. Antagonist (yellow) in outbred mice to induce a local mucosal immu- discovered by the Lewis mimics a key turn conformation (red) in human C5a (white). noglobulin-A response capable of significantly reduc- and Alewood team. It is ing GAS colonisation of the throat following intranasal GAS a potent blocker in vitro and in vivo of the reuptake of challenge. We are now planning to commence the “Good noradrenaline by the noradrenaline transporter and has Manufacturing Process” production of our peptide-conjugate/ shown excellent efficacy in preventing chronic pain in rats. alum formulation for Phase I human clinical trials. It is now under pre-clinical development by the spin-off Michael F Good, Director, QIMR company Xenome. Brian Kay, Director, Australian Centre for John J S Mattick, Director, IMB International and Tropical Health and Nutrition

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NORTHERN TERRITORY NEW SOUTH WALES

Scabies and skin health: Scabies and compli- Developing microsurgery: Earl Owen returned to cating streptococcal pyoderma are major Australia in 1967 from postgraduate studies in the causes of morbidity in Indigenous communi- UK where he had been involved in developing ties in central and northern Australia. The surgical techniques for whole-organ transplanta- templates for communities to develop their own skin-health tions. An appointment to the Children’s Medical programs have resulted from a mix of clinical, public health Research Institute from 1967–1970 as the James and laboratory initiatives leading to evidence-based best Fairfax Surgical Research Fellow provided him with the practice. The first molecular genetics studies ever undertaken opportunity and resources to develop his expanding interests on scabies mites were specifically directed at determining in the field of microsurgery. This had evolved from his whether current dog and human scabies infections are sep- appreciation of the importance of surgical repair of blood arate epidemics. This research enabled the focus of programs vessels and nerves in transplant survival. He designed or to be on prevention and treatment of scabies in children — modified a range of instruments and magnifying devices rather than targeting the dogs. which facilitated these procedures. His enthusiasm and skill Community-based healthy skin in promoting the advantages of microsurgical techniques programs have resulted in large led to their rapid widespread adoption in Australia and decreases in both scabies and internationally, particularly in the disciplines of plastic and reconstructive surgery. streptococcal pyoderma, and cur- rent initiatives are directed at sus- Gene therapy: In 1995 the Institute and the Children’s Hos- taining the programs. pital Westmead created a Gene Therapy Research Unit, based on a longstanding interest within the Institute in the Reversing Indigenous renal failure: Aboriginal people in use of retroviral gene vectors in biomedical research. Directed many remote parts of Australia are experiencing an epidemic by Dr Ian Alexander, the unit has established a gene-vector of diabetes, cardiovascular disease and end-stage renal dis- production unit which is unique in Australia. In March 2002 ease. The introduction of a systematic pharmacotherapy in conjunction with the Hospital Necker in Paris, this unit program over several years on the Tiwi Islands (NT) address- and the Immunology Department of the Hospital treated a ing albuminuria, hypertension, dyslipidaemia and diabetes child with X-linked severe combined immunodeficiency by was associated with a marked fall in rates of renal failure and transducing the infant’s haemopoetic stem cells with a normal natural death, reversing a consistent historical trend for both copy of the mutant gamma-c subunit of the interleukin to increase. Rates of the combined endpoints of renal failure receptors. This has resulted in a successful reconstitution of and natural death per 100 person-years were 2.9 for the the T cell compartment and the patient remains free of treatment group and 4.8 for the control group. Current infection 18 months later. While gene therapy is far from challenges are how to resource and sustain such activities being routine clinical practice, there is no doubt that it will within the day-to-day clinic activities. play a major role in future therapy of a range of diseases from single gene defects to cancer. Improving dietary quality in remote Aboriginal Peter B Rowe, Director, CMRI communities: Poor nutrition in remote Aboriginal communi- ties is linked to high rates of obesity, diabetes and cardiovas- L-Arginine and vascular adhesion: Research by cular disease. Two well evaluated community-based Mark Adams, David Celermajer and Wendy Jessup, intervention programs to improve the quality of diets through in a collaboration between the Institute and the improved quality of foods in the communities’ local stores Department of Cardiology at Royal Prince Alfred have been accompanied by a marked reduction in risk Hospital, found that L-arginine reduces human monocyte markers for vascular adhesion to vascular endothelium and endothelial expression disease across the adult of cell adhesion molecules. Subsequent clinical studies populations. The focus showed that oral L-arginine improves endothelium-depend- of the Minjilang Nutri- ent dilatation and reduces monocyte adhesion to endothelial tion Program and the cells in young men with coronary artery disease. This Looma Healthy Life- research has translated into the clinical use of oral L-arginine style Program has been as a treatment in patients with intractable angina. to reduce the high con- A surrogate marker for advanced atherosclerosis: Len Krith- sumption of sugar and arides and co-investigators are developing non-invasive tests fat, and to increase for the presence of vascular disease. Using samples obtained consumption of fresh from patients undergoing bypass surgery and coronary angi- fruit and vegetables. ography, they found that coronary arteries release a number Kerin O’Dea, Director of molecules into the blood stream. One of these is hap- Menzies School of Health Research toglobin, a protein not normally measured in patients with

MJA Vol 179 1/15 December 2003 609 THE RESEARCH ENTERPRISE atherosclerosis, but which is present at elevated levels in the This proof of principle has been adopted by a collaboration circulation in patients with advanced coronary disease. This between two major multinational pharmaceutical companies, non-invasive test has the potential to identify the presence of Organon and Schering, to develop a marketable product. vulnerable atherosclerotic plaques before their rupture. David J Handelsman, Director, ARI Philip J Barter, Director, Heart Research Institute New antiviral strategies for herpes: Diabetes and obesity: In 1973 a small team The herpes virus periodically reactiv- led by Les Lazarus at the Garvan developed ates from dormancy and is transported the low-dose intravenous insulin infusion down sensory nerves to skin causing method to treat a major complication of genital lesions. WMI virologists including Tony Cunning- diabetes, ketoacidosis. This has saved the ham, Russell Diefenbach and Monica Miranda first showed lives of innumerable Australians and has that the virus is transported down these nerves as two been taken up around the world. Over the components, the inner core and outer (glyco) proteins, past 20 years, the diabetes research team, including Ted subsequently assembling at the nerve terminus. Transport Kraegen, Lesley Campbell and Don Chisholm, has made along microtubules (the “railway tracks” of the nerve) was major contributions to our understanding of the impact of found to be mediated by the interaction of a virus core protein lifestyle on type 2 diabetes. They were one of the first groups (US11) with a cellular protein, kinesin. The exact regions of to show that exercise training improves whole-body insulin the interaction were mapped and patented as a drug target. A sensitivity. They were also one of the first to unravel the collaboration with Pharmacia is now seeking small molecule impact of dietary lipids on insulin sensitivity and to show that inhibitors of this interaction as a new drug strategy for herpes. fat deposition in specific regions plays a key role in the development of insulin resistance. These findings have made First success in herpes simplex vaccines: The first success major contributions to the management of this extremely in vaccine development for genital herpes by GlaxoSmith- complex and common human disease. Kline (GSK) has just been reported. This development was partly guided by, and depended upon, key discoveries by Breast cancer: Garvan scientists led by Professor Rob Suth- WMI scientists, Tony Cunningham and Zorka Mikloska, who erland carried out an extensive series of studies which helped showed that the immune control of herpes lesions was elucidate the mode of action of the breast cancer drug, mediated by an early influx of CD4 and later CD8 lym- tamoxifen. Garvan scientists pioneered research demonstrat- phocytes. Both cell populations secrete interferon gamma, ing the role of the cell cycle regulatory protein cyclin D1 in which controls viral transmission from nerve to skin and viral development and progression of breast cancer. Recently, this mechanisms for evading immune control. The key viral research was judged by the international ISI Essential Science stimulant for CD4 lymphocytes was glycoprotein D (gD). Indicators as one of the top 20 advances (and most cited The GSK vaccine incorporated gD and an adjuvant to papers) in breast cancer in the past decade. Further work has stimulate these mechanisms. This proved 75% successful. confirmed this molecule as an adverse prognostic marker and therapeutic target in breast cancer. Refined advice for those at genetic risk of melanoma: John Shine, Executive Director, GIMR Cancer researchers at WMI, led by Richard Kefford and Graham Mann, have been unravelling melanoma susceptibil- Established 3 years ago, the ANZAC Research ity genes. They confirmed that the major melanoma gene, Institute is one of Australia’s youngest medical CDKN2A (“p16”), is located on chromosome 9p, and went research institutes, located on the campus of Con- on to perform the largest analysis of mutations in this gene in cord Hospital and affiliated with the University of 132 Australian families. WMI researcher Helen Rizos and her Sydney. Its primary research focus is on ageing. team have established the importance of p14ARF, an alter- Hepatic pseudocapillarisation and cardiovascular disease: nate product of the CDKN2A gene, in the genesis of David Le Couteur’s observations that ageing is accompan- melanoma, and have recently described a number of highly ied by obliteration of endothelial pores that allow the liver to novel functions of this molecule in regulating the cell cycle at metabolise circulating macromolecules has led him to a several key points. Collaborative research between WMI and novel approach to examining the liver and postprandial Nicholas Hayward of the Queensland Institute of Medical hyperlipidaemia as pivotal elements linking ageing and Research, together with the members of the international cardiovascular disease. Melanoma Genetics Consortium, has enabled this genetic information to be translated into clinical guidelines for man- Genetics of neurodegeneration: Garth Nicholson’s discovery aging those at high risk of developing melanoma, including of the gene for hereditary sensory neuropathy provides an the use of genetic testing. elegant and unique neurogenetic model for classical sensory Anthony Cunningham, Director, WMI neuropathies of leprosy and diabetes which both feature painless damage to joints and extremities.

Hormonal male contraception: Recently published work by REFERENCES

David Handelsman first proved the efficacy of a hormonal A version of this article with references is available on the eMJA website: male contraceptive using a prototype combination depot. www.mja.com.au/public/issues/179_11_011203/b2b_fm.html ❏

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