Pathways to Excellence: 50 years of the Garvan Institute by Refraction Media

PATHWAYS TO EXCELLENCE Hope, vision and innovation in biomedical sciences

thAnniversary

Garvan Institute of Medical Research

PATHWAYS TO EXCELLENCE 50 YEARS OF THE GARVAN INSTITUTE A co-production of Cosmos Media and Refraction Media

Publisher Kylie Ahern Editor-in-chief Wilson da Silva Managing editor Heather Catchpole Deputy editor Jonathan Nally Sub-editor Rivqa Rafael Art director Lucy Glover Designer Fern Bale Additional design Tim Verrender Writers Stephen Pincock, Gemma Black, Heather Catchpole, Therese Chen, Catherine de Lange, Phillip English, Tara Francis, Jonathan Nally, Cherese Sonkkila, Mischa Vickas Publisherâ&#x20AC;&#x2122;s assistant Nicole Atencio Office PO Box 254, Toorak VIC 3142, Australia info@cosmosmagazine.com

Publisher Karen Taylor Editor Heather Catchpole Art Director Tim Verrender Sub-editor Jo McKinnon Writers Tara Francis, Heather Catchpole, Stephen Pincock Office PO BOX 38, Strawberry Hills, NSW 2012 Tel: 0414 218 575 www.refractionmedia.com.au info@refractionmedia.com.au

Editorial assistance provided by Andrew Giles Dianne Lavender Gabriella Lang Garvan Research Foundation Garvan Institute of Medical Research 384 Victoria Street Darlinghurst Sydney NSW 2010 Australia www.garvan.org.au Thanks to all of the researchers and staff at the Garvan Institute for their assistance in contributing to this publication. Published by Cosmos Media Pty Ltd, a boutique publishing house in Melbourne, Australia, in conjunction with Refraction Media, a custom publishing house based in Sydney, Australia. Copyright 2014 Cosmos Media Pty Ltd. All rights reserved. No part of this publication may be reproduced in any manner or form without the express written permission of the Publishers. Printed in Australia by Metro Graphics Group. The views expressed herein are not necessarily those of the editors or publishers. This book went to press on 21 January 2014.

INTRODUCTION

Message from Her Excellency Ms Quentin Bryce

AC CVO

Governor-General of the Commonwealth of Australia I send warm greetings on the occasion of the Garvan Institute of Medical Research’s 50th anniversary – what a significant milestone! It brings an opportunity to reflect on the Institute’s living legacy: breakthrough treatments, advances in disease prevention and life-changing science, championed by brilliant, dedicated minds. Researchers and staff of the Institute are inspiring role models, respected and admired for their contributions to medical science across the global research community, in clinics and centres in Australia, and in families’ quiet moments of hope and courage. You have so much to be proud of, and we have so much to be grateful for. On behalf of all Australians, I extend my best wishes for a joyous 50th anniversary. Thank you for what you do, for what you give.

Her Excellency Ms Quentin Bryce AC CVO Governor-General of the Commonwealth of Australia Government House Canberra, ACT

www.garvan.org.au

GARVAN 50-YEAR ANNIVERSARY

INTRODUCTION

Message from the prime minister, Tony Abbott I am very pleased to congratulate the Garvan Institute of Medical Research on its 50th anniversary. For five decades, the Garvan Institute has been at the forefront of medical research in Australia. Its 50th anniversary is an opportunity to remind people of the achievements of scientists and researchers in this field. Despite having less than one per cent of the worldâ&#x20AC;&#x2122;s population, Australia produces between three and four per cent of refereed health research publications. Australian medical research has led to the bionic ear, a cure for stomach ulcers and a cervical cancer vaccine. The achievements of the sector have been recognised on the international stage, with four Australians in the health and medical research field winning Nobel Prizes in the past decade alone. The Government continues to support a strong and vibrant medical research sector. We will protect the sectorâ&#x20AC;&#x2122;s future funding and streamline the grant application process so our researchers and scientists can focus on what they do best. I congratulate everyone who has been involved with the Garvan Institute over the past 50 years for their achievements and innovations. I look forward to continued successes.

The Honourable Tony Abbott MP Prime Minister of Australia

PRIME MINISTER 4

GARVAN 50-YEAR ANNIVERSARY

www.garvan.org.au

Message from Cardinal George Pell

CATHOLIC Archbishop of Sydney A few lines to express my warmest congratulations to the researchers and staff of the Garvan Institute of Medical Research on the 50th anniversary of its foundation. This is a wonderful occasion. The distinctive mission of the Garvan – to bring together different disciplines to focus, in an integrated manner, on complex diseases in a clinically effective way – sets it apart from other research institutions. It continues to be blessed with outstanding researchers who have deservedly won for the Institute its high international reputation and the gratitude of the patients who have benefited from its medical breakthroughs. The Garvan Institute’s long relationship with the Sisters of Charity and St Vincent’s Hospital is reflected in its core values and its commitment to medical research in accordance with the highest ethical and scientific standards. Its Christian roots are evident in the priority given to the dignity of the human person and respect for human life in all its stages. Along with the Catholic community of Sydney, I am deeply grateful to all at the Garvan Institute for their ongoing commitment to medical research in accordance with the ethics of healing. The Institute stands strongly within the tradition of compassion and service to the sick and suffering, embodied by the motto of the Sisters of Charity, ‘The love of Christ compels us’. I am sure that the Garvan Institute will continue to express the extraordinary legacy of the Sisters of Charity and that it will continue to be a beacon of hope for those who suffer serious diseases and their families.

Cardinal George Pell AC Catholic Archbishop of Sydney

www.garvan.org.au

GARVAN 50-YEAR ANNIVERSARY

INTRODUCTION

Message from Her Excellency, Professor Marie Bashir AC CVO

Governor of New South Wales

I wish to extend warmest congratulations to the Garvan Institute for 50 years of discovery, learning and commitment to a wonderful cause – advancing human health. From humble beginnings as a St Vincent Hospital’s clinical research unit in 1963, the Garvan now takes its place among the leading international medical research institutes. This success over the past 50 years is due to the talented and dedicated researchers, professional support services, a committed Board and strong collaborators. I commend all past and present staff for their invaluable contribution to medical research – such critically important work so vital in creating a healthier community for future generations. The Garvan’s success has also been the result of great leadership and vision – firstly by the Sisters of Charity who had the foresight to create a medical research unit on the St Vincent’s campus, and the Garvan family who had the foresight to help fund it. And then Professor Leslie Lazarus, Professor John Shine and now Professor John Mattick, who have grown and changed the Institute to be the powerhouse of research which it is today. It was a great pleasure for me to see firsthand the Garvan’s most recent expansion when I visited the new Kinghorn Cancer Centre to formally open the ACRF Molecular Genetics facility last year. It is exciting to consider the possibilities for the future when some of the finest minds are at work in a facility such as this. The Garvan has achieved some of the most outstanding medical research discoveries this country has seen. Equally important are the hundreds of scientists who have been nurtured through the Institute. Many have stayed to continue their research at the Garvan, many have gone to achieve success in other parts of the world and some have returned to the Garvan after developing new skills abroad. This 50th anniversary celebration is an occasion when all staff and those closely associated with the Garvan can be thanked for their outstanding achievements. This well-deserved commemoration will provide a positive and proud environment which will lead to greater scientific breakthroughs in the coming years.

Professor Marie R Bashir AC CVO Governor of New South Wales

GARVAN 50-YEAR ANNIVERSARY

www.garvan.org.au

Message from the Premier, Barry O’Farrell Premier of New South Wales I send my best wishes to the Garvan Institute of Medical Research as it celebrates its 50th anniversary. Focussing on the role of genes and molecular processes, the Institute has been at the forefront of breakthroughs in health and medical research, working towards an improved capacity for researchers to better understand and find cures for some of the major diseases that affect our community such as cancer, diabetes, Alzheimer’s disease, obesity and arthritis. Over the years since its formation, the Garvan Institute has developed new technologies and has been at the cutting edge of health and medical research. The Institute produced the first genetically engineered human therapeutic growth hormone (TGH); opened the gene chip facility in Australia; developed and commercialised an antibody treatment for anti-inflammatory diseases; and has achieved many more groundbreaking advances. In all of this, the Institute has demonstrated its ability to not only undertake original and groundbreaking research, but to be just as innovative in its strategic planning and partnerships to maximise support for that research and to create opportunities from its application. The recent opening of The Kinghorn Cancer Centre has further demonstrated the Garvan’s commitment to innovative personalised medicine, breaching the translation gap between research and clinical practice. The New South Wales Government continues to support the excellent research being done at the Garvan Institute and has committed more than $12 million over the next two years in infrastructure funding as well as $37.3 million (from 2012 to 2016) each year towards health and medical research. Through the Medical Research Support Program, support for medical research is the highest it has ever been, and I am proud to be part of the Government which holds that title. I congratulate the Garvan Institute on this 50th anniversary of excellent health and medical research and thank them for their contribution to the health of the NSW community. I look forward to seeing more groundbreaking research from the Institute in the future.

The Honourable Barry O’Farrell MP Premier of New South Wales

www.garvan.org.au

GARVAN 50-YEAR ANNIVERSARY

INTRODUCTION

Message from the Sisters of Charity of Australia Congregational Office As Congregational Leader of the Sisters of Charity of Australia, on behalf of the Sisters, I congratulate you and all involved with the Institute now and throughout its 50-year history on the wonderful achievements of those years and to offer the assurance of our prayers and best wishes into the future. We value highly the partnership between the Sisters and the Garvan over these years. In 1957 St Vincent’s Hospital celebrated the centenary of its foundation. The Sisters of Charity of the time, with great vision, used funds raised through the Centenary Appeal to establish the Garvan Institute of Medical Research. It began its existence as a small research department of St Vincent’s Hospital in Sydney. Helen Mills, who had contributed £100,000, asked that the Institute be named after her late father, James Patrick Garvan (1843–1896), a distinguished NSW parliamentarian and business leader. From that small beginning, the Garvan Institute of Medical Research has grown into a large and highly respected contributor to the advancement of medical knowledge and to its translation into clinical practice in Australia and the world. The respect of both New South Wales and Australian Governments led to grants that, together with privately contributed funds, allowed the construction of the impressive Garvan building and the recently opened Kinghorn Cancer Centre, a joint facility of the Institute and St Vincent’s Hospital, Sydney. Even more impressive is the research that underpins this respect, and the fact that the Institute has remained true to the Sisters’ initial vision that high-quality research is ever more necessary to ensure best practice in the clinical treatment of disease. Infrastructure has also been able to be developed to support the needs of researchers. The involvement of clinicians in the Garvan ensures that this research, from basic to applied, is geared to clinical need, and that translation of basic research findings into treatment occurs as soon as this can be safely achieved. Links of both the Garvan and the Hospital with the University of New South Wales strengthen this focus. So the Sisters offer sincere congratulations on the achievements of the Institute, to all involved in the basic research divisions of Cancer, Diabetes and Obesity, Immunological Diseases, Neurological Diseases and Osteoporosis and Bone Biology, and to all those whose roles support these. We assure you of our support and prayers into the future.

Sister Annette Cunliffe RSC Congregational Leader

GARVAN 50-YEAR ANNIVERSARY

www.garvan.org.au

Message from dr brett gardiner acting Chief Executive Officer St Vincent’s Health Network It is quite apt that both the Garvan Institute of Medical Research and the Sisters of Charity are celebrating significant milestones this year – 50 and 175 years respectively. Exhibiting extraordinary foresight, the Sisters envisaged the huge potential in medical research to tackle human diseases and thereby reduce human suffering. With the help of a £100,000 donation from Mrs Helen Mills in honour of her late father, James Patrick Garvan, the Garvan Institute was established in 1963. From these humble beginnings ‘the Garvan’ is now deservedly regarded as one of the world’s great medical research centres. The phenomenal research breakthroughs I have witnessed by the Garvan in my time on the campus have been nothing short of amazing. From the discovery of a molecule that can switch appetite on and off, unravelling the role of abdominal fat in determining type 2 diabetes and influencing insulin resistance, to the identification of how a stress hormone in the brain can suppress the immune system and the utilisation of stem cell research towards the restoration of hearing. Many of these research endeavours have led to breakthroughs that have directly and profoundly impacted our patient care. Last year we proudly assembled to open The Kinghorn Cancer Centre, a joint partnership between the Garvan and St Vincent’s Hospital. This wonderful facility continues the relationship between the two great institutions that share a common ancestry. The establishment of the Kinghorn sees cancer specialists and researchers working together to find solutions to cancer and translating these efficiently into new treatment modalities. The new centre inspired then incumbent Prime Minister, Julia Gillard, to state that within the Garvan, Victor Chang and St Vincent’s Public and Private Hospitals there exists a hub of research and clinical care that is “per square metre, perhaps the greatest concentration of medical care and research excellence in the nation.” The Garvan’s journey continues as it moves to build on its strength in genomic research and create a future health care centred around personalised responses to healthcare prevention and treatment. For all those associated with the Garvan, may you continue to imprint the decades ahead with innovation, dedication and excellence. Dr Brett Gardiner Acting Chief Executive Officer St Vincent’s Health Network St Vincent’s Hospital Sydney

www.garvan.org.au

GARVAN 50-YEAR ANNIVERSARY

FOREWORD

PENELOPE CLAY

The Garvan’s first 50 years have been a great Australian success story, and Bill Ferris, the Garvan’s immediate past chairman, believes the next 50 will be just as exhilarating.

A pioneering spirit

T WAS ON THE 17th day of February in 1963 that the Garvan research building was officially opened. This brave start was made possible by the foresight and wisdom of the Sisters of Charity who decided to put the majority of funds raised from their Centenary Appeal towards a new medical research facility within St Vincent’s Hospital. A donation of £100,000 by the James Patrick Garvan family contributed significantly to the cause, and also gave the Garvan its name. From its beginnings in a small, 1,400 square metre, three-storey building, the Garvan has grown to be one of Australia’s premier medical research institutes. It’s a great Australian success story, achieved through visionary leadership, a pioneering spirit and the generosity of a supportive community and governments. We are delighted to share the Garvan’s story in this 50th anniversary

GARVAN 50-YEAR ANNIVERSARY

commemorative publication. During my time as Chairman I’ve marvelled at the number and nature of Garvan discoveries. Behind these breakthroughs are the brilliant minds of our researchers – always searching and innovating to find answers to the most complex questions we face in medical science. Many of these outstanding researchers are featured here, and there are hundreds more committed scientists tackling these questions every day in the Garvan’s labs. In this book we also pay tribute to the philanthropists who have given so much to help Garvan realise its vision. Philanthropic supporters have facilitated some remarkable achievements, including establishing our Immunology program and the new Kinghorn Cancer Centre, a joint initiative of the Garvan and St Vincent’s Hospital, which was opened in 2012. I would like to acknowledge

the pioneers who so successfully developed the Garvan in the early days, including Professor Les Lazarus, Professor John Hickie, Dr Margaret Stuart, Professor Ted Kraegen and Professor Don Chisholm. Upon those foundations much more was to be built by Professor John Shine, the late Professor Rob Sutherland, Professor David James, Professor John Eisman, and so many more of the outstanding scientists you will read about in this publication. I also wish to acknowledge three exceptional people who have supported the Garvan through thick and thin. The late Mr Keith Cousins (Chairman Management Committee 19811985, Founding Chairman 19851988), Mr Charles Curran AC (Chairman 1988-1993), and Mr Peter Wills AC (Chairman 1993-2011) all showed wise stewardship and unswerving support for this great institute. The first 50 years have gifted the Garvan with the opportunity and the obligation to be a leader in the health and medical research sector of this country. The Garvan is wonderfully positioned to continue its proud record in basic science and discovery, and to accelerate the translation of much of this into improved clinical practice in the hospital, in The Kinghorn Cancer Centre, and in the health service delivery nationally and beyond. Under the leadership of our Executive Director, Professor John Mattick, and with the continued dedication and support of Garvan faculty and staff, the Garvan’s future will be an exhilarating one. Just imagine what the next 50 years of discovery and translation could mean for national health, productivity, and happiness! Mr Bill Ferris AC – Chairman Garvan Institute of Medical Research (2001-2013) www.garvan.org.au

CONTENTS Introduction 10

Foreword by Mr Bill Ferris AC Boards, Life Governors & The Kinghorn Cancer Centre Visionaries Improving life through research 50 years of discovery

12 14 16

Celebrating 50 years An unassuming start A story of hope; the history of the Sisters of Charity Profile: Professor John Shine AO FAA Profile: Professor Leslie Lazarus AO Profile: Dr Margaret Stuart OAM Profile: Professor Ken Ho Profile: Professor Paul Compton

22 30 32 34 35 36 37

Garvan today Profile: Professor John Mattick AO FAA Creating excellence; introduction by Professor Ian Frazer AO FAA

38 40

Immunology division The fight back: preventing disease 42 Profile: Emeritus Professor Antony Basten AO FAA 43 Profile: Professor Charles Mackay FAA 47 Profile: Professor Robert Brink 50

Metabolic Diseases division Profile: Professor Ted Kraegen A step towards healthier lifestyles Profile: Professor Trevor Biden Profile: Professor Lesley Campbell AM Profile: Professor David James FAA Profile: Professor Don Chisholm AO Profile: Professor Greg Cooney

51 52 54 57 59 60 61

Neuroscience division Inside our most intricate organ Profile: Professor Herbert Herzog Profile: Professor Peter Schofield Profile: Associate Professor George Smythe

62 65 68 71

Cancer division New pathways to cancer treatment Profile: Professor Susan Clark Profile: Professor Roger Daly The Kinghorn Cancer Centre Profile: Professor Liz Musgrove Profile: Vale Professor Rob Sutherland AO FAA Profile: Professor Andrew Biankin

72 74 83 84 85 86 87

Osteoporosis and Bone Biology division

www.garvan.org.au

Reducing the burden of bone disease Profile: Professor Peter Croucher Profile: Vale Professor Philip Sambrook The Dubbo Osteoporosis Epidemiology Study Profile: Professor John Eisman AO Profile: Professor Tuan Nguyen

88 90 92 94 95 96

The future of Garvan

GARVAN 50-YEAR ANNIVERSARY

BOARDS, LIFE GOVERNORS AND THE KINGHORN CANCER CENTRE VISIONARIES

Garvan Institute Board of Directors William D Ferris AC

Garvan Research Foundation Board of Directors

Warren Scott

Geoff Dixon

Jonathan Anderson

Jane Allen

Sister Annette Cunliffe RSC

Bruce Baird AM

Geoff Dixon

Melinda Conrad

John Horvath AO

Gabriel Farago

Anne Keating

William D Ferris AC

John Mattick AO FAA

Lyn Gearing

Lisa McIntyre

Loftus Harris AM

Annette Pantle

Wal King AO

Greg Paramor

John Landerer CBE AM

Daniel Petre AO

John Mattick AO FAA

Jillian Segal AM

Simon Mordant AM

Peter J Smith

Sister Clare Nolan RSC

Bernadette Tobin

Brad Rees Jeanne-Claude Strong All Board members and Life Governors as of 17 February 2013

The Kinghorn Cancer Centre Visionaries The Kinghorn Foundation Australian Cancer Research Foundation The NELUNE Foundation Ferris Family Foundation Roy and Cindy Manassen Greg and Kerry Paramor Petersen Family Foundation Laurie Sutton Nicholas and Angela Curtis Cyril Golding John Porter and Susan Mougey Tony and Coleen De Saxe Simon and Catriona Mordant The Trustees of St Vincentâ&#x20AC;&#x2122;s Hospital Sydney The Kinghorn Cancer Centre is supported by a grant from the Australian Government 12

GARVAN 50-YEAR ANNIVERSARY

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Life Governors Allind Pty Limited Amadeus Energy Limited Mr John Armati ASX Group Australian Cancer Research Foundation Mr Charles P Curran AC The Curran Foundation Mr & Mrs Geoff and Dawn Dixon Mr & Mrs Peter and Val Duncan The Late Mr Alan Elder Mrs Janice Gibson & Ernest Heine Family Foundation Lady (Mary) Fairfax AC OBE Ferris Family Foundation Mr Laurence S Freedman AM Elizabeth Fyffe Mr James Patrick Garvan & Family George Patterson Pty Ltd Mr Berel Ginges and Mrs Agnes Ginges Mr Cyril Golding Mr William A Gruy Mr & Mrs Paul and Judy Hennessy HIH Insurance Mr Pieter H Huveneers Mrs Virginia Kahlbetzer Mr Trevor Kennedy AM and Mrs Christina Kennedy Mr & Mrs Ralph and Lorraine Keyes The Kinghorn Foundation Mr & Mrs Roy and Cindy Manassen Mrs Mabs Melville MLC Community Foundation National Australia Bank Dr Graham Oâ&#x20AC;&#x2122;Neill The Late Mr Kerry Packer AC Mrs Roslyn Packer AO The Paramor family Petersen Family Foundation The Petre Foundation The Lady Proud Foundation The Bill and Patricia Ritchie Foundation The Ross Trust Mr & Mrs Tim and Sally Sims Mr Robert Strauss MBE Mr Laurie Sutton Dr John Tonkin Westfield Holdings Ltd E J Whitten Foundation Witchery

www.garvan.org.au

GARVAN 50-YEAR ANNIVERSARY

OVERVIEW

Improving life through research Expertise and creativity nurture medical innovation at the internationally renowned Garvan Institute.

NTERING THE lobby of the Garvan Institute of Medical Research for the first time, a visitor’s gaze is drawn to a white ribbon of stairs that curves towards the ceiling of a dome-covered atrium, six storeys above. More than an audacious architectural work, the staircase is symbolically central to the institute, with its shape echoing the double-helix structure of DNA. The discovery of the doublehelix structure, published in a landmark paper by James Watson and Francis Crick in 1953, triggered a series of revolutions in medical research. Ten years later in 1963, the Garvan was founded and in the 50 years since then, its progress has mirrored the exponential explosion of knowledge sparked by Watson and Crick’s momentous discovery. Notable breakthroughs from the Garvan’s early days include a life-saving insulin infusion technique to treat a complication of diabetes. In the 1980s, Garvan scientists discovered the beneficial effects of fish oil in the diet and the institute produced Australia’s first genetically engineered human therapeutic growth hormone. During the following decade, Garvan scientists cloned a gene for a brain chemical involved in anxiety and depression and another that helps control the immune system and appetite.

GARVAN 50-YEAR ANNIVERSARY

They identified a region of the human genome implicated in susceptibility to bipolar disorder and clarified the role of several genes linked to developing asthma. Using the latest technological advances, the Garvan’s researchers have also helped expose the role of gene mutations in cancers; developed an antibody treatment for inflammatory diseases such as rheumatoid arthritis; created an online fracture risk calculator and designed a way to prevent the rejection of insulin-producing cells in people with type 1 diabetes. These successes and many more have helped the Garvan evolve dramatically within just five decades. From an initial handful of staff, the institute is now home to a workforce of about 600 deployed across five key research areas: cancer, metabolic diseases, immunology, neuroscience and osteoporosis and bone biology. EACH research area has had its significant research breakthroughs, but some of the greatest successes have come through projects that have brought together scientists from different disciplines. In 2012, the institute’s researchers published 224 scientific papers, with many bridging research areas to bring society better ways of managing complex disorders such as Alzheimer’s disease, cancer, osteoporosis, diabetes and obesity,

The staircase at the centre of the Garvan Institute echoes the double-helix structure of DNA.

arthritis and asthma. Such multidisciplinary collaborations – combined with its capability to rapidly translate clinical success into patient treatments – are hallmarks of the Garvan’s mode of operation. While other medical research enterprises can be defined by a narrow focus on basic research, a single disease area, major technology or commercial potential, the Garvan’s unique profile on the world stage results from the way it fosters many diverse connections, says the institute’s executive director, Professor John Mattick. In the coming decade, being able to sequence an individual’s entire genome and study their patterns of gene expression will transform medicine and medical research. The Garvan Institute will be at the forefront of that new revolution. “We will be leading the nation in the application of genomic medicine, in understanding www.garvan.org.au

human disease, and in advancing the prevention and treatment of complex diseases,” says Mattick. The Garvan has a partnership with Sydney’s St Vincent’s Hospital that extends back to the institute’s earliest days and the connection with the hospital has helped ensure that cutting edge medical research translates into a clinical setting.

into clinical practise took a leap forward with the opening of The Kinghorn Cancer Centre. This joint initiative of St Vincent’s Hospital and the Garvan Institute aims to realise the promise of innovative personalised medicine for people affected by cancer. “With The Kinghorn Cancer Centre opened, our ability to integrate teaching, research

“Imagination, based on knowledge, is the key to discovery.” “The institute was predicated on the vision and foresight of the Sisters of Charity, who recognised that their mission to heal the sick could not be fulfilled without research to prevent disease,” explains Mattick. “We are the portals to the world of advanced discovery, to the next generation of technology and to the next level of treatment options as well.” The ethos of the Garvan in translating medical research

www.garvan.org.au

and clinical translation on our expanding Darlinghurst campus has never been stronger,” says the immediate past chairman of the Garvan, Bill Ferris. IN THE SUMMER OF 2010, the Garvan’s second executive director, Professor John Shine, stood in the Great Hall of Parliament House in Canberra to receive the prestigious Prime Minister’s Prize for Science.

Shine had been the Garvan’s leader for 20 years and that night he reminded the audience of the enormous progress medical research had made during the previous century. “Not so long ago, in the early 1900s, the average life expectancy was 55. Today, it’s closer to 80 for men and 85 for women,” he noted. This huge improvement in both life span and the quality of life are the products of medical research, Shine pointed out. Breakthroughs have included antibiotics, vaccines, blood pressure and cholesterollowering drugs, and preventative public health measures based on improved knowledge about the causes of disease. “Imagination, based on knowledge, is the key to discovery,” Shine observed. “Humanity has always been rich in imagination, and in scientific research we have an exponentially growing database of knowledge.” – Stephen Pincock GARVAN 50-YEAR ANNIVERSARY

CELEBRATING 50 YEARS

50 years of discovery 1960s 1964

Garvan director Professor Les Lazarus and neurologist Kevin Bleasel demonstrate that cryohypophysectomy (freezing of the pituitary gland) is an effective way of providing hormone-ablative therapy for the treatment of patients with advanced cancer.

1970s 1968

For the first time, it’s shown that the hormonal responses to physical exercise are different in physically fit and unfit people.

Garvan scientists develop a radioimmunoassay technique for the measurement of growth hormone in humans, an Australian first.

It’s demonstrated that, following treatment, patients with heart failure have increased secretion of the hormone aldosterone.

GARVAN 50-YEAR ANNIVERSARY

1970

It’s found that a number of gut hormones are involved in the insulin response to feeding.

1970

It’s shown that a measure of hormone production widely used internationally to predict the responses to hormoneablative surgery of women with advanced breast cancer is ineffective and should be ceased.

1965

1966

ALL IMAGES GARVAN

The Garvan Institute’s record of research highlights over the past half-century has been outstanding.

1973 Above: The Garvan’s namesake, James Patrick Garvan, was a politician and insurance entrepreneur. Top: Garvan scientists Dr Paul Compton (left) and Dr Rick Symons (right), with Chinese endocrinologist Dr Wang de Quan.

Garvan scientists develop a new and simple treatment for ketoacidosis, a potentially life-threatening complication associated with diabetes. The novel treatment involves administering continuous, low-dose intravenous insulin.

1973

Garvan neuroscientist Dr George Smythe and endocrinologist Professor Leslie Lazarus successfully identify the role of brain serotonin and melatonin in regulating secretions of the pituitary gland, for example growth hormone.

1975

One of the first experimental versions of an ‘artificial pancreas’ is developed by Professor Ted Kraegen, with important implications for future diabetes treatments.

1976

For the first time, scientists recognise that patients with diabetes may be unable to produce the hormones needed to prevent low blood glucose levels. www.garvan.org.au

1983-1987

Garvan scientists discover that consuming fish oil (polyunsaturated omega-3 fatty acids) in place of vegetable and other animal fats helps combat insulin resistance in rats. The research is published in the U.S. journal Science in August 1987.

1984

Garvan scientists discover a connection between blood glucose levels and a stress-response hormone and neurotransmitter called noradrenaline. Noradrenaline, also known as norepinephrine, underlies the ‘flight-or-fight’ response, triggering increased heart rate and the release of glucose from the body’s energy stores.

Peter Anderson, NSW Minister for Health 1986–1988, with Professor Rob Sutherland (at back), who was director of the Garvan’s Cancer division for 27 years.

1986

The Garvan Institute, working with the University of New South Wales (UNSW) and biopharmaceutical company, CSL Limited, produces Australia’s first genetically engineered human therapeutic growth hormone.

1986

Director of the Garvan Cancer division, Professor Rob Sutherland, working with Dr Colin Watts, demonstrates the mechanism of action of tamoxifen, an oestrogen receptor antagonist, on breast cancer growth.

1980s 1985

In October 1985, in the journal Diabetes, Garvan scientists describe how they used novel techniques to reveal in vivo and for the first time, the different effects of insulin among its target tissues such as muscle, heart, liver and fat. The researchers use the so-called glucose clamp technique – maintaining blood glucose levels at a certain concentration to measure glucose metabolism or sensitivity – along with radioactive tracer molecules.

1985-1989

Physicist and artificial intelligence expert at the Garvan Institute, Dr Paul Compton, successfully applies artificial intelligence techniques (called “expert systems”) to laboratory-based clinical diagnosis.

www.garvan.org.au

1990

Molecular biologist and newly appointed director of the Garvan Institute, Professor John Shine, working with PhD student Helen Evans, clones human galanin, a brain chemical that regulates appetite, anxiety and depression and is linked to diseases including Alzheimer’s and epilepsy.

1991-1994

Endocrinologists Professor Ken Ho and Professor Anthony O’Sullivan demonstrate that oral oestrogen (in pill form) can lead to fat accumulation in menopausal women, a change that does not occur when oestrogen is administered through the skin.

1990s 1987

Associate Professor Nicholas Pocock, Professor Philip Sambrook and Professor John Eisman, working with scientists from the University of Melbourne and St Vincent’s Hospital’s department of nuclear medicine, publish the results of a twin study demonstrating the heritability of bone density, and therefore osteoporosis risk.

1989

The Dubbo Osteoporosis Epidemiology Study is established, and is set to become the longestrunning large-scale study of osteoporotic fractures in men and women. Its data contributes to the development of fracture predictive models and research into the genetic basis of bone density.

1991

Garvan researchers clone the neuropeptide Y (NPY) receptor, leading to a greater understanding of how this brain molecule controls functions such as the immune system and appetite. The research is published in the Proceedings of the National Academy of Sciences in July 1992.

1991

The Garvan’s John Eisman and Rob Sutherland, working with a visiting research fellow from Japan’s Osaka University Hospital, Masafumi Koga, establish the role of retinoic acid in progesterone receptor action in breast cancer.

From left: Ron Mulock (NSW Minister for Health 1984–1986), Professor Don Chisholm and Professor Ted Kraegen.

GARVAN 50-YEAR ANNIVERSARY

CELEBRATING 50 YEARS Left: The Garvan’s opening in 1963 was attended by 1,500 supporters and dignitaries. Below: Professors Ted Kraegen (back) and Don Chisholm (front).

1998

Garvan scientists, working with Macquarie University and UNSW researchers, identify the chromosomal region responsible for susceptibility to bipolar disorder.

1992

Garvan scientists, led by John Eisman, demonstrate that variations in the vitamin D receptor gene contribute to differences in bone density and therefore osteoporosis risk.

1992-1993

Garvan researchers including Professor Chris Ormandy and Rob Sutherland, elucidate the role of the prolactin receptor in breast cancer that interacts with the prolactin hormone involved in lactation.

1995

Garvan researchers Professor Roger Daly, Rob Sutherland and Michele Binder demonstrate the role played in breast cancer of the GRB2 gene, which encodes a protein involved in cell communication.

1995-2000

Twin studies conducted by Garvan scientists reveal that abdominal fat is genetically influenced, and that it is strongly related to insulin resistance and the risk of developing type 2 diabetes.

1998

2000-2006

A report is published describing HIV-associated lipodystrophy, a condition associated with the loss of subcutaneous fat, as the result of a collaboration between the Garvan Institute and the UNSW National Centre in HIV Epidemiology and Clinical Research.

Using human tissue banks and patient databases, significant advances are made identifying the exact role of gene mutations in cancers.

1998

The role of a key oncogene (a gene with the potential to cause cancer) called c-Myc in breast cancer is established.

2000s 1993

Results are reported from the first randomised control trial of bone-loss prevention treatments, including vitamin D and calcium.

1993-1994

Rob Sutherland’s research team makes one of the most significant advances in cancer research of the decade, revealing the role played by cell cycle genes (cyclins) in the progression of breast cancer.

1997

A study of rats fed on a high-fat diet leads to the discovery of the importance of an enzyme called protein kinase C in the development of insulin resistance.

1997-2006

Garvan endocrinologists uncover many of the 300-plus physiological functions of the hormone prolactin, including its role in the development of mammary glands and of cancer.

2000 1999

Garvan researchers show that there’s an increased risk of premature death after all types of osteoporotic fractures.

1999

Research led by Dr Carsten Schmitz-Peiffer shows the accumulation of ceramides (fat-derived molecules) in muscle cells reduces the effectiveness of insulin.

1999-2005

Garvan scientists from the Neural Stem Cells group, led by Professor John Shine and senior researchers Dr Kharen Doyle and Yvonne Hort, develop methods of culturing adult nerve stem cells taken from the nasal cavity, which are capable of generating new brain cells. 18

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In a project driven by leading prostate cancer expert Associate Professor Phillip Stricker, the Garvan Institute, in collaboration with St Vincent’s Hospital, establishes the largest prostate tissue bank and database in the Southern Hemisphere.

2000-2002

A Garvan research group led by Professor Fabienne Mackay demonstrates that a hormone called BAFF (B-cell activating factor) controls the survival of B-cells, a group of white blood cells (or lymphocytes), which form a vital part of the immune system. A link is established between elevated levels of BAFF and several autoimmune diseases.

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Professor Herbert Herzog and Dr Tiina Iismaa examining gels in 2000.

2006-2010

2002

Collaborative research between Garvan osteoporosis researchers and neuroscientists reveals the role of a brain hormone called neuropeptide Y in regulating bone formation.

2002

Gut hormone peptide YY is identified as playing a major role in satiety, or feeling full.

2002

Prognostic markers of pancreatic cancer progression are identified.

2001

A team of Australian researchers, including Garvan Institute scientists, identify the first prognostic markers of prostate cancer progression. The groundbreaking research is published in the journal Clinical Cancer Research in March 2001.

Garvan immunologist Professor Charles Mackay develops an antibody to a molecule called c5a receptor, associated with inflammation. The research spurs a spin-off company and a licensing agreement with a major pharmaceutical company to commercialise and develop a novel treatment for chronic inflammatory diseases such as rheumatoid arthritis.

2006 2004-2012

Collaboration with the Shanghai Institute of Materia Medica enables identification of mechanisms of molecules derived from traditional Chinese medicines (such as berberine, an ammonium salt found in the roots and bark of a number of plants), with promising potential as a treatment for type 2 diabetes.

2003

Microarray technology helps identify the role of several genes in asthma development.

Brain hormone neuropeptide Y is found to link the nervous and immune systems, suggesting novel treatments for stress-related disorders.

2006

Professor Susan Clark and Garvan researchers in the Cancer division identify epigenetic markers for detecting colorectal or bowel cancer.

2005

Collaborative research between Garvan immunologists and neuroscientists reveals how neuropeptide Y can suppress the immune system in response to stress.

From left: The late Professor Rob Sutherland, Professor John Eisman, Professor John Shine, Professor Don Chisholm and Ms Norma Perry circa 1990.

2006-2010

GRB (growth factor receptorbound) proteins are recognised as novel regulators of insulin signalling and muscle size.

2007

Collaborative research between St Vincentâ&#x20AC;&#x2122;s Hospitalâ&#x20AC;&#x2122;s Professor Sam Breit, UNSW and Garvan immunologists determines the function of MIC-1, a molecule that targets brain receptors for appetite, and is responsible for the extreme weight loss that can accelerate death in late-stage cancer.

2007

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Garvanâ&#x20AC;&#x2122;s Associate Professor Trevor Biden and Dr Ross Laybutt publish a landmark paper in the April edition of the journal Diabetologia demonstrating that the death of insulin-producing cells, which occurs during type 2 diabetes, is associated with a cellular stress response known as endoplasmic reticulum stress.

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GARVAN 50-YEAR ANNIVERSARY

CELEBRATING 50 YEARS

2009 2009 2008

Using data collected over 17 years from the Dubbo Osteoporosis Epidemiology Study, Garvan scientists develop a web-based tool to predict an individual’s risk of bone fracture – since used widely by doctors and patients worldwide.

2008

Garvan joins the American Association for Cancer Research Human Epigenome Task Force and plays a key role in the establishment of the International Human Epigenome Consortium. Epigenetics concerns the chemical interactions that impact the function and behaviour of genes without changing the DNA sequence.

Associate Professor Shane Grey and PhD student Eliana Mariño discover a promising new therapy for the prevention of type 1 diabetes, by using a molecule called BCMA to make the body’s immune cells tolerate the insulinproducing cells they would normally attack and destroy prior to the onset of diabetes.

2009

In research published in Nature, Professor Charles Mackay and PhD student Kendle Maslowski establish a connection between diet, gut bacteria and the immune system, highlighting the importance of dietary fibre in potentially keeping many diseases, including asthma, at bay.

Garvan immunologists Professor Jonathan Sprent and Dr Kylie Webster successfully test in experimental mice a method of adjusting the immune system for just long enough to receive and accept a tissue transplant without the need for toxic immunosuppressive drugs.

2009

Garvan endocrinologists observe a high frequency of vitamin D deficiency in critically ill patients, finding a direct correspondence between deficiency and disease severity.

2009

Large-scale studies of proteins expressed in cells, called phosphoproteomics, are used to map out new actions of insulin and its signalling events.

2010-2011

Scientists discover a sub-class of white blood cells that produces a key regulatory molecule of the immune system called IL-21 which, when blocked, protects transplanted insulin-producing pancreatic cells and reverses type 1 diabetes in mice.

2010’S 2007

Garvan’s Professor Herbert Herzog, working with scientists from the U.S. and Slovakia, demonstrates that stress hormone neuropeptide Y (NPY) can ‘unlock’ Y2 receptors in the body’s fat cells, stimulating the cells to grow in size and number, leading to obesity.

2008-2012

In 2008, research led by Chris Ormandy reveals that transcription factor ELF5 regulates mammary development during pregnancy. In a 2012 study, Ormandy, in collaboration with Drs Maria Kalyuga and David Gallego-Ortega, found that levels of ELF5 determine the molecular subtype of breast cancer and the sensitivity of a tumour to anti-oestrogen treatment.

2008-2013

Garvan scientists play a key role in international multi-centre studies identifying novel genes involved in osteoporosis.

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2010

The gene STAT3 is revealed as essential for the generation of ‘memory’ cells in the immune system, explaining why patients with mutations to this gene are susceptible to recurrent infections.

2010

Even modest weight loss of just six kilograms is shown for the first time to reverse many of the damaging changes often seen in the immune cells of obese people, particularly those with type 2 diabetes.

2010

Garvan researchers use sophisticated new protein screening technology to profile the characteristics of basal breast cancer, an aggressive sub-type of breast cancer, identifying specific targets for future treatments.

2010

In a paper published in Nature Cell Biology, a group of Garvan scientists led by Professor Susan Clark discover that extensive gene silencing is common in cancer, with up to 3% of the genome affected by epigenetic changes to DNA in cancer cells.

2010

A collaborative study between the Garvan Institute and the University of Sydney reveals, to scientists’ surprise, that insulin resistance caused by hepatitis C occurs in muscle and not in the liver, despite hepatitis C being a liver disease.

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From left: Sister Marie Haren, Mr Gilles de Weck and Mr Keith Cousins (far right), chairman of Garvan’s Management Committee, stand by as Dr (now Professor) David James receives the Sandoz Junior Award in 1984 for best original scientific presentation by a junior member of the Endocrine Society of Australia.

2011 2011

A new technique is developed for iron chelating (removing excessive iron stores), with the potential to enhance the function of transplanted insulin-producing cells in people with type 1 diabetes.

2011

Using data from the Dubbo Osteoporosis Epidemiology Study, Garvan researchers discover that people taking bisphosphonates, an effective treatment for osteoporosis, extend their life expectancies by five years.

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Researchers reveal why a common saliva-borne virus called Epstein-Barr virus, which leads to glandular fever in about 10 to 20% of people, can be fatal in people with a rare immunodeficiency called X-linked lymphoproliferative disease.

2011

Biochemical changes that commonly occur in the DNA of women with ovarian cancer are identified, with potential for improved early detection of ovarian cancer.

2012

Scientists identify the conditions under which the production of autoantibodies (antibodies that attack themselves) is prevented during normal immune responses.

2012

An international team of more than 100 researchers, led by Garvan’s Professor Andrew Biankin and Professor Sean Grimmond from the University of Queensland, sequence the pancreatic cancer genome as part of Australia’s participation in the International Cancer Genome Consortium.

2013

Remodelling of the cancer epigenome is shown to cause large regions of the genome to become activated, or ‘switched on’, and genetically unstable.

2013

A neurotransmitter called neuropeptide Y is shown to control temperature regulation in brown fat, affecting the ability of obese people to lose weight.

GARVAN 50-YEAR ANNIVERSARY

HISTORY

An unassuming start From humble early days to a world-class research institute: the Garvan’s journey has been a story of hope, dedication and vision.

N AN AUTUMN day back in 1963, young clinician– scientist Les Lazarus walked from his lab at Sydney’s St Vincent’s Hospital across the road to the newly opened Garvan Institute of Medical Research. “I remember vividly feeling a sense of excitement coupled with an appreciation that this move had the potential to be an important step up for the future of endocrinology at St Vincent’s Hospital and for the future of research at St Vincent’s Hospital,” he recalls.

to the new facility. “To make it look like something was going on,” he recalls being told. On that day in 1963, May 1, he was curious to see if the building’s interior was as impressive as its facade but, after walking through the institute’s glass double-doors, he was quickly disappointed. The building included a basement and three upper floors but at that time, when it was first opened, only part of the ground floor and the first floor had been fitted out as research laboratories. “There was no equipment; no reagents, nothing. Not even a telephone,” Lazarus recalls with a laugh. A lift

“I could see that I just needed to be patient and it would grow into something good.” From outside, the building looked the very model of a sharp-angled 1960s research facility. On the Victoria Street side, its facade was white marble. Down the Burton Street frontage, three floors of tall windows stretched towards the red brick nurses’ home behind. The ambitious and energetic Lazarus – now a professor of endocrinology and, since 1988, an Officer of the Order of Australia – had been lured back from London to Sydney to set up Australia’s first endocrinology lab at St Vincent’s. The administrators found space for him in the hospital’s biochemistry department and, together with his young collaborator Margaret Stuart, he began analysing steroid levels in blood. But it wasn’t long before Lazarus was asked if he would mind moving his operations 22

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shaft had been built, but there were no lifts, so he and his team used the space for storage. It was a challenging start. Lazarus, Stuart and a handful of other scientists were soon making runs across to the hospital supply cupboards to “borrow” the materials they needed. But Lazarus was undaunted. “I was 30-something and I had plenty of energy and optimism,” he says. “I was committed to the idea of the clinician-scientist and I could see that I just needed to be patient and it would grow into something good.” THE IDEA OF BUILDING a research institute at St Vincent’s Hospital emerged in 1957 with a fundraising appeal held to celebrate the hospital’s centenary

The original Garvan building on the corner of Victoria and Burton Streets in Sydney’s Darlinghurst.

year. A hundred years before, a small group of Sisters of Charity, originally from Ireland, had founded the hospital with the mission of helping the poor and disadvantaged (see ‘A story of hope’ p30). Its Centenary Appeal aimed to raise funds “to enable the extension of the hospital facilities for the sick and to promote medical education, and also for medical and nuclear medical research.” The post-war years were an exciting era for science and medical research. In 1946, the Australian Government had agreed to build the John Curtin School of Medical Research in Canberra. And a little later the United Kingdom’s National Institute for Medical Research opened its Mill Hill headquarters north of London. When St Vincent’s Centenary www.garvan.org.au

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Appeal was supplemented by a £50,000 pledge from the NSW Government and a £25,000 donation from philanthropist Adolph Basser, the hospital had a tidy sum to deploy. After three years of vigorous debate about how to use the funds,

the purpose of research. The donation had come from Helen Mary Mills, the widow of Arthur Edward Mills, a former professor of medicine at the University of Sydney. Decades before, Arthur had visited medical schools in Berlin and been

The post-war years were an exciting era for science and medical research. in late 1960 the hospital’s advisory board allocated £60,000 to build a medical research institute. A committee was appointed to advise on the building’s design and function. Then, in July 1961, a hospital announcement substantially improved the financial standing of the new institute: a generous donation of a further £100,000 had been received for

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impressed by medical educators placing importance on teaching the physiological and biochemical principles underlying clinical medicine. He brought those German-inspired principles of integrating medical research and practice back to Sydney and passed them on to medical students. His wife was honouring that vision when she required that

Professors Les Lazarus and John Shine view a model of the new building.

her donation be used to employ a director of clinical research of world standing. Helen and her family at first wished to remain anonymous, but later agreed that the new institute be named GARVAN 50-YEAR ANNIVERSARY

HISTORY

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Establishing a research facility was a new challenge and hospital authorities were unsure of the qualifications needed for the role, the type of studies that should be undertaken or how the institute’s hierarchy should be structured. Hickie, Lazarus and Gerry Milton were appointed co-directors in 1966 for an initial three-year period. And then, in 1969, Lazarus became the first sole director of the institute.

Professor Shine joined the Garvan as its deputy director in 1987, and from 1990–2011 was its executive director and a major force in driving the Garvan’s new research directions.

in honour of Helen’s father, James Patrick Garvan, a business entrepreneur and politician. On Sunday 17 February 1963, the Garvan Institute of Medical Research was blessed by Cardinal Norman Thomas Gilroy, and officially opened by Bernard

between Australia and England and the Duke was the English team’s manager. By the time the Garvan’s first annual report was printed in 1964, it had three research groups led by John Hickie, Jim Biggs and Lazarus. Studies at

It was diabetes and obesity research that first placed the Garvan on the international medical research map. Marmaduke Fitzalan-Howard, the 16th Duke of Norfolk. Some 1,500 supporters and dignitaries attended the ceremony. Apparently Sunday was the only day the occasion could be scheduled: it was a rest day in a cricket match underway 24

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the time included investigation of a hormone called aldosterone and its role in heart failure, and research into another hormone, gonadotrophin, and its connection with breast cancer. Although research had begun, Garvan still didn’t have a director.

THE PRIMARY RESEARCH interest of Lazarus was endocrinology. So it comes as little surprise that hormonal research was a dominant force in the Garvan’s research in its early years. “Endocrinology was a very interesting academic specialty in those days because assays for hormones had just been invented, and there was a lot of research into measuring hormone levels for the first time,” says Don Chisholm, who joined the institute in the 1960s and is now the Garvan’s group leader for Diabetes and Obesity Clinical Studies. “Les was in the right specialty and he had a drive to do research… and a tremendous ability to drive others, and he was always looking for new ideas, new avenues.” Before 1960, there was no effective way of measuring hormones, such as insulin, in blood. It made diagnoses of many endocrine diseases “just a clinical guess,” says Lazarus. That changed when Americans Rosalyn Yalow and Solomon Berson developed the first ‘immunoassays’, opening a new era in endocrinology. In 1964, Lazarus travelled to New York on a New South Wales Cancer Council grant to learn the technique directly from Yalow and Berson and that year he established his own radioimmunoassay service at the Garvan. It became a significant part of the institute’s research www.garvan.org.au

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activity and provided a steady source of funds. The money was much-needed as, during its early years, the institute relied heavily on uncertain funding grants for survival. In the 1970s, Cres Eastman, John Carter and others provided another important research thrust with thyroid hormone assays and related research. Later, Paul Compton achieved world-first status with an expert system for the interpretation of hormone assays, which is still used worldwide by pathology laboratories to provide automated interpretations of pathology test results. Lazarus’s own research was focussed on pituitary hormones and disease. His work with Stuart, Steve Judd and later Ken Ho made the institute prominent in this area. “The main areas we were involved

Cardinal Gilroy meeting the three daughters of the Duke of Norfolk, who officially opened the Garvan Institute in 1963.

in included hormone-dependent cancers such as some breast cancers and prostate cancers,” Lazarus recalls. “We were involved in investigating the hormonal triggers for those cancers.” Diabetes research was another important focus from the beginning and it was diabetes and obesity research that first placed Garvan on the international medical research map. In the early years, Lazarus, Chisholm and Ted Kraegen began to study the effect of gut hormones known as incretins on insulin secretion. Kraegen’s computer modelling methods for studying the action of insulin in humans grew increasingly sophisticated through the 1970s. With the help of clinical colleagues, this research led to improved treatments for the potentially life-threatening condition diabetic ketoacidosis. It also led to the development of an ‘artificial pancreas’ and,

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subsequently, the first bedside insulin infusion system. “[Kraegen] was the second or third person in the world to develop such a system,” says Chisholm. “It was a great piece of research.” Chisholm left the Garvan in 1969, but returned in 1978, after which he, Kraegen and Lesley Campbell further developed diabetes research. In 1982, together with Lazarus, they were awarded the first National Health and Medical Research Council (NHMRC) program grant in diabetes focussing on insulin resistance, obesity and the development of type 2 diabetes. In those early years of diabetes work, they were joined by a young PhD student called David James. “I got my first job working as a 20-year-old research assistant at the Garvan Institute in 1980,” says James, now a professor and leader of Garvan’s Diabetes & Obesity Research division.

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Cancer and diabetes research… have remained defining points of focus for the institute.

Dr Margaret Stuart (left), the Garvan’s assistant director from 1978, with the CSIRO’s Dr Anne Underwood.

“In those days the institute was just a little thing,” he recalls. “There were only two PhD students in the building. My job as a PhD student was to run the insulin assays for the hospital. Les Lazarus had a vision that you could do clinical work and research in parallel. In fact, a lot of the research was done around the radioimmunoassays.” Cancer and diabetes research, which played such an important role in the Garvan’s early years, have remained defining points of focus GARVAN 50-YEAR ANNIVERSARY

HISTORY

for the institute and areas where its researchers have led the world. THE 1980s WERE a momentous decade for the Garvan. Increasing financial security coincided with the arrival of research heavyweights from other institutions, providing the kind of critical mass needed to thrive long-term.

Lazarus: “Funding was the biggest problem we had for 20 years.” In 1984, John Eisman, a leader in calcium, vitamin D and bone disease research, moved his lab from the University of Melbourne to the Garvan. It built on a ‘disease of ageing’ research theme that the Garvan had established. Along with Philip Sambrook and Nick Pocock, Eisman set up the Bone and

Many of the Garvan’s scientific breakthroughs of the next 20 years would help unravel the genetic underpinnings of disease. In May 1984, the NSW Parliament incorporated Garvan as an autonomous non-profit research institute. Two years later, after two decades of financial struggle, Garvan was awarded a NHMRC block grant. At the time, only five medical research institutions had this far-reaching funding status in Australia. The news came as a huge relief, says 26

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Calcium Research Program and a hospital clinic to treat and prevent osteoporosis and measure bone density. Towards the end of the 1980s, the bone program further developed with the arrival of Tuan Nguyen and Jackie Center and the 1989 establishment of the Dubbo Osteoporosis Epidemiology Study (DOES), now the longest-running study of its kind in the world.

Another major new group was established in 1985 when Rob Sutherland and his research team transferred from the Ludwig Institute for Cancer Research at the University of Sydney to study hormone antagonists and cancer. It was the beginning of a research program that currently has around 120 staff and continues to grow. By the late 1980s, the Garvan was beginning to burst the seams of its modest 1960s building. The initial solution was to build an overpass between the back of the Garvan building and the fourth floor of the nurses’ home behind. But in the mid-1990s, the facilities were completely rebuilt into the Frank Woolley-designed building of today with the iconic double-helix staircase at its heart. LAZARUS RETIRED IN 1990, after 25 years at the helm of the Garvan. The institute’s new executive director was John Shine, a man who had made his name www.garvan.org.au

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iStockphoto

In 1964, the first lab at the Garvan was shared by two scientists assisting Les Lazarus and John Hickie: Anita Freeman (left) and Margaret Stuart (right).

with groundbreaking work in the 1970s and ’80s that eventually led to gene cloning. Lazarus was delighted with the choice. Shine had been working at the institute since 1987 and his appointment as executive director was, according to Don Chisholm, “a game changer”. “His arrival had an enormous impact on the institute,” recalls Chisholm. “He was probably the best-known biomedical researcher in Australia of his generation.” Molecular biology came to define the research activity of the Garvan. Shine himself established a lab studying neuropeptide receptors. And he reorganised the institute’s scientific effort into four key research programs that reflected the emerging belief that understanding the molecular basis of disease was a realistic prospect. The four new programs focussed on bone and mineral, cancer, neurobiology and

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In the 1990s, molecular biology became a focus for the Garvan Institute.

metabolic research. Shine recognised that the hormone assay service that had been such a vital part of the institute’s early development was, at this stage, confusing the organisation’s vision and purpose. So it was transferred to SydPath, St Vincent’s Hospital’s pathology service, where Lazarus became director after his retirement

from the Garvan. Many of the Garvan’s scientific breakthroughs of the next 20 years would help unravel the genetic underpinnings of disease. In 1991, for example, one of Shine’s young collaborators, Herbert Herzog, became the first to clone the neuropeptide Y receptor, a molecule in the brain that plays vital roles in GARVAN 50-YEAR ANNIVERSARY

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HISTORY

the immune system, appetite regulation and bone synthesis. Herzog is now a professor and leads the Garvan Institute’s Neuroscience division. Another significant breakthrough came in 1997, when the group led by John Eisman and Tuan Nguyen published data showing that the vitamin D receptor gene is responsible for differences in bone density. In 2000, another key component of the modern Garvan Institute emerged when a bequest to St Vincent’s Hospital allowed it to

would not have existed without those forward-looking donors.” By this time, the genome revolution was in full swing around the world. The publication of the first draft of the human genome, in mid-2000, helped usher in new generations of technology that allowed scientists to study genes far more quickly and cost-effectively. The Garvan leapt onto these new approaches, becoming the first institute in Australia to install new gene array machines built by American firm Affymetrix. In 2008, the Garvan

“The whole program would not have existed without those forward-looking donors.” begin forming its outstanding immunology program. Researchers Charles and Fabienne Mackay were brought onboard from the U.S., followed by Tony Basten and many other excellent researchers associated with the Royal Prince Alfred Hospital’s Centenary Institute, another prestigious medical research facility in Sydney. The new and exciting immunology program that these eminent scientists added helped to infuse immunological science into all the Garvan’s other programs, says Shine. “The whole program 28

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also built a new state-of-the-art breeding and holding facility for experimental mice in the NSW town of Moss Vale. The facility, which is used by researchers from Garvan and elsewhere, provides critical infrastructure for medical research and biotechnology. “It’s all about being in the right place at the right time,” observes Shine. “Smaller institutions like the Garvan are able to embrace new technologies quickly and be at the cutting edge. We were lucky that we were young and had molecular biology expertise

Past and current chairs and executive directors of the Garvan (from left): Charles Curran, Professor John Shine, Peter Wills, Professor Leslie Lazarus, Bill Ferris and Professor John Mattick.

just as molecular biology was revolutionising the world.” One of the other significant Sydney-based research facilities that’s had direct involvement with the Garvan is the Victor Chang Cardiac Research Institute. This prestigious organisation first occupied space in the Garvan building in 1994, and later moved into its own premises nearby in 2008. “The critical mass of this research precinct adds to the attractiveness of the Garvan for researchers,” says Shine. “It’s one of the factors that helps us attract the best people, who are leaders in their fields.” DISCUSSIONS BEGAN in 2006 about expanding that critical mass even further in the area of cancer by establishing a new research facility to help close the gap between discoveries in the research labs and improved patient care. Around the world, researchers were realising that the kind of research that connected scientists and clinicians – called ‘translational research’ – was vital. Once again, the Garvan Institute set out to catch this new wave. “We saw that this was the future, not just for the Garvan but around the world,” says Shine. www.garvan.org.au

Out of those discussions emerged plans for The Kinghorn Cancer Centre (TKCC), a stateof-the-art translational research facility established by Garvan and St Vincent’s Hospital with generous support from donors, including the Australian Government, Kinghorn Foundation, the Australian Cancer Research Foundation and the NELUNE Foundation. The TKCC’s beautiful new building adjoining the Garvan is home to cancer clinical services from St Vincent’s Hospital as well as research facilities. And it supports multidisciplinary teams that span the clinical and basic research disciplines. Just as the appointment of John Shine as the Garvan’s executive director coincided nicely with the gene cloning revolution, his recent successor’s arrival chimes neatly with the emergence of another scientific revolution –

expression of other genes. These technological changes will allow scientists to glimpse larger views of the complex genomic system that goes on in every cell, says Mattick. “My ambition is to make Garvan the first of the biomedical research institutions in Australia to fully embrace next generation genomic and bioinformatic approaches, which will be essential to the understanding of human development, physiology, brain function and disease,” he says. THE MOST VISIBLE manifestation of that change at the Garvan, but certainly not the only one, is TKCC, he says. It is becoming clear that genome sequencing will soon be a routine part of cancer research, allowing scientists to identify changes in cancer cells that can be targets for new diagnostic

“The critical mass of this research precinct … helps us attract the best people, who are leaders in their fields.” genomics. Genomics is allowing scientists to look holistically at all the complex changes that take place during human development, in brain function and in complex diseases, explains the Garvan’s third executive director, Professor John Mattick, who took up his post in January 2012. As genomic technology has become vastly more powerful and dramatically less expensive, scientists have been able to gather great swathes of data about human genetic variation. Mattick himself has been part of that revolution by contributing to our understanding of parts of the human genetic sequence that do not code for proteins. These sequences, once wrongly described as ‘junk DNA’, are now known to play many important roles such as regulating the

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tools and treatments. The close relationship between research scientists and clinicians at TKCC is a prime example of ‘translational’ research, which helps advances in the lab benefit patients more quickly. This concept is also embedded in the inaugural John Shine Research Fellowship, launched in 2012. Mattick, whose sister once lived in the nurses’ quarters that were incorporated into the Garvan 20 years ago, sees all this as a kind of return to the Garvan’s original vision: to bring science and medicine closer together. “It reconnects us more powerfully to the hospital, and means that research and the clinical endeavour can be more closely melded,” he says. “In a way, it brings us full circle.” – Stephen Pincock

Garvan RECOGNISES THE MLC Community Foundation A shared history and a common ethos have made the MLC Community Foundation a natural fit with the Garvan Institute of Medical Research and its mission to better people’s lives. Insurance entrepreneur and politician James Patrick Garvan founded the Citizens’ Life Assurance Co. Ltd in 1886, which later became the Mutual Life and Citizens’ Assurance Co. It was his daughter, Mrs Helen Mills, who in 1961 first generously contributed to the new institute at St Vincent’s Hospital. Almost a decade ago, the MLC Community Foundation turned to the Garvan to help fulfil its philanthropic goals of improving mental health. Since then, it has contributed more than $1 million to the Garvan, specifically ensuring the 24/7 operation of the MLC Flow Cytometry Facility, a facility that rapidly sorts, counts and analyses the chemical and physical properties of particles for the purposes of clinical research, and which includes equipment that was the first of its kind in Australia. “It is certainly a great relationship, not simply due to the shared history and ideals of our organisations, but because of the vital research work the Garvan does to battle disease and develop cures,” says the MLC Community Foundation’s executive manager, Luke Branagan. “The Garvan really does provide important and often unrecognised service for our community, delivering new technologies and research to improve people’s health for a longer life. We’re also about positivity and improving health outcomes for all Australians. And we believe the notfor-profit sector can do great things with the right support,” he says.

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HISTORY

SVMH Archives

A story of hope The vision of the Sisters of Charity has been integral to the foundation of the institute and its ongoing mission.

HILE THIS YEAR marks the Garvan Institute’s 50th anniversary, the story of the women whose vision inspired its foundation began almost 200 years ago in Dublin, Ireland. It was here, in 1815, that Mary Aikenhead founded the Sisters of Charity – an order devoted to serving the poor. Twenty-two years later, Archbishop John Bede Polding requested the Sisters’ help to care for female convicts transported to New South Wales and imprisoned in the Parramatta Female Factory. On the last day of 1838, five of the Sisters arrived in Sydney. The Sisters walked long distances to tend to the prisoners, the sick and the poor. “They were clearly resilient and resourceful women,” says Anne Cooke, an archivist at St Vincent’s Hospital. “There was never really any funding to cover the Sisters’ living costs and their mission. These were pretty desperate times – often they were living a handto-mouth existence and relying on the charity of people.” In 1855, supporters held a charity bazaar in Sydney, raising enough for the Sisters to set up their 30

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The community of Sisters at St Vincent’s Hospital in 1984.

first convent and hospital – St Vincent’s – which opened in 1857 at Potts Point (and later relocated to Darlinghurst). The Sisters managed these facilities with integrity – even making sure to blow out their hospital candle and relight another paid for by the convent when they reached the threshold between the buildings at night. Over the years, the Sisters established more schools and hospitals. St Vincent’s Hospital also quickly grew, becoming a teaching hospital in 1923. By the hospital’s centenary in 1957, it was caring for 7,000 people a year, and still needed more beds,

equipment, education facilities and research space. An inaugural research journal, The Proceedings of St Vincent’s Hospital, was published during the centenary, and a Department of Experimental Medicine had been started in 1947, but there were few resources for doctors to do pure research. To provide that support, the Rectress of the Hospital Community (first Mother Michael Farrell and later Mother Sarto Peardon) supported a fundraiser celebrating the centenary. In 1961, Helen Mills, the daughter of James Patrick Garvan, gave a substantial donation of £100,000, www.garvan.org.au

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Top: The Sisters with singer and cancer survivor Delta Goodrem at the conclusion of the 400-km ‘Nun’s Run’. Below: The Sisters attending a morning tea to honour their work during Garvan’s 50th anniversary year, with Professors John Mattick and Leslie Lazarus at rear.

and the new Garvan Institute was officially opened in 1963. As teaching and nursing became more specialised, the Sisters’ roles changed. Handing over management of the institute, they returned to their core ministry but still remained closely involved – notably serving on the Garvan Research Foundation Board and the Institute Board. In 2009 the Sisters helped raise funds to construct the new Kinghorn Cancer Centre, a joint facility of the Garvan Institute and St Vincent’s Hospital. Harking back to the Sisters’ past as a walking ministry, a dozen nuns led

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by Sisters Helen Clarke and Leone Wittmack embarked on a 400 km, 13-day walk from Dubbo to Darlinghurst, raising more than $200,000 for the Centre, which was officially opened in 2012. Sister Helen Clarke lost both her parents to cancer and has sat with many patients who were suffering. The ‘Nun’s Run’ let her raise the profile of the new centre as well as pray for the many cancer patients they met along the way. The Sisters’ mission to alleviate suffering will continue to underpin these institutions. “The Sisters of Charity provide the founding story – the ethos on which the Garvan

and St Vincent’s were founded,” says Sister Helen. “The Sisters had the vision to found these facilities and they will stay connected with them for as long as they exist.” The Sisters of Charity Congregational Leader, Sister Annette Cunliffe, echoes these sentiments. “Our vision and hope is to always have a special focus on the access of those greatest in need to the highest quality of treatment. Research will seek to prevent suffering as well as alleviate it when it does occur, leaving a legacy of better health into the future.” – Tara Francis GARVAN 50-YEAR ANNIVERSARY

CELEBRATING 50 YEARS

Professor John Shine AO FAA Garvan’s Executive Director from 1990 to 2011, Professor John Shine’s outstanding career took off early.

ROFESSOR JOHN Shine was aged just 16 when he enrolled in a veterinary science degree at the University of Sydney in 1962. He’d finished high school early as a result of moving with his family through different schooling systems in Brisbane, Melbourne and Sydney. He says he went into vet science because he liked animals but, probably due to his youth, lasted only three years in the course. And ironically, given his later achievements in the field, he found biochemistry particularly boring. “It was a subject I hated most,” he confesses. After moving to his parents’ home in Canberra, Shine took up a part-time science degree at the Australian National University. It was there that a particularly talented teacher, Professor Lynn Dalgarno, changed his mind about biochemistry and helped him achieve an important scientific breakthrough that would bear both their names. To many biology students today, Shine is best known not as Executive Director of the Garvan Institute for 21 years, but for a gene sequence responsible for ‘switching on’ protein synthesis – the process that translates genetic information into proteins with a biological function, such as hormones. Uncovering the role of the Shine–Dalgarno sequence was the work of Shine’s PhD thesis, supervised by Dalgarno and described in the journal Nature in 1975. The discovery would be instrumental in the foundations of the biotechnology industry. 32

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After his PhD success, Shine took a postdoctoral research position at the University of California, San Francisco in 1975. There, he and his colleagues joined the race to become the first to ‘clone’ genes – that is, isolate human genes into bacterial cells, with potentially game-changing implications for medicine. The Shine–Dalgarno sequence became very important, enabling scientists to ‘trick’ bacterial cells into recognising human genes as their own, initiating the allimportant mechanism to translate the genes into biologically functioning proteins. Using this method, the researchers were the first to clone both the human insulin gene – a momentous feat for millions of diabetes sufferers worldwide – and the human growth hormone gene. In 1978, Shine set up a research lab back at the Australian National University. There he cloned both the human endorphin gene and the renin gene, which encodes an enzyme associated with regulating blood pressure. In 1983, aged 37, Professor Shine returned to the U.S. at an exciting time for the burgeoning biotechnology industry. He co-founded and directed a small start-up called California Biotechnology. It changed its name to Scios in 1992, and in 2003 was bought for more than $2 billion by healthcare giant Johnson & Johnson. But by that time, Shine was no longer at the helm. In 1987, he had decided the company had grown sufficiently that it “needed a businessman, not a scientist” as president.

He was also married, with two high school-aged children whom he hoped would grow up in Australia. So he “grabbed” an opportunity to join the Garvan Institute as Deputy Director, and then Executive Director and has “enjoyed every minute since”. The most rewarding aspect of his time with Garvan was sharing in the breakthroughs of other researchers at the institute. “As director of a major, rapidly growing, outstanding research institute, you can share in all of these highlights,” he says. In 1996, Shine was awarded an Order of Australia for services to medical research, and in 2010 he won the prestigious Prime Minister’s Prize for Science. Although he retired as head of the Garvan Institute in 2011, he still leads a research group there, and is also the chairman of a major biopharmaceutical company. The latter, he says, gives him “an opportunity to participate in the translation of research discoveries into real, practical applications, which I really enjoy.” It’s been 40 years since the Shine–Dalgarno sequence set his career on its trajectory, but he’s still at the forefront of research. His current focus is on stem cells in the nasal cavity, where nerve cells are replenished every 60 days. “We take a biopsy of the nose, grow these stem cells in culture, and we’re trying to figure out ways to get them to multiply in culture, and to differentiate or convert them into mature nerve cells,” he says. These could potentially replace nerve cells affected by disorders such as Alzheimer’s and Parkinson’s disease. “It’s early days and it’s basic science,” he says, “but it’s very interesting.” – Gemma Black www.garvan.org.au

Lauren Trompp

“As director of a major, rapidly growing, outstanding research institute, you can share in all of these highlights.”

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GARVAN 50-YEAR ANNIVERSARY

CELEBRATING 50 YEARS

Professor Leslie Lazarus AO Profile

GARVAN 50-YEAR ANNIVERSARY

Lauren Trompp

S A STUDENT AT Sydney

Boys High School in the 1940s, Professor Leslie Lazarus excelled in mathematics and planned a “fall-back” career as an actuary if he didn’t win a scholarship to follow his true ambition: a degree in medicine at the University of Sydney. Born in 1929 in Sydney to British immigrants, Lazarus wanted a career that would offer “a background in science, and involvement with people at the same time”. He won a coveted scholarship in 1947, and translating pure science into clinical medicine later became the core principle of the Garvan Institute, which Lazarus was instrumental in establishing. After graduating in 1953, he worked at St Vincent’s Hospital in Sydney, spending time in the Diabetes Clinic before taking up a two-year scholarship to Middlesex Hospital in London in 1960. There, he worked under renowned physician and endocrinologist Sir John Nabarro, who helped galvanise his commitment to applying research in the clinic. “He insisted all the research fellows worked both in the laboratory and in the wards,” says Lazarus. “I’ve followed through with that for the rest of my life.” Before 1960, there was no effective way of measuring hormones, such as insulin, in blood, so the diagnosis of many endocrine diseases was “just a clinical guess,” Lazarus says. That changed when New York scientists Rosalyn Yalow and Solomon Berson developed a technique called radioimmunoassay. Scientists could then measure

the underlying cause of diabetes, for example, revealing it could be one of two disorders – either a lack of insulin (type 1) or insulin resistance (type 2). Yalow received a Nobel Prize for the research in 1977. (Berson died in 1972.) Returning to Australia in 1962, Lazarus established Australia’s first endocrine laboratory at St Vincent’s. The lab was incorporated into the newly founded Garvan Institute in 1963, and in 1964 Lazarus travelled to New York, on a grant from the NSW Cancer Council, to learn directly from Yalow and Berson. He brought the new method back to Australia a month later, and used it in his research,

Garvan’s first executive director, Les Lazarus oversaw the growth and direction of the Garvan for more than 20 years.

particularly in the study of treatment options for women with hormone-dependent breast cancer. Lazarus was appointed codirector of the Garvan in 1966, was sole director from 1969 to 1985, and executive director from 1985 to 1990. In 1988 he was awarded an Order of Australia for services to medicine and medical research. Professor Lazarus oversaw the Garvan’s growth into a large, diverse research organisation. “The most rewarding factor was being able to combine laboratory work together with clinical work, and being able to develop a team of scientists, nurses, doctors and trainees to look after people,” he says. – Gemma Black www.garvan.org.au

Dr Margaret Stuart oAM Profile

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Lauren Trompp

ORN IN NEWCASTLE, New South Wales, in 1939, Dr Margaret Stuart was just 11 when she told her parents she wanted to become a medical researcher – to understand how and why people get sick. She doesn’t remember exactly where the desire came from, except perhaps a conversation with a friend’s father, who was an anaesthetist. “I can remember having spoken to him about how anaesthetics worked, and I thought, isn’t that exciting! You actually have a material that works at the subcellular level,” she says, adding with a laugh: “Not that I think I could say ‘subcellular’ at that age.” Moving to Sydney, Stuart attended Presbyterian Ladies’ College before graduating from the University of Sydney in 1960 with a Bachelor of Science, majoring in biochemistry and microbiology. She started at the St Vincent’s Hospital pathology department as a biochemist, and in 1962 joined Professor Leslie Lazarus to set up Australia’s first endocrinology laboratory; this was incorporated into the Garvan Institute when it was established in 1963. Stuart then moved to London, working for two years at the Middlesex Hospital Medical School, and spent time researching in the U.S. and Canada. She returned to Garvan in 1966, where she would remain in various roles and as a leading biochemist until 1990. In 1972, Stuart completed a masters degree on human growth hormones at the University of Sydney. That same year, she travelled to Bangkok, Thailand, as a consultant for the World Health Organisation to establish a

hormone immunoassay program and train local staff to measure hormone levels in blood. As well as receiving her PhD from the University of New South Wales in 1982, the early 1980s was a period at the Garvan that Stuart recalls as a highlight of her research career. She led a team of Garvan scientists who collaborated with the CSIRO to apply a new cell-cloning technique to produce abundant supplies of antibodies for diagnostic purposes. The Sydney Morning Herald described the work as “a biological coup of major importance”. The technique let researchers fuse antibody-producing cells from the spleen of a mouse with mouse cancer cells. The resulting

Dr Stuart has contributed world-leading research to the Garvan over 25 years.

hybrid cells provided monoclonal antibodies with a number of potential applications, including, initially, diagnosing human infertility. This research led to Stuart’s appointment as head of the Garvan’s new Biotechnology Resource group. In 1990, Stuart joined Macquarie University’s school of biological sciences. She was awarded an Order of Australia Medal for her services to medical research in 2012. Of her quarter of a century at the Garvan, Stuart says, “I’ve seen some big changes, but I’ve also seen a continuum of the vision from those early days, the vision to apply science to the medical field, and always at the frontier level.” – Gemma Black GARVAN 50-YEAR ANNIVERSARY

CELEBRATING 50 YEARS

Professor Ken Ho Profile

“H

ORMONES FORM the basis of what makes life worth living, and the pituitary gland is where the action is,” says Professor Ken Ho, although he wryly admits that he might be a bit biased – in early 2013 the highly respected scientist was elected president of the international Pituitary Society. Graduating in medicine from the University of Sydney in 1975, Ho went to St Vincent’s Hospital in Sydney to complete his specialist training as an endocrinologist. “In the final year of my training my mentor was Professor Leslie Lazarus, the founding director of the Garvan Institute… it was he who got me interested in pituitary biology,” says Ho. “The pituitary gland sits at the base of the brain and is the gateway through which the brain talks to the rest of the body, with the hormones being the messengers,” says Ho, who until recently was head of pituitary research at Garvan, and chairman of the department of endocrinology at St Vincent’s Hospital. Without hormones, we reduce ourselves to mere machines, he says. “Hormones define the difference between men and women, they underline our survival in relation to reproduction, they allow us to enjoy food, and they control nutrition and metabolism.” Pituitary gland damage can have serious effects. For example, if there is no production of growth hormone in children, then they stop growing. Ho’s team has been researching what growth hormone’s function is in adult life, because even after 36

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we stop growing the pituitary gland continues to produce growth hormone – it’s the gland’s most prevalent hormone. “Our research has shown that it is a very important metabolic hormone,” Ho says. Ho’s work in metabolism encompasses disturbances of fat and protein balance. Obesity is one well-known disturbance, but less well understood is why some people, such as the elderly, lose muscle and body protein. If unchecked, this can lead to physical frailty, disability and dependency. “It is a huge hidden timebomb for society, this whole basis of physical frailty,” says Ho. In terms of research, Ho’s team at the Garvan is the only lab in Australia that can accurately study the rates of breakdown, metabolism and synthesis of protein. And as far as treatment

Professor Ho’s research into hormones has been fundamental to our understanding of growth and physical frailty.

is concerned, the group is looking at hormone-based agents that can restore muscle and body protein. “Most of them are hormones that we are familiar with, but we are working out the form of the hormones, the method of delivery… lots of biologically important determinants that can be delivered safely without side effects,” he says. Now in Brisbane as chairman of the Princess Alexandra Hospital Centres for Health Research, which is a partner within the $350 million Translational Research Institute, Professor Ho says he still feels “very much a part of the Garvan family; I still have a small lab running in the Garvan, and I visit at least once a month,” he says. “The Garvan has been instrumental in shaping my career – I have been trained well for the position I now occupy.” – Jonathan Nally www.garvan.org.au

Professor Paul Compton

Early work in metabolic research led Professor Compton to create a knowledge acquisition technique now used in laboratories around the world.

Profile

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Janelle McIntosh

rofessor Paul Compton’s career might have followed a very different route if it had maintained its initial trajectory. “I studied to be a Catholic priest, but I only got halfway through,” he says. This training – including three years of philosophy – provided him with the tools to teach expert medical computer systems how to correctly diagnose patients. It all started at the Garvan Institute, where Compton worked first as a student of a Master of Science, looking at models of glucose metabolism (his research was motivated by his sister’s diagnosis with type 1 diabetes). During his time at the Garvan, he helped the institute implement a laboratory information system to manage its endocrine assay service: processing requests, setting up worksheets and preparing reports. So when the then Executive Director Les Lazarus issued a challenge to see if the clinical advice that endocrinologists manually added to the institute’s assay reports could be automated, Compton and his colleagues developed one of the first medical expert systems to be put to everyday clinical use. The system was based on hundreds of logical rules which used assay hormone levels and other patient information to provide very specific clinical advice. The trouble was, you couldn’t be sure the endocrinologists had given you all the rules needed to deal with the exceptional cases that might occur, or if the rules were precise enough. “If I’ve got a rule that says if the patient has high

pregnancy hormones then they are pregnant, that could be completely wrong. Certain tumours can occur in males that produce pregnancy hormones. The problem is that if an endocrinologist is telling you about hormone levels in pregnancy, they probably won’t tell you that the rule needs to check that the person is female,” Compton explains. Debugging the system and adding and fixing rules took a long time and increased the size of the knowledge base exponentially. To solve this problem of timeconsuming corrections, Compton proposed a knowledge acquisition technique known as ‘Ripple Down Rules’, which let experts easily add logical rules but controlled the context in which the rule could be applied. “Initially it just came from trying to avoid having to go back and edit and recheck everything. But because I had a

philosophical background I went back and thought ‘Holy Toledo! This could be more than just a little fix’,” says Compton. He was right. Today, Ripple Down Rules are used by many pathology laboratories in Australia, Europe and the US, and outside of medicine by companies such as IBM to perform data cleansing. When he was first writing rules for the medical expert system, it might have taken Compton, who for the last decade has been Head of the UNSW School of Computer Science and Engineering, all day to fix half-a-dozen logical mistakes. Now, using Ripple Down Rules, the median time it takes to write a rule is 78 seconds. “The ease with which you can fix errors and add new knowledge, is unbelievably fast. There’s no other technology that’s quite like that,” he says. – Phillip English GARVAN 50-YEAR ANNIVERSARY

Lauren Trompp

GARVAN TODAY

GARVAN 50-YEAR ANNIVERSARY

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Professor John mattick AO FAA A brilliant geneticist, Professor John Mattick took up the reins as Garvan’s Executive Director in 2012 with customary skill.

ROFESSOR JOHN Mattick has been described as a maverick geneticist, a visionary and an optimist. He has been made an Officer in the Order of Australia, received a Eureka Prize for Leadership in Science and the 2012 Human Genome Organisation Medal, to name a few honours. He has transformed the way we understand the genome and, since 2012, been Executive Director of Garvan Institute. “In an institute like this is, it’s not just about what we discover… it’s also a place for the most

assumed to mean that genes encode (only) proteins, through the intermediary of RNA, and that proteins perform all cellular functions. It was an assumption he was to eventually overturn. AFTER COMPLETING HIS PhD at Monash University in Melbourne, Mattick undertook postdoctoral research at Baylor College in Houston, Texas. “It really introduced me into science,” he says. But five years later, with his mother unwell, Mattick returned to Australia to work at the CSIRO. He brought with him skills in cloning genes

“It’s not just about what we discover, it’s also a place for the most intellectually gifted, visionary and altruistic scientists in the nation These are the people who’ll invent the future.” intellectually gifted, visionary and altruistic scientists in the nation,” Mattick says. “These are the people who’ll invent the future.” The eldest of four children, Mattick was raised by a single mother in tough circumstances in Sydney’s inner west. By his own account he was a bit of a larrikin, often skipping first-year classes at the University of Sydney to go sailing on Sydney Harbour. Pulled up by his family in his second year, he developed an interest in biochemistry and genetics. It was molecular biology’s early days: scientists had only just developed a concept of DNA’s function. Mattick learned that ‘DNA makes RNA makes proteins’,

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– revolutionary techniques that are now central to modern biological and medical research. After he worked on the first recombinant vaccine (against footrot) made in Australia, the University of Queensland asked him to apply for a professorship – at 37 – and to head a major new research centre, which became the Institute for Molecular Bioscience. In 1993, Mattick took a sixmonth sabbatical to the University of Cambridge to scratch an intellectual itch: What was the role of the vast amount of DNA that did not code for proteins and had long been regarded as ‘junk’? “I had a strong instinct that something was going on that we

didn’t expect and that was worth looking into,” he says. Could the non-coding RNA be sending some other type of information? In those days, when cloning a gene could take a year or more, it was a tricky theory to test. So Mattick started looking for answers in the libraries at Cambridge, which had long been a hotbed of molecular biology research. At the end of his sabbatical, Mattick gave a talk – which in 1994 became his first paper on the subject – and “dashed off in chalk” his idea: “I think that everyone’s got it wrong,” he observed. Technology wasn’t yet sophisticated enough to test the idea, so in 2000 Mattick went to the University of Oxford to gather more evidence. This led to two papers in 2001 making a more detailed case that the 98% of the human genome previously regarded as nonfunctional comprises a “second tier of information” which is essential for the development of complex organisms. For the next decade, Mattick searched for observations that would falsify the theory. He didn’t find one, and his idea has since redefined biology: “This whole protein-centric zeitgeist in biology is wrong. It was wrong from the beginning, and nobody knew it. And it changes everything,” he says. Mattick is equally proud of the Garvan’s work. He notes that as well as being a major site for medical science, the Garvan connects Australia to the entire world of advanced medical research. “We are portals to the next generation of technology and the next level of treatment options,” he says. When he first started at the Garvan, Mattick told staff: “The community… puts their faith in you – you’ve got to live up to that. You have to be ambitious, in the best sense of the word, to make a difference – to have an impact.” – Heather Catchpole GARVAN 50-YEAR ANNIVERSARY

RESEARCH TODAY – INTRODUCTION

Creating excellence It’s the quality of the Garvan’s people that has led to its outstanding success in medical research, writes Professor Ian Frazer AO FAA.

GARVAN 50-YEAR ANNIVERSARY

to identify ways to remain healthy and also treat diseases. IT’S THE PEOPLE who work at a medical research institute who bring it success. Their individual strengths in creativity, leadership, vision and project management enable the successful pursuit of research programs focussed on specific health problems. Within the following pages, you will find details and progress reports of

penelope clay

He following pages show how researchers at the Garvan Institute, one of Australia’s leading medical research facilities, are helping to find solutions for a range of common and serious diseases. Significantly, it also describes how the Garvan’s research findings are being translated into practical outcomes for patients. The importance of translating knowledge gained from medical research into practical benefits was highlighted as a key challenge by the experts of the McKeon Committee, in their recent review of Australian medical research for the Federal Government. The rising cost of healthcare was also noted as a significant issue. We are, on average, likely to live longer than our parents and grandparents. Our challenge for the 21st century is not so much to lengthen the average human life span, but to ensure our later years of life are of a high quality, free of chronic diseases that can rob us of good health. Modern medical research has the potential to achieve this goal. It enables a better understanding of how our bodies remain healthy and in good working order. And it also reveals how genetic and environmental variations can influence disease. Armed with this knowledge, we can attempt

Our challenge for the 21st century is not so much to lengthen the human life span, but to ensure our later years are free of chronic diseases that can rob us of good health. the work of Garvan researchers in five key areas: immunological diseases, such as asthma and arthritis; metabolic diseases, including diabetes; Alzheimer’s, Parkinson’s and other neurological diseases; cancer; and osteoporosis and bone biology. Diabetes is not one but two diseases, each of which has become an increasing problem in the developed world. We have drugs and the hormone insulin to relieve the acute problems of diabetes. But the longer-term complications are serious and, as yet, largely unpreventable. Bone, joint and muscle disorders – once regarded as ‘wear and tear’ diseases – are clearly more

complex than originally envisaged. They reflect interactions between tissue damage and the body’s repair mechanisms, which become impaired with age. Neurology is one of the major challenges for the 21st century: as the brain ages it causes damage to itself and this can destroy our personalities and memories, leaving us in a child-like state. Interestingly, the body’s defences against infection contribute to each of the disease processes studied at the Garvan. Inappropriate responses by our immune system appear to underlie many chronic disease states, while also leaving us more vulnerable to the consequences of infection. www.garvan.org.au

Dr Tyani Chan from the B Cell Biology group. The lab has pioneered a highly sensitive experimental mouse model that is capble of studying protective immune responses as well as autoimmune disease.

RESEARCH TEAMS and their programs are the external evidence of success at a research institute. But praise must also be given to those working behind the scenes to ensure core technologies supporting research teams are of the highest quality. Major breakthroughs in research

how cells signal each other. And, during the 1980s, the molecular biology revolution and gene cloning enabled major breakthroughs in protein production and the development of antibody therapies. The 1990s brought transgenic animals to the fore as a key resource and

We increasingly recognise each other’s skills, learn from each other’s successes and share the credit between those involved in making significant improvements in human health. generally stem from early adoption of new core technologies. And these have changed in major ways since the Garvan was established. During the 1960s, for example, the ability to grow cell lines from human cells in the lab enabled breakthroughs in biochemistry. A decade on, protein chemistry drove progress in understanding

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helped reveal the extent to which genetic errors contribute or initiate diseases. The turn of the millennium ushered in the era of genome sequencing and gene mapping began, linking disease predisposition to particular inherited gene variations. The 2010s promise a focus on

proteomics and systems biology. These will link together previous technologies to explain how gene variations combine with environmental challenges and infections to cause particular disease in individuals. It is, however, also the era of translational and personalised medicine with treatments increasingly being fine-tuned to problems causing disease in particular patients. RESEARCH IS COMPETITIVE. So why am I, as head of one research institute, writing in praise of the work of another? It’s not hard to answer. Although institutes and research teams might prefer not to do so, it’s a necessity that they compete for the limited funding pool available for their work. Individual researchers, on the other hand, love to collaborate and that is the key to solving health problems through research. We increasingly recognise each other’s skills, learn from each other’s successes and share the credit between those involved in making significant improvements in human health. Medical research programs of high international standard, such as those of the Garvan, are now generally collaborative. I look forward to there being sufficient funding for medical research to enable all those with the talent and inclination to help fight the war against disease. When that happens the time and effort expended on competing for research funds can be reduced, and we will be free to collaborate on achieving the benefits from medical research that the community deserves. Prof Ian Frazer is the co-inventor of the human papillomavirus vaccine for cervical cancer and Chief Executive Officer and Director of Research at the Translational Research Institute in Brisbane. GARVAN 50-YEAR ANNIVERSARY

immunologY DIVISION

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The fight back: preventing disease The immune system has evolved extraordinarily effective ways of defending us against disease. By understanding the system in great detail, Garvan researchers are pinning down where and why it sometimes fails us.

N SPRING 2012, in a basement laboratory in the Garvan Institute, Dr Tri Phan was chasing immune cells with a laser. It was afternoon and the immunologist, with his colleague Dr Tatyana Chtanova, had already spent that morning staring intently into a specialised microscope, struggling to follow the erratic movement of a fuzzy, green blob across the screen. Their attention was focussed on a B-cell, part of the immune defences that protect us against infection.

operations remain a mystery. How do cancers and infectious diseases get around the protection it offers? And why does the immune system, which is supposed to defend us against infection, sometimes turn on the body’s own tissues and attack them, triggering autoimmune diseases such as rheumatoid arthritis, lupus and type 1 diabetes? At the Garvan, about 80 scientists under the leadership of Professor Robert Brink, have been trying to provide answers

If successful, the Garvan scientists would become the first in the world to view the immune system in such detail, a development of profound importance. Phan had spent months working out how to track the movements of single B-cells as they worked to protect the body against invading microbes. If successful, the Garvan scientists would be the first in the world to view the immune system in such detail, a development of profound importance. Each of us owes our survival to our immune system. It protects us against a constant barrage of bacteria, viruses, fungi and other invaders. Yet many aspects of its 42

GARVAN 50-YEAR ANNIVERSARY

to these questions. They are using sophisticated genetic and molecular techniques to probe how the body responds to tumours, infections and autoimmune malfunctions. The benefits are clear, says Brink. If we improve our understanding of the immune system, we could boost its operations and create many new treatments for diabetes, asthma, cancer and other widespread ailments. And one of the key gaps in our knowledge of the immune

system has been our inability to follow individual cells on protection patrol and watch where they travel in our bodies and how they interact with other cells. HENCE PHAN’S EFFORTS. He wanted to find out how to distinguish one tiny, individual cell from all the millions of others in the body. That specificity would be critical. Phan used a fluorescent protein called Kaede, which Japanese researchers isolated from coral a decade ago. Of course, fluorescent proteins are routinely used as tags in genetic studies, but Kaede – named after the Japanese maple leaf – is special. It fluoresces green in normal circumstances but turns red, irreversibly, when exposed to ultraviolet light. Phan’s idea was to use Kaede to make a large number of immune cells fluoresce green and inject them into an anaesthetised mouse. This part of his experiment had gone well. The mouse was sleeping peacefully and the green cells were visible in its skin beneath the powerful microscope that allowed the team to study the mouse’s living tissue. CONTINUED ON PAGE 44

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immunologY DIVISION Professor Basten’s discoveries have profoundly changed our understanding of the body’s immune system.

Emeritus Professor Antony Basten

ao FAA

Profile

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Lauren Trompp

ECOGNISED internationally as the “driving force” behind the Australian model of clinical immunology – now also operating in Britain – Professor Tony Basten has long advocated the importance of marrying clinical practice with research. It’s a successful mix, and one that no doubt stems from his early training in research and clinical medicine. Basten graduated from the University of Adelaide in 1964, then trained as a physician before completing a PhD at the University of Oxford in Britain. He then returned to Australia to work at the Walter and Eliza Hall Institute in Melbourne, at a time when immunology was “really taking off as a significant discipline,” he says. In the early 1970s, he took a position at the University of Sydney, working there until 2005. In 1979, his immunology unit was one of the first 10 research groups to be awarded a Commonwealth Centres of Excellence grant. Basten was counted among the top 1,000 scientists in the Citation Index in 1983 (one of just seven Australians), and received the inaugural Wellcome Australia Medal in 1980 and the Centenary Medal for service to Australian society and immunology in 2003. He is also a Fellow of the Australian Academy of Science and the Australian Academy of Technological Sciences and Engineering. Having served as the inaugural executive director of the

University of Sydney’s Centenary Institute of Cancer Medicine and Cell Biology from 1989 to 2005, he now works as a senior principal research fellow in the B Cell Biology group of the Immunology division at the Garvan Institute. His scientific record is similarly impressive. In 1968, Basten discovered the mechanism that releases eosinophils (white blood cells) from bone marrow. Eosinophils are important for protection against parasitic infection and as mediators in allergic reactions. And in what he describes as a “serendipitous” result, in 1971 he discovered Fc receptors, which enable antibodies in the bloodstream to attach to cells, greatly amplifying the body’s capacity to fight infection. This discovery sparked an avalanche of further research, greatly increasing our

understanding of how immune responses are controlled. Basten is currently investigating the mechanism that allows intravenous immunoglobulin (a pool of antibodies from healthy people) to treat a variety of inflammatory conditions. In his time as a researcher, Professor Basten has seen the field of immunology progress rapidly. Immunology has a “profound impact” on ideas about disease causation and the development of novel treatments, he says, most recently in the form of antibody-based therapeutic drugs. “One in three new drugs that come on the market are now antibodies. So this is having a profound impact in medicine and will continue to do so. The future for immunology is very bright,” he adds. – Cherese Sonkkila GARVAN 50-YEAR ANNIVERSARY

immunologY DIVISION

SHANE T GREY

Insulin-producing beta cells in red

after two and a half minutes, glimmers of red started to appear, like fireworks. The cell that had been green was now fluorescing red. “The first thing that crossed my mind was that all those years playing computer games had finally paid off!” says Phan. With this remarkable new tool at their disposal, the researchers could begin to visualise aspects of the immune system in a way that had never been done before. Immune cells move around the body with purpose. “It’s a whole new picture of the immune system,” says Brink. New insights into how the immune system responds to vaccinations, and how immune system cells move along the surfaces of bones have already emerged from the Garvan research. “We can address very fundamental questions about how the immune system works,” Phan says. “It’s really exciting.”

under attack from T cells in green

GARVAN 50-YEAR ANNIVERSARY

in a pancreatic islet.

Scanning electron micrograph of an immune cell.

PENELOPE CLAY

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The next part was trickier. Phan wanted to switch a single cell from green to red by shining a UV laser onto it. However, the laser had to be gentle enough not to damage the cells. Because the light they had to use was weak, Phan and Chtanova would need to keep their laser focussed on an individual cell for about three minutes to get it to switch colour – and that was proving easier said than done. “We had been trying all morning, and failing,” Phan remembers. “So we went out for a long lunch to clear our heads and have a cup of coffee before we tried again.” Refuelled and back in the lab, Phan took the controls of the laser while Chtanova served as navigator. As the target cell moved around in the mouse’s tissue she called out directions: “Up a bit. Left. More. Hang on, right. Deeper.” The seconds ticked by. Slowly, they realised that they were keeping their prey in focus. After about a minute, most of the green fluorescence had gone from the cell they were tracking. Another minute passed. The team held their breath. Then,

THE YOUNGEST OF THE Garvan’s research divisions, the Immunology division was founded in the late 1990s from a bequest that provided funds to improve our understanding of inflammatory diseases such as rheumatoid arthritis, a painful and debilitating disease that affects around 400,000 Australians. Since then, the research program has widened its scope to include detailed study of the many different cells of the immune system and a wider range of diseases. In recent years, Garvan breakthroughs have included the identification of the chemical messenger that is the main driver of successful antibody responses in our immune systems and the discovery of the role of several genes in the development of asthma. Like Phan’s work, many of the program’s recent discoveries have unveiled fundamental aspects of the immune system directly applicable to human health. For example, an antibody treatment developed by Garvan researchers for diseases such as rheumatoid arthritis promises to benefit millions of people worldwide. In 2008, Garvan researchers identified a possible way to treat extreme allergic reactions after identifying how two molecules www.garvan.org.au

Garvan IS GRATEFUL TO Mr Greg Paramor and Mrs Kerry Paramor

Garvan scientists Dr Umaimainthan Palendira (left) and Associate Professor Stuart Tangye.

working together stimulate the production of large amounts of a class of antibody known as IgE. The IgE antibody is usually present in only very small quantities. It becomes damaging when the body makes too much and triggers an allergic reaction. The Garvan team found that when two interleukins (types of cell-signalling molecules)

This serious, lifelong disease affects thousands of Australians. It develops in childhood when cells in the body's immune system errantly attack and destroy specialised cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. Lacking these cells, people with type 1 diabetes are reliant on

The crucial point is that with this remarkable new tool at their disposal, the researchers could begin to visualise aspects of the immune system in a way that had never been done before. known as IL-4 and IL-21, are involved in the same ‘conversation’ with a B-cell, they stimulate the production of large amounts of IgE – around 10 times more than either molecule in isolation. The study suggests it should be possible to target the IL-21 molecule with an antibody to block its ability to activate B-cells. This may prove an effective treatment in cases where allergic responses are caused by the synergistic effect of the two signals. From their labs on the 10th floor of the Garvan building, Associate Professor Shane Grey and his team have recently made a set of exciting breakthroughs that could transform our ability to treat type 1 diabetes.

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daily injections of insulin to keep them alive. One promising treatment for type 1 diabetes is to transplant insulin-producing cells from a healthy person into a diabetic patient. However, researchers have found that the recipient’s immune system often rejects the transplanted cells, meaning the treatment fails. To try and overcome the problem of transplant rejection, doctors and researchers have tried using drugs to suppress the recipient’s immune system – however these drugs can result in serious toxicity and even cancer in some cases. The Garvan group has taken another approach to preventing transplanted cells being

It was a Garvan Research Foundation dinner about 15 years ago that first brought Greg and Kerry Paramor into contact with the Garvan Institute. The calibre of the science and scientists immediately impressed the property industry expert, and “that was the start of the journey,” he says. The Paramor family decided the Garvan would be a regular part of its giving program, which includes contributions to conservation and the arts as well as Youth at Risk via the Property Industry Foundation. “We have a belief that you should put back in,” says Paramor, the managing director of property funds manager and developer Folkestone. Eleven years ago, Paramor was asked to join the Garvan Institute Board of Directors, and he says learning more about the institute’s work “blew him away”. “When you come from a commercial background you’re used to measuring things such as profit and loss in monetary terms. This opened up my mind to another world where benefits are about the social dividend, measured by the wellbeing of the community in question – not just the eureka moments of medical research, but also the steps along the way,” he says. The Paramors have most recently been involved in funding The Kinghorn Cancer Centre, a joint facility of the Garvan Institute and St Vincent’s Hospital, that translates cutting-edge medical research directly into patient treatments. “In the history of research advancement, this is perhaps a tipping point where we can accelerate the impact of medical research – and that really excites Kerry and me. I think in terms of giving – if you can in whatever capacity – now is a better time than ever before.” – Heather Catchpole

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immunologY DIVISION

Research by Garvan scientists Dr Tri Phan and Dr Tatyana Chtanova have opened up a new way of visualising the immune system.

rejected. Instead of focussing on dampening down the immune system, they have figured out a means of stopping the transplanted cells from releasing signalling chemicals that induce immune cells to attack them. Through careful analysis of insulin-producing cells, they have identified a kind of “master controller” gene, called A20. The potential benefits of manipulating this immune controller gene are enormous. “It’s super-exciting stuff,” says Grey. “This gene not only reduces the number of immune-stimulating molecules the transplant releases, but also encourages the release of molecules that induce a phenomenon called ‘tolerance’ – a system that leads the body to leave the transplanted cells alone.” In mice, the researchers have already shown that increasing the expression of this gene can dramatically improve the success rate of transplantation. Together with Swedish colleagues they’re now ready to begin human trials. If those trials bear fruit, it could mean a better life for millions of people with type 1 diabetes around the world. 46

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Another approach with a huge potential to improve health that’s being developed by Garvan researchers is antibody engineering. IL-21 featured in another Garvan breakthrough made by Dr Cecile King and PhD student Alexis Vogelzang. While IL-21’s role in the immune system was

by Garvan researchers is known as antibody engineering. More than one in three drugs in pharmaceutical development are antibodies. However, in molecular terms they are large and fragile. Many promising antibodies never make it to the market because they are not stable enough for production in large amounts, injection into patients and longterm storage. Those that do make it to market require a lot of time and money to turn them into useful drugs. Dr Daniel Christ and his colleagues at the Garvan are collaborating with a range of companies to make antibodies stronger and easier to work with – improvements that could reap billions of dollars worth of savings. Recently, the team garnered worldwide attention when they published a paper in the journal Proceedings of the National Academy of Sciences, which described particular mutations in genes involved in the manufacture of antibodies that altered their

An antibody treatment developed by Garvan researchers for diseases such as rheumatoid arthritis promises to benefit millions of people worldwide. well known to immunologists, King and Vogelzang showed the molecule also plays a key role in the development and survival of T follicular helper (TFH) cells. These cells play a critical role in communicating with and activating B-cells to produce highaffinity antibodies that fight off infection. Without IL-21, TFH cells wouldn’t survive. “Without IL-21, we probably wouldn’t be completely immunodeficient, just severely compromised,” says King. “These [TFH cells] are the only ones that can move into the B-cell zone and initiate high affinity antibody production.” Another approach being developed

structure, making them more stable. “It was a fundamental change that we showed could apply generally to the antibody repertoire,” Christ explains. “That’s been a great success.” IN MARCH THIS YEAR, Robert Brink and fellow Garvan researcher Dr Dominique Gatto revealed how immune system ‘gatekeepers’, known as dendritic cells, halt invading microbes in the spleen and digest them. Once these dendritic cells have captured viruses or bacteria, they go on to deliver molecular information about the invading microbes CONTINUED ON PAGE 48

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Professor CHARLES MACKAY FAA

MONASH UNIVERSITY

immunologY DIVISION

Profile

T ISN’T SURPRISING that Professor Charles Mackay forged a successful career in immunology. His father, Ian Mackay, is considered one of the founders of autoimmune disease research. Charles Mackay has contributed to the field significantly in his own right, making several important breakthroughs in his nearly 30-year career. Like his father, Mackay attended Melbourne Grammar School. He then completed a Bachelor of Science at Monash University in 1980, followed by a PhD at the University of Melbourne with the department of veterinary science. For his PhD, completed in 1987, Mackay used sheep as a model to study the way a group of white blood cells, called lymphocytes, travel through the body, seeking out and fighting infections. He continued this research at the Basel Institute for Immunology in Switzerland. In Switzerland, he discovered that once a lymphocyte has encountered an antigen or pathogen, the way it travels around the body changes. These differing migration pathways are associated with different functions of the white blood cells, and increase the efficiency of the immune system. It’s now part of textbook science. Mackay spent the next seven years in the biotechnology industry in Boston, U.S., applying his research to the development of new therapeutics. “I went from basic understanding of how cells migrate, to more mechanismbased research,” he says. “What are the molecules responsible, what

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happens when you inhibit them, and can you make a drug?” Mackay returned to Australia in 1999 and joined the Garvan, where he led the Immunology division for 10 years. At the Garvan, he developed an antibody for a molecule associated with inflammation, called the C5a receptor. Seeing the potential for a new treatment for autoimmune diseases associated with chronic inflammation, particularly rheumatoid arthritis and lupus, a spin-off biotechnology company called G2 Therapies was formed in 2002. In 2006, after promising results in mice, G2 Therapies signed a US$118 million licensing agreement with Danish pharmaceutical giant Novo Nordisk, and human trials began in 2008. Mackay, who remains a major shareholder, board member and scientific consultant at G2 Therapies, says he is eagerly awaiting the results.

A lifelong career in immunology has seen Professor Mackay change the basic understanding of how our cells function.

Towards the end of his time at the Garvan, Mackay’s research moved in a new direction. In October 2009, he co-authored a paper in the journal Nature, revealing a link between gut microbes and inflammatory diseases, including asthma. The notion that what the bacteria in our guts digest could be driving inflammatory diseases was groundbreaking at the time. Now head of the immunology laboratory at Monash University, Mackay is continuing his research on gut microbes, and says he is excited about where it could lead. The burgeoning field, he adds, could herald a paradigm shift in our understanding of the causes behind diseases from asthma to certain cancers. In 2010, Mackay won the annual Australia Award for Research Excellence from pharmaceutical and healthcare company, GlaxoSmithKline. – Gemma Black GARVAN 50-YEAR ANNIVERSARY

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This fundamental finding provides more understanding of how the adaptive immune response works. Ultimately, tHE Garvan’s immunologists hope to improve human health and prevent disease, although many of their experiments are performed in the laboratory with isolated cells or in animal models. One researcher who takes a more direct approach is Associate Professor Stuart Tangye. He is one of Australia’s leading investigators of individuals with rare and often fatal immunodeficiencies that develop when a person’s immune system fails to work properly. “We work on incredibly rare diseases, some of which might affect as few as three surviving individuals in the entire world,” says Tangye. His primary goal is to help people with these diseases and understand the genes that underpin them. In doing so, he’s also uncovering the causes of much more common autoimmune diseases such as lupus. “A lot of the genes that are mutated in immunodeficiency… also seem to be overactive in autoimmune disease,” he says. “When you have too little of one gene it causes immunodeficiency, while if you have too much it can lead to autoimmune disease.” One recent Garvan discovery illustrates the point. It relates to a condition known as X-linked lymphoproliferative disease (XLP), which affects roughly one in every one million males around the world. Boys with the condition have relatively normal immune responses to almost all diseasecausing microbes. There is just a single pathogen that triggers the disease

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to other immune cells known as T-helper cells, which in turn deliver information to B-cells, the makers of antibodies. “The parts of the spleen where these dendritic cells cluster, known as marginal zone bridging channels, are very important filtering points or portals for capturing blood-borne infections,” Brink says. “Blood seeps around the outside of the spleen, carrying antigens, and they tend to get trapped at these points, like particles in a sieve, allowing the exquisitely wellplaced dendritic cells to capture them. When you see images of the way cells cluster in the spleen, the whole system looks like a wellorganised transport hub, with a T-cell area in the middle, B-cell zones around that, and clear entry points, guarded by dendritic cells.” The researchers found that dendritic cells express a cell surface receptor known as EBI2, which is essential for the cells to marshal where they’re needed. “Remove EBI2 and you don’t have dendritic cells sitting where they have to be in order to capture antigens and activate other cells,” says Brink.

The Immunology division is the Garvan’s newest research group.

Immune research could help allergy sufferers alleviate their symptoms.

– a virus known as Epstein–Barr virus, or EBV, which is among the commonest viruses around. The cause of glandular fever, the virus is spread through kissing and also via saliva on toys or on carers’ hands. In most people, the symptoms of EBV infection include a fever, swollen lymph glands and a sore throat. Half of those infected develop no symptoms at all. But in boys with XLP, the immune system spirals out of control, and can result in bone marrow failure, liver failure and a type of cancer called lymphoma. Many boys with the condition die before their 10th birthday and most live less than 40 years. The disease posed a riddle: why would an infection of just one type of otherwise relatively benign virus trigger such a deadly reaction? Over the 14 years Tangye has been studying the disease, answers have begun to emerge. The first clue was www.garvan.org.au

the cell type that EBV infects. While hepatitis B virus infects the liver, and influenza infects the respiratory tract, EBV infects the immune system’s antibodyproducing B-cells. Under normal circumstances, B-cells that are infected by EBV are killed by another type of immune cell called a cytotoxic T-cell. Careful analysis of the genomes of boys with XLP revealed that they had mutations

molecule in individual cells. He asked an undergraduate honours student, Carol Low, to set up the experiment. Low’s first job was to test the cells of individuals who had XLP. They were to serve as ‘negative controls’ – lacking a functioning version of the gene, they would give a negative result on the test, which would help the scientists be sure the test was set up properly.

“When you have too little of one gene it causes immunodeficiency, while if you have too much it can lead to autoimmune disease.” in a gene that coded for a signalling molecule within these T-cells. Although many boys with XLP die very young, not all do. Some live into their 50s. To try to understand why, in 2009 Tangye and his post-doctoral fellow Dr Umaimainthan Palendira designed an experiment that would measure the expression of that signalling

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But Low’s results turned expectation on its head. After testing men with the disease, she found that some of their cells were producing the crucial signalling protein. “She kept saying that the cells were mostly negative but there were 5% or 10% of cells that were positive,” Tangye says. “I told her she must have done the

experiment wrong and sent her back to try again. It shouldn’t be like that.” Low tried again, three or four times, and got the same result. Eventually, Tangye and Palendira were convinced that some men with the disease were producing the signalling molecule – at least in some of their cytotoxic T-cells. All became clear when Tangye and Palendira found that the abnormal gene had in fact reverted to being normal again in some T-cells. “That was the eureka moment,” remembers Tangye. The reversion to normal in a subset of T-cells was enough to confer some protection against infection with EBV. The scientific term for the process of a mutated gene returning to its original state is ‘somatic reversion’. It is a fascinating phenomenon, which has been characterised in a handful of other rare diseases, but never before been seen in XLP. As well as explaining the mystery of the long-lived XLP patients, this discovery has wider implications. “This is clinically relevant because it tells us that you only need a small population of cells that are functionally capable of responding to EBV to give you good immune protection,” Tangye explains. “If XLP patients were to receive gene therapy in the future, it should be possible to confer some protection by getting the gene into only a small number of effector T-cells – a very targeted therapy.” If such a treatment does eventuate, it may be years away. Either way, the struggle to understand how the disease works has given scientists deeper insight into the immune system more generally. “That’s been part of the excitement of this disease,” says Tangye. “It’s been such fertile ground for discovery.” – Stephen Pincock GARVAN 50-YEAR ANNIVERSARY

immunologY DIVISION

LAUREN TROMPP

Pioneering research into ‘gene knockout’ mice is one of the ways Professor Robert Brink has contributed to studies of allergies and autoimmune diseases.

Professor ROBERT BRINK Profile

ICE ARE IDEAL animals for scientific research, but too much time spent working with them can lead to an allergy. This is what happened to Professor Robert Brink early in his research career. In a twist of irony, he later used mice in his research on the allergen response. Brink became fascinated with immunology during his undergraduate degree at the University of Sydney. The discovery that B-cells – which produce antibodies to fight infections – rearranged their genetic structure to generate antibody diversity piqued his interest in studying antibodies and B-cells, says Brink. He went on to work at Sydney’s Royal Prince Alfred Hospital with a group of researchers producing some of Australia’s first genetically modified mouse strains. “There

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was a revolution going on in experimental biology, which was particularly important for immunology,” he says. In the early 1990s, Brink’s research group at Royal Prince Alfred Hospital merged into the Centenary Institute, an independent medical research organisation directed by Professor Tony Basten. Brink developed his mouse allergy a few years later, and to have a break from working with animals, he relocated to the Whitehead Institute in Boston to research protein signalling. However, he eventually returned to the Centenary Institute, pioneering ‘gene knockout’ mice, in which individual genes were manipulated to mimic diseases in humans. In 2006 the Garvan recruited Brink to head its program investigating B-cells. The team wanted to understand what mechanisms influenced B-cells to “go out of control and lead to diseases such as lymphoma, asthma, allergies and autoimmune disease,” he says. He was awarded an NHMRC research fellowship in 2005 to further this work. In 2010, Brink was promoted to head the Immunology division

at the Garvan, but he retains his active research work. Brink is looking at ways to stop the immune system from initiating an auto-antibody response to a foreign bacteria or virus. “We’ve been able to show that there is a way for the body to stop that happening,” he says. This has important applications for autoimmune diseases, which arise when an immune response targets tissues or substances that are normal components of the body. This research has also led to insights into allergies, as Brink’s team found that IgE antibodies, a class of antibodies that can cause allergies, can form as a byproduct of some auto-antibody responses. “That’s an exciting pathway we’re looking into – if we can get an idea of how these IgE responses are normally avoided, we can get an idea of how they’re being triggered in the cases of allergens,” he says. It’s a discovery that could lead to better treatment of allergies and autoimmune diseases. For Brink, publishing findings such as these, that significantly advance the medical field, is one of the most rewarding aspects of what he does. – Cherese Sonkkila www.garvan.org.au

METABOLIC DISEASES DIVISION

Professor Ted Kraegen Profile

ROFESSOR TED KRAEGEN

never forgets when a physicist came to visit his high school class. “I distinctly remember because he took his shoe off and he put his foot with his sock on up on the table, with a big hole in it, and said, ‘of course, physicists don’t make too much money’.” Despite the warning, Kraegen was determined to study physics. “I went to high school in the era of Sputnik, putting up satellites – a golden time for physics,” he says. Kraegen undertook a physics degree at the University of New South Wales (UNSW), but a new branch, biophysics, began to grab his attention. Being able to apply his physics knowledge to biological systems saw Kraegen become UNSW’s first biophysics honours student in 1964, and he continued on with a PhD exploring feedback systems such as glucose and insulin. He collected some of his PhD data at the Garvan Institute in the late 1960s, and joined the staff in 1970. “If you count my years here as a student, I’ve been here 46 years,” he says proudly. In that time, he has gone from creating an artificial pancreas (which initially took up half a room) to discovering the importance of continuously delivering low rates of insulin into patients with very high blood glucose levels. “My theoretical work with the computer modelling suggested that low-level insulin delivery was more effective than people realised at that time. They thought you had to give much larger doses,” explains Kraegen. But insulin has

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In 46 years at the Garvan, Professor Kraegen has contributed a great deal of insight to metabolic research.

a half-life of only a few minutes, so single injections had little effect on patients, such as those with diabetic ketoacidosis, and continuous infusions quickly became the global standard of treatment. “I regard that as one of the good achievements we’ve made,” he says. “It was a nice off-shoot of our basic research at the time.” After this, Kraegen was co-awarded the first NHMRC program grant for diabetes and began developing animal models. This led to an adaptation of the ‘glucose clamp’ – not a physical clamp, but a method of infusing glucose and insulin that provides feedback on how well the body is able to maintain blood glucose

levels. It was the first time this had been done in small animals, “and it’s now used as a standard method worldwide to assess insulin action,” says Kraegen. As he looks to retirement, he says he is very happy with the changes he’s seen at the Garvan, and with the consistency over the years of its people and its culture. “I think what’s kept me here is, first, I’ve had the privilege of working with capable and smart people and I’ve benefited a lot from that,” he says. “And the aim from year to year of understanding more about how insulin works or doesn’t work has been a challenge.” – Tara Francis GARVAN 50-YEAR ANNIVERSARY

METABOLIC diseases DIVISION

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A step towards healthier lifestyles Garvan research is revealing the genetic and environmental factors that contribute to obesity and diabetes.

BESITY HAS become an epidemic in Western nations. Recent figures suggest it costs the Australian economy more than $58 billion a year, primarily by making people vulnerable to cardiovascular disease, cancer, Alzheimer’s disease, asthma and diabetes. At the Garvan, researchers work to understand the links between the environment, obesity and disease. Their ultimate goal is to help identify a path toward earlier diagnosis and prevention of all of these diseases. This work has been an important part of the Garvan’s identity since its earliest days, when a young David James ran tests for St Vincent’s Hospital to measure insulin levels in patients’ blood. In the early 1980s, James was one of just two PhD students at the Garvan. Today, there are dozens working in many research groups and James – now a professor – is the head of the Metabolic Diseases division. After 33 years studying diabetes, Professor James knows only too well that metabolic processes are far from simple. “If we’re to understand a complex disease like diabetes, we’ve got to be able to bring it to the level of understanding we have for motor vehicles. You should be able to go

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down to your garage, take your car apart, put all the pieces on the floor and put it back together again. We need to be able to do the same thing with the cell.” To help drive home his message, James keeps on his office wall a print of The Last Judgement, a painting by 15th-century Dutch artist Hieronymus Bosch. Surreal, and more than a little grisly, the image shows a host of unfortunates being tortured by an assortment of demons. Bosch probably intended his painting to be a warning to sinful Christians. James uses it for a different purpose. “When a new PhD student starts up, I bring them in and say, ‘this is your life for the next few years’.” EVERY single DAY, an estimated 280 Australians develop one of the diseases known collectively as diabetes. Some may have no symptoms at all, at least at the start. Others might begin feeling excessively thirsty, or tired and lethargic. Perhaps they will experience headaches and mood swings. Their cuts may heal slowly, or itchy infections may attack their skin. With or without symptoms, a person with diabetes is suffering www.garvan.org.au

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A fat cell shown in a coloured scanning electron micrograph. Body fat is a key factor in type 2 diabetes.

a disruption in one of the major biological systems within their body. Without treatment, it is a disruption that can lead to serious illness and death. Put simply, diabetes occurs when the body’s system for converting glucose from food into energy goes awry. For our bodies to perform this vital task, we need insulin, a hormone produced in the pancreas that regulates the amount of glucose in the blood. There are two major forms of diabetes. In type 1 diabetes, which is usually detected in children and young adults, the body does not produce insulin. The exact cause of type 1 diabetes is not yet clear, although scientists know it is an autoimmune condition, has a strong family link and it cannot yet be prevented. In type 2 diabetes, by far the most common form of the disease, either the body does not produce enough insulin, or the body’s cells ‘ignore’ insulin – a condition known as insulin resistance. Type 2 diabetes is often referred to as a lifestyle disease, because it is promoted by a poor diet,

obesity, lack of exercise and having an ‘apple-shaped’ body, where extra weight is carried around the waist. Researchers at Garvan’s Metabolic Diseases division work to understand the fundamental body changes leading to type 2 diabetes in the hope of developing better treatments.

The key difference between these last two groups was the sensitivity of their cells to insulin. When cells lose their ability to respond to insulin, they stop absorbing glucose, and the body pumps out more of the hormone in an effort to control blood sugar levels. This development of insulin resistance is one of the earliest features of type 2 diabetes. In one group of non-diabetic obese participants, this insulin resistance was apparent. In the other, their cells were still sensitive to insulin. “We were trying to work out which parts of the insulin signal pathway were defective in insulin-resistant cells,” Tonks explains. “By studying overweight people with and without insulin resistance, we could figure out whether the molecular changes were a result of fat or insulin resistance.” The aim was to take muscle biopsies from the participants and examine the various molecules that were altered in a cell exposed to insulin. But the study was proving difficult. First, Tonks

A person with diabetes is suffering a disruption in one of the major biological systems within their body. RESEARCH suggests that overweight individuals who do not develop type 2 diabetes tend to have less fat around their liver and other organs than would be expected for someone of their weight. They also appeared to have differently sized fat cells. To find out why, Garvan researchers Associate Professor Jerry Greenfield, Dr Katherine Tonks, and colleagues have studied the effects of insulin on muscle cells from lean people without diabetes, people with diabetes, and two groups of people who were obese, but didn’t have diabetes.

had to develop a new method for taking muscle biopsies because the traditional approach took too long, causing some delicate proteins in the cells to degrade before they could be tested. Then, when the researchers put out a call for volunteers, they were flooded with responses from people with diabetes, while their quota of participants without the disease took months to fill. “I believed my PhD supervisor, Associate Professor Jerry Greenfield, when he said this was one-year project,” says Tonks. “I was naïve.” CONTINUED ON PAGE 55

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METABOLIC diseases DIVISION

Professor Trevor Biden

A major contributor to diabetes research, Professor Biden is optimistic about our ability to improve treatments.

Profile

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Lauren Trompp

FORTUITOUS combination of events led Professor Trevor Biden to spend his career investigating type 2 diabetes. When the biochemist applied for an Honours project as part of his undergraduate degree at the University of Sydney, a place in the head of department’s diabetes project was vacant because its star recruit had just left to study medicine. When his supervisor, Keith Taylor, returned to Britain to continue similar diabetes research, Biden tagged along, undertaking his PhD at the University of London. After completing a postdoctoral fellowship at the University of Geneva Medical School in Switzerland, he was awarded a Queen Elizabeth II fellowship in 1987, enabling him to return to Australia to work at the Garvan Institute. Now the director of the Diabetes Signalling Unit and group leader of Garvan’s Cell Signalling group in the Metabolic Diseases division, Biden has made major contributions to diabetes research. Type 2 diabetes, the most common form of the disorder, is associated with deficiencies of and resistance to insulin. In the mid 2000s, Biden identified a mechanism that contributes to the loss of insulin-producing cells (beta cells) in people with type 2 diabetes. He found that when the transport of insulin within the cell itself is disrupted, it leads to programmed cell death. More recently, he found that inhibiting an enzyme called PKC restores insulin secretion that was once defective.

Biden says that the limited understanding of exactly how beta cells fail in diabetes is a big gap in terms of developing suitable therapies. “We’re using these models of beta-cell failure to try and push them to extremes, and tinker around with the various pathways that are involved to try to get a better handle on what’s causing that failure,” he says. Beta cells were paid very little attention in research until the past decade, says Biden. It used to be thought that the major defect of type 2 diabetes lay in insulin’s mechanism of action. Yet over time, a growing weight of

evidence, some of it contributed by Biden, has made it clear that the production and release of insulin by beta cells plays a crucial role in this common illness. Understanding this process better could be of great benefit. “There are some old drugs that have been around for a while and there are some newer ones that are coming through, but there’s nothing that specifically addresses this defect in the release of insulin,” he says. With 25 years at the Garvan behind him, Professor Biden is hard at work trying to solve these problems. – Cherese Sonkkila www.garvan.org.au

METABOLIC diseases DIVISION

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Around 280 Australians develop diabetic illnesses every day.

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Once she had finally recruited enough people for her study, and had taken biopsies from all 80 participants, Tonks began to analyse their molecular processes with the help of researchers from James’s laboratory – and quickly produced some intriguing results. She found that not all of the functions of insulin were defective in resistant cells. Some insulin regulated molecules were inactivated by excess weight, others not. This tantalising finding needed to be followed up, so Tonks and her colleagues started to analyse the activity of several different molecules to see if they were differentially resistant to insulin. Analysing the results of this experiment in 2010, she noticed something strange was happening with a molecule called FOXO. FOXO proteins play a vital role in cleaning up damaging molecules called reactive oxygen species. Scientists already knew that insulin turned off the actions of FOXO. In healthy individuals, this isn’t an issue because insulin levels are only elevated for a short time each day, leaving FOXO active the rest of the time. The surprise was that in Tonks’s study, FOXO was chronically inactive in participants with

insulin-resistant cells. Even though the cells were resistant to insulin, which should have meant that FOXO was permanently active, somehow insulin was still ‘switching off’ this important junk-disposal molecule. The finding meant that even in cells that are resistant to insulin, some of insulin’s functions remain active. “My first thought was, ‘I’m the only person in the world who knows this right now’,” Tonks recalls. “My second was, ‘now I had a whole new set of questions to answer’.” Tonks and her colleagues are still asking questions about FOXO.

Dr Katherine Tonks’s research is pointing to a new way of thinking about diabetes and other diseases associated with obesity.

James believes the finding will point to a new way of thinking about diabetes, and potentially other diseases associated with obesity. “In the pre-diabetic state, we predict that this junk disposal unit is completely blocked,” he says. “If we could find a way of keeping FOXO switched on in the appropriate organs, we might be able to keep the system healthy.” ONE OF THE real strengths of the Garvan’s Metabolic Diseases division is the wide range of approaches used by its scientists. “We have about a hundred researchers in the program, and we’re unique because we cover the full spectrum from basic research on small molecules and bits of DNA, all the way through to cells, animals and humans,” says James. This means Garvan researchers can take fundamental research discoveries from the laboratory into a clinical research setting where potential new treatments and diagnostic tests can be created. In general, the division focusses on two areas. One concerns the problem of insulin resistance. The second looks at the organ that produces insulin, the pancreas.

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The pancreas is a factory for insulin, the hormone that regulates blood sugar levels.

This latter part of the diabetes equation concerns Professor Trevor Biden and his team. The association between type 2 diabetes and obesity is well documented. However, only around 20% of obese people develop full diabetes, where their blood glucose levels and body’s ability to use glucose are impaired enough to meet the diagnosis of the disease, Biden explains. “These people have had a failure in either the release or the production of insulin. There is a separate genetic defect that underpins that, and we don’t really understand what it’s all about.” Trying to solve this mystery has involved Biden in research on beta cells – insulin-producing pancreatic cells – in laboratory animals and specimens of 56 GARVAN 50-YEAR ANNIVERSARY

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METABOLIC diseases DIVISION

human pancreas. These studies have revealed two fundamental processes that lead to beta cell failure. In the first process, an oversupply of fat blocks the movement of insulin within the cell. “This blockage sends a signal

long known this process can be disrupted in diabetes, but their efforts to pinpoint the site of that disruption had failed. That string of failures ended recently when Biden, together with a team led by the Garvan’s Dr Carsten SchmitzPeiffer, discovered that an enzyme called PKC epsilon plays a key role in stopping insulin secretion. The discovery of PKC epsilon’s role in diabetes was a piece of scientific serendipity. The Garvan team had suspected the protein was important in insulin resistance, so they bred a strain of mice lacking the gene for PKC epsilon and found that the mice were indeed protected from developing insulin resistance. But the team were still “scratching their heads as to what the mechanism was because we couldn’t understand it,” Biden says. The breakthrough came when the researchers switched from studying the levels of insulin in the blood of mice and turned to another molecule, called C-peptide. When insulin is released from the pancreas, cells in other parts of the body quickly take it up. That makes it difficult to measure. To overcome this, scientists instead measure C-peptide, which is released by the pancreas in the same ratio as insulin but, unlike insulin, isn’t

“We’re unique because we cover the full spectrum from basic research on small molecules and bits of DNA, all the way through to cells, animals and humans.” to the cell that there is something really wrong here and that it needs to ‘commit suicide’,” he explains. The other mechanism that leads to beta cell failure is a loss of insulin secretion. Under normal circumstances, insulin is released from beta cells when we digest food, and glucose levels in the blood increase. Scientists had

taken up by other body tissues. When the mice that lacked PKC epsilon were fed high-fat diets, they became fat and insulin resistant, but failed to develop diabetes. Instead, they produced extra C-peptide, an indication their pancreas was producing insulin in greater amounts to CONTINUED ON PAGE 58

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Lauren Trompp

One of the Garvan’s strengths is its links between clinical practice and research, something Professor Campbell takes full advantage of.

Professor Lesley Campbell AM Profile

ROWING UP IN psychiatric hospitals isn’t the most normal childhood experience. But for Professor Lesley Campbell, seeing her psychiatrist mother’s care for her patients was a spur to pursue her own career in medicine. After finishing a medical degree at the University of Sydney, Campbell worked at several hospitals – even giving paediatrics a go – before landing at St Vincent’s Hospital in Sydney with an interest in endocrinology. The appointment came with a research component and, before long, Campbell was thrown into Professor Ted Kraegen’s artificial pancreas work at the Garvan Institute. Campbell started as a registrar at St Vincent’s in 1975 and concurrently began endocrinology research at the Garvan. Since then, she has taken

on numerous projects at Garvan and at St Vincent’s Diabetes Centre. “It’s very female,” she jokes about the workload – which is no laughing matter. She began her career when there were few other women in science, let alone benefits such as maternity leave. She still remembers going home after work and doing calculations with “the baby on one knee and the calculator on the other”. One of Campbell’s main projects has been a study of individuals whose family members have developed type 2 diabetes. Her research aims to explain the genetic reasons why relatives of people with diabetes are more likely to be overweight, overeat and put on weight. By looking directly at healthy relatives, her studies also help these people by identifying risk factors early and prescribing treatments and lifestyle change where indicated. “We find abnormalities years before they’ll get diabetes,” she says. Due to a heartfelt request of an elderly man to help his twoyear-old grandchild, Campbell also spent time recently testing a

therapeutic treatment for Prader– Willi syndrome, the most common genetic disorder that can cause severe obesity. Her hunch about using an existing diabetes drug to treat Prader–Willi for a short period was a success, and full clinical trials for this application of the drug are now underway in the U.S. She is also looking at how people with type 2 diabetes inherit ‘fatness’, and at ways to relieve stress and lessen secret drug taking in type 1 diabetes. She hopes to see another positive outcome after she reported high morbidity among young people with cystic fibrosis whose untreated prior diabetes rendered lung transplants less successful and increased mortality. The immediate potential of this study to save young lives illustrates why Professor Campbell loves the flexibility of being able to join her research and clinical work at the Garvan and St Vincent’s. “If you have done something that’s really right on the spot, you can see something happening for the patients you’re trying to help.” – Tara Francis

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counteract the insulin resistance. “We realised that PKC epsilon wasn’t working in insulin signalling, it was working on the other piece of the equation, which is what is going on in the pancreas,” Biden says. Like Tonks’s work, this finding overturned much conventional wisdom about PKC epsilon and left the Garvan group with more questions to answer. “Nothing has been simple on this project or straightforward,” says Biden. His group is now picking through a complex web of molecular reactions that relate to PKC epsilon in search of a step in the chain of reactions that could be halted with a drug. “We’re homing in on a useful drug target,” he says. “We will be able to protect people at high risk of developing diabetes from losing the ability to produce insulin. Fine-tuning insulin production in this way is a big advance on current drugs targeting the pancreas, which can overstimulate beta cells and so reduce the effectiveness of insulin.” IT’S ALSO CLEAR in the Garvan’s research into diabetes and obesity that the diseases result from an interaction between a person’s genes and 58 GARVAN 50-YEAR ANNIVERSARY

the environmental factors that affect their body, such as diet and exercise. “The challenge is to figure out the genetic factors that predispose us to develop certain diseases, and to understand how they interweave with the things that we all are exposed to in our lives, particularly food,” says James. Tackling these questions will involve going beyond the old approach of studying one molecule at a time. Instead, researchers need to understand how these single molecules

Lifestyle factors, such as overeating, are only one part of the diabetes puzzle. Research into the enzyme PKC epsilon (above left) shows it also plays a role in developing diabetes.

multiple copies of between 10,000 and 12,000 protein types, which communicate with each other using various methods, the most common of which is a process known as phosphorylation. Phosphate molecules are added to proteins to convey information, thus changing the protein’s function. These changes represent one of the most important changes in regulating a cell’s biological processes. James and PhD student Sean Humphrey discovered 37,248 phosphorylation sites on 5,705 different proteins, 15% of which changed in response

The Garvan team [provided] a comprehensive blueprint for understanding what goes wrong in diabetes. combine into the complex systems that allow our bodies to function. The Garvan team recently showed how powerful this kind of approach could be, by providing a comprehensive blueprint for understanding what goes wrong in diabetes. They achieved this breakthrough by using a mass spectrometer to study the changes that take place in a cell’s proteins when it’s exposed to insulin. Proteins represent the working parts of cells, which use energy to perform all essential functions, such as muscle contraction or heartbeats. Each cell contains

to insulin. “Until this study, we did not really appreciate the scale and complexity of insulin regulation,” says James. “When insulin is released from the pancreas after we eat, it travels to cells and initiates a cascade of protein phosphorylation – millions of interactions, some instantaneous, some taking minutes or hours.” Understanding this complexity opens a new window into metabolic disease, and possible future avenues for treating diabetes. “The process is precise and intricate, and at the same time monumental in its scope,” James says. “It’s truly astounding.” – Stephen Pincock www.garvan.org.au

Lauren Trompp

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The genetics revolution has allowed biochemists a far greater insight into the body, says Professor James.

Professor David James FAA Profile

WASN’T SMART ENOUGH

to get into medicine,” says Professor David James with a laugh. But over three decades, the biochemist has forged a stellar career investigating how metabolism influences obesity, diabetes and other diseases. After a PhD at the Garvan Institute in the early 1980s, James undertook postdoctoral research at Boston University and Washington University in St. Louis. He and his colleagues discovered and cloned GLUT4, a ‘transporter’ protein found in muscle and fat cells that is regulated by insulin, and published their work in Nature. “Those papers have now been cited more than 1,000 times, so they’ve been fairly popular,” he says with some understatement. After more work at Washington University and the Institute of

Molecular Bioscience in Brisbane, he returned to Garvan in 2002, where he is now the leader of the Metabolic Diseases division. James’s team uses an approach called systems biology to understand how insulin works to coordinate metabolism, by creating a ‘virtual cell’ in a computer and watching how it works. This requires characterising all the 12,000 kinds of proteins found in a fat cell. “So far we’ve identified 8,500,” says James. “With systems biology, you’ve got to be prepared to look at everything,” he adds. “Not only do we look at the proteins, but we also look at the genes, and the RNA, and how all of these change in real time in a cell as it becomes diabetic.” “The size of the data sets is a real challenge. That’s why we’ve forged some terrific relationships with both mathematicians and physicists,” says James. Wrangling these data into shape could have huge benefits for pharmaceutical production – for example, saving money by performing preliminary drug screens on a computer.

Obesity is associated not just with diabetes, but also with cancer, osteoarthritis, Alzheimer’s disease and more. The trouble is, scientists don’t know which obese people are at highest risk. “There are a significant number of obese people in Australia who, as far as we can tell, are completely healthy,” says James. “So onesize-fits-all solutions are not the answer. We aim to come up with good diagnostics so we can stratify different obese people into different risk groups so that we can channel them into appropriate public health care outcomes.” And it’s not just about genetics; there are also lifestyle and environmental factors. “I see this as the biggest challenge for the future… understanding the interaction between genetics and the environment,” says James. He’s optimistic about the future of this research, and about the latest generation of researchers. Working with “so many wonderful, smart young people, has been a real joy,” he says. “I can’t imagine doing anything else.” – Jonathan Nally

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Professor Don Chisholm AO Profile

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Lauren Trompp

HERE AREN’T MANY scientists who openly admit their greatest achievement was related to a brothel – even if only by accident. “One of the things I’m proud of is that I had a substantial involvement in setting up the hospital Diabetes Centre,” says Professor Don Chisholm, who became the first director of the St Vincent’s Hospital Diabetes Centre in Sydney in 1980. “It was originally set up in a terrace house a few doors down the road in Darlinghurst towards Kings Cross… and it was mistaken for a new brothel opening by the local population!” Despite this, the centre was a success. Chisholm, who had worked at universities in the U.S. and at St Vincent’s Hospital in Melbourne, was part of the first team in Australia to treat patients with insulin pumps, which slowly infuse insulin into the body to provide more even blood glucose control. “The first patient we ever started on an insulin pump in the early 1980s is still going strong, still on a pump – and he has had diabetes for nearly 70 years now,” he says. The Garvan’s strongly patientfocussed research is part of its culture. “The way the Garvan is set up creates opportunity and encouragement for basic and clinical researchers to work together,” Chisholm explains. “The reason for the success we’ve had has been the close interaction between a few of us clinicians and the really top-rate scientists.” Such collaboration was key to Chisholm identifying that abdominal fat (not overall fat) is a risk factor for insulin resistance. This discovery

laid the foundations for a related but more unusual health issue – early HIV drugs killed fat cells in the arms, legs and periphery but didn’t affect abdominal fat cells. This meant there was a high chance of people with HIV developing insulin resistance, then diabetes. “The first three papers we published with Professors Cooper and Carr from the National HIV Centre on that subject have more than 3,000 citations. Usually you feel fantastic if you get 100 or 200 citations,” he says.

Professor Chisholm was part of the first team in Australia to treat patients with insulin pumps.

Chisholm is expecting big things to come of recent work looking at molecular pathways that become hyperactive in the presence of insulin resistance, when the pancreas over-produces insulin. These are incredible achievements for someone who first came to the Garvan in 1967 to learn some new assay techniques before beginning work as a physician. “But once I got involved in the research I really got stirred up about it, and 45 years later I’m still at it,” he says. – Tara Francis www.garvan.org.au

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Lauren Trompp

Doing something that’s important for human health drives Professor Cooney’s research into obesity.

Professor Greg Cooney

Profile

“I

WAS ALWAYS interested in scientific things,” says Professor Greg Cooney. This interest was no doubt helped along by having a biochemist for a school science teacher and an uncle who was a microbiologist. After gaining a PhD in biochemistry from the University of Sydney in 1980, he spent four years at the University of Oxford, then 12 years at the Royal Prince Alfred (RPA) Hospital in Sydney. “While I was at RPA, I started collaborating with scientists who were working at the Garvan,” he says. Eventually he joined them, and he is now deputy director of the Garvan’s Diabetes and Obesity division. “I’m interested in the way we get energy from our food and what our tissues do with it, and whether that can be manipulated to save us all from

dying young because we’re too fat,” he explains. One mystery of obesity is why some obese people seem reasonably healthy, while most have many health problems. “The difficulty is trying to find out why one person can carry extra weight and it not be a burden to their health, while someone else who carries a similar amount of weight is unhealthy,” says Cooney. Obesity “costs billions every year,” says Cooney. “Almost every month, there is a new association between obesity and the incidence of some disease” – including cancer, diabetes, arthritis, asthma, heart disease and dementia. “One reason that most obese people tend to have metabolic problems like cardiovascular disease, liver disease and diabetes, is because they have a lot of fat in tissues where it isn’t normally stored in a lean person,” Cooney explains. So his team is trying to find ways to help burn off excess fat by subtly increasing our energy expenditure, while we sleep, for instance, and

especially for those who have limited ability to exercise. One outcome of his team’s research in collaboration with Professor Roger Daly is the discovery that the absence of a protein called Grb10 in mice results in bigger muscles. Muscles are the body’s largest users of glucose and fat, so if a drug can be found to inhibit Grb10, and thereby increase muscle mass, it could be a way for the body to ‘burn’ glucose and fat more effectively. It also has implications for those with other muscle problems. “If you could manipulate the Grb10 gene, or you knew the processes that were being manipulated by the Grb10 protein it might help some of the problems of muscle wasting in elderly people,” Cooney says. Investigating these kinds of problems is a challenge Professor Cooney loves, and the Garvan is “a great place to work,” he says. “There’s a family feeling. Although we may work on different diseases there is one goal: doing something important for human health.” – Jonathan Nally

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NEUROSCIENCE DIVISION

Inside our most intricate organ The complexity of the human brain continues to amaze us. In understanding the brain’s fundamental function, Garvan’s Neuroscience division has revealed some surprising benefits.

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to do with how our bones grew, or affected how strong or weak they became during our lives. The prevailing wisdom was that only three things affected our bones: body weight, levels of calcium and other minerals in our tissues, and our hormones. But not the brain. IN HIS EXPERIMENTS, Herzog had bred a strain of mice that lacked the gene for a specific receptor for NPY, called Y2, which is mostly found within the brain. After his chat with his colleagues in the bone lab, Herzog left them a request: when you have time, please take a look at the bones in these mice. For nine months, Herzog kept going back, but the researchers were initially too busy to explore his left-of-field hypothesis. Finally, Dr Paul Baldock, then a key member of the Osteoporosis and Bone Biology division and now group leader of the Bone Regulation group within the Neuroscience division, took time off from his research on vitamin D to examine the thighbone of the mice lacking the Y2 receptor. Examining slices of the bone under a microscope for the first time, Baldock was astounded. “I can still remember seeing the first section. It had some of the biggest bones I’d ever seen,” he says.

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NE DAY IN early 2001, neuroscientist Herbert Herzog headed out of his office on the seventh floor of the Garvan Institute to visit colleagues who were investigating diseases affecting bones and muscles. He was on a mission: Herzog wanted to change how we think about our brains and bones. But first he had some convincing to do. Herzog’s interest in the link between our neurological and musculoskeletal systems had begun in the 1990s, when he isolated, cloned and characterised a cell-surface molecule known as a neuropeptide Y (NPY) receptor. Scientists knew NPY was a signalling molecule produced in the brain – but that was about it. Herzog’s research promised to provide some answers. If you knew which cells had receptors for NPY on their surfaces, you could start figuring out where the signalling molecule was delivering its messages. Herzog had a hunch NPY had an effect on bones, and it was this idea that he wanted to discuss with his colleagues downstairs. Initially the idea was laughed off – and this reaction was understandable. In 2001, almost nobody in the scientific world thought the brain had anything

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Garvan warmly thanks THE ST VINCENT’S CURRAN FOUNDATION

Studying the neural pathways in the brain and the signals it sends to the body led Garvan scientists to a better understanding of how the body burns energy.

Somehow, removing the gene for this single brain signal receptor had a radical effect on the growth of bones. It was a startling discovery. Contrary to what almost every scientist in the world believed, Herzog and Baldock had discovered that signals from the brain affected the way our bones grow. Since then, Garvan researchers and others have gone on to describe exactly how this process occurs, and to show that NPY

the neuropeptide also plays a major role in controlling whether the body burns or conserves energy. In simple terms, their research helps explain why it can be so hard to lose weight by dieting – the less food you eat, the less energy you burn, and the less weight you lose. Herzog and colleagues Dr Shu Lin and Dr Yanchuan Shi found that NPY produced in a region of the brain called the arcuate nucleus inhibits the activation of ‘brown fat’ – one

Somehow, removing the gene for this single brain signal receptor had had a radical effect on the growth of bones. It was a startling discovery. is central to the way our bones respond to our diet, particularly to starvation. “The work we’ve done suggests that NPY is the – capital T, H, E – regulator of how the bone responds to starvation,” Baldock says. The new understanding of the role of NPY has transformed what we know about how bone strength is regulated. “It’s added a whole new control system to an organ, which doesn’t happen very often in science,” adds Baldock. And there is more. NPY’s relationship with food intake is also generating excitement among obesity researchers. In February 2013, Herzog’s group reported in the journal Cell Metabolism that

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of the primary tissues where the body generates heat. “This study is the first to identify the neurotransmitters and neural pathways that carry signals generated by NPY in the brain to brown fat cells in the body,” says Herzog. “Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight – and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs.” THE STORY OF NPY illustrates one of the strengths of the Garvan, says its former Executive Director, Professor

The St Vincent’s Curran Foundation (formerly The Curran Foundation) has been supporting medical research, patient care and clinical education on the St Vincent’s Hospital campus for nearly 30 years. The Foundation was established in 1984, at a time when a lack of discretionary funding prevented St Vincent’s Hospital from commencing its heart transplant program under Dr Victor Chang, AC. A generous donation from a grateful patient meant the transplant program could go ahead. The gift also kicked off The Curran Foundation, which was set up to create a continuing financial endowment to the hospital and to ensure that other important initiatives could be supported in the future. Charles Curran, AC, Chairman of The Curran Foundation Trustees, was also Chairman of St Vincent’s Hospital at the time. The Foundation has provided more than $18 million across the St Vincent’s campus, with more than 500 grants going towards patient care, research, equipment and education. The Foundation has supported the Garvan Institute by providing the funds to establish the Curran Foundation Library and to endow the Chair of Neuroscience Research (a conjoint appointment with the School of Medical Sciences, University of New South Wales), under the leadership of Professor David Ryugo, whose research is focussed on the field of hearing. Charles Curran says, “Clearly, the success achieved by the Garvan Institute depends upon the quality and commitment of the researchers and those who support them. They have chosen to join the Garvan because of the inspirational leadership of the Institute, the achievements of past and present researchers and their support of the principle of combining medical research and clinical care.” – Jonathan Nally

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John Shine, whose own research interests include neurological stem cells (see p82). “If you look at the Garvan’s neuroscience groups, one of the things that really strikes me is the strides we’ve made in understanding how the brain controls other systems of the body such as bone metabolism and the immune system,” he says. “This work offers hugely exciting opportunities to treat various diseases and disorders based on molecules from the brain.” Shine’s arrival at the Garvan in 1987 gave impetus to its Neuroscience division. He set up a lab studying neuropeptide receptors and worked with Herzog, now a professor and the current leader of Garvan’s Neuroscience division. The division has around 50 researchers split into eight groups who focus on areas including neurodegenerative diseases, eating disorders, hearing loss and pain. It’s a range of diseases that inflict a heavy burden on

Dr Kharen Doyle uses a ‘microtome’ to slice waxembedded tissue samples. Doyle investigates the potential of adult neural stem cells for treatment of neurodegenerative diseases.

“If you look at the Garvan’s neuroscience groups, one of the things that really strikes me is the strides we’ve made in understanding how the brain controls other systems of the body.” individuals and on our national healthcare. Obesity costs Australia some $120 billion a year, while Alzheimer’s disease cost US$604 billion worldwide in 2010. In 2013, Garvan researchers Dr Bryce Vissel and PhD student Amanda Wright made a discovery that could help improve the diagnosis and treatment of Alzheimer’s disease. Studying mice, Vissel and Wright showed that the brain plaques that have long been considered the hallmark of Alzheimer’s occur long after memory loss. “Ever since Alois Alzheimer first described this disease in 1906, plaque has been regarded as the 64

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definitive Alzheimer’s diagnosis,” Vissel explains. “The first-ever method of plaque detection through positron emission tomography was recently introduced into the clinic to assist in the diagnosis of Alzheimer’s disease – precisely because plaque is regarded as the conclusive marker for Alzheimer’s disease. Our study suggests that this method may not be accurate in earlier disease stages,” he says. Vissel’s group found that significant nerve cell loss and a range of brain problems, including inflammation, begin at the same time as subtle memory problems appear, early in the

disease process. Plaques only occur much later. “Our study supports the increasingly common view that treatment should start much earlier in the disease process. It also suggests that brain inflammation and cell loss may be an earlier indicator of disease pathology than plaque and an alternative target for treatment,” he says. ANOTHER GARVAN scientist who is passionate about helping people avoid disease later in life is hearing researcher Professor David Ryugo. After a distinguished career at Harvard Medical School and Johns Hopkins University, Ryugo recently joined the Garvan, where he leads a laboratory whose focus is on understanding the brain CONTINUED ON PAGE 66

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Lauren Trompp

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Professor Herbert Herzog expected to stay 12 months at the Garvan, but has stayed 22 years, and is investigating how the brain’s wiring could provide the key to treating eating disorders.

Professor HERBERT HERZOG Profile

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WAS ALWAYS curious to see how things worked and fascinated with what’s inside, in discovering and in thinking how you could make it better,” says Professor Herbert Herzog. That’s why, at age four, he took apart his father’s pocket watch. But his words also apply to his role as director of the Neuroscience division at the Garvan Institute, as NHMRC principal research fellow and as conjoint professor in the Faculty of Medicine at the University of New South Wales. After applying his analytical streak to a degree majoring in chemistry, then a PhD in biochemistry at the University of Innsbruck in Austria, Herzog

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joined the Garvan Institute as a postdoctoral fellow in 1991. What he thought would be a 12-month stay has now lasted 22 years, and Herzog heads around 50 staff in the Garvan’s Neuroscience division. Herzog’s contribution has been broad, but of particular note are his discoveries around neuropeptides and gastrointestinal peptides – molecules that his team has shown play a key role in appetite regulation, immune function and even bone density. How the brain is wired and what signals are sent when a person is hungry may be the answer to why some people find it more difficult to lose weight, says Herzog. By identifying and controlling these ‘switches’, he hopes to provide effective remedies to eating disorders. Gaining a better understanding of peptides – short chains of amino acids that are the building blocks of proteins – adds to a

complex puzzle Herzog is trying to solve: how the brain interacts with the rest of the body. “The brain influences pretty much all the processes that go on: the liver, heart and the muscles, because it’s the centre of where everything is coordinated,” says Herzog. “We’re trying to work out how the neural network in the brain functions.” That is, how the billions of neurons within the human brain are connected. Such a quest naturally requires a multi-disciplinary approach, and the Garvan Institute provides just that. “Garvan is a fantastic place, a rare example where it’s not just a cancer institute or just a diabetes institute,” notes Herzog. “We have a lot of diverging areas of expertise, and because I’m working with the interaction of the brain with the rest of the body, this is very advantageous for me. We can start collaborating and use the knowledge much better.” – Therese Chen GARVAN 50-YEAR ANNIVERSARY

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By mapping how pain genes appear in the genome of fruit flies, Garvan scientists are gaining insight into improving pain treatments for humans.

mechanisms involved in hearing and how hearing loss and deafness alter the way the brain’s processes are structured. Simply distinguishing human speech from background noise is a remarkable feat of neural processing, Ryugo points out. Even in his quiet office at the

says. “When you’re young with good hearing, you can do that easily. But as we lose hearing, the neural pathways that help with this process tend to fade.” Ryugo’s group traces the neuron connections linked to hearing, and explores how those connections change when hearing loss occurs.

In 2013, Garvan researchers Bryce Vissel and Amanda Wright made a discovery that could improve the diagnosis and treatment of Alzheimer’s disease. Garvan, there are many kinds of background noises to filter out – the air-conditioning whirring overhead, a motorcycle outside, the noise of a drill nearby. “Without a doubt, separating the complex waveforms of human speech from everything else we hear is one of the biggest sensory challenges our brains face,” Ryugo 66

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In Australia, just over 20% of the adult population are thought to suffer from hearing loss, and that jumps to 50% for those over 65. The impact can be dramatic. Among children, hearing loss impairs speech and language development, and can undermine academic achievement. In adults, it diminishes

employment opportunities and social functioning. “As we lose more and more hearing, the environment gets harder and harder for us to navigate, which can lead to isolation and depression,” says Ryugo. “People with hearing loss are five to seven times more likely to develop dementia.” Ryugo wants to educate the public about how to minimise the risk of these outcomes. “One of the sensory systems we take for granted is hearing,” he says. “It’s a classic example of not knowing what you’ve got until it’s gone.” PERHAPS THE MOST insidious and widespread neurological condition studied by Garvan researchers is pain. From back pain and headaches to shingles and arthritis, chronic www.garvan.org.au

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Chronic pain afflicts close to half the population at some stage in their lives. pain afflicts close to half the population at some stage. The human cost can be devastating, and the economic burden is huge. Dr Greg Neely, leader of the Functional Genomics group, is trying to track down the genetic underpinnings of pain by comparing the genomes of humans with other animals, including fruit flies. Neely is using the flies, which live inside fridge-sized incubators, to help figure out which of the many hundreds of disease-related genes will be useful for further research into pain. Remarkably, around 70% of all the genes identified so far

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in the human genome are also found in fruit flies. This means the fast-breeding flies can serve as the perfect ‘filter’ to test the usefulness of the flood of genetic data being generated by scientists around the world. “The genomic revolution is going to transform medicine in the future, but there’s just way too much data out there for us to make sense of it all,” Neely says. To sort through this data, he maps pain genes in fruit flies and cross-references his discoveries with genes that have already been identified in people.

Garvan IS GRATEFUL TO Lady Mary Fairfax Lady Mary Fairfax’s generous contributions have led to some of the most significant research being carried out at Australian medical institutions, to which she has, through the years, donated more than $10 million. Born Marie Wein in Warsaw, Poland in 1922, Lady Mary Fairfax came to Australia as a child, and in her adulthood set up a successful clothes business. She married newspaper scion Sir Warwick Fairfax in 1959, and has been active in charities since the 1950s. She has been involved with the work of St Vincent’s Hospital for decades, says her long-time friend, former Supreme Court Judge Justice Barry O’Keefe. “Lady Mary Fairfax is an incredible, generous-hearted person. She is very concerned for the welfare of those less fortunate than she has been. She doesn’t just express it in words but also through her donations. There have also been many functions at ‘Fairwater’, the family home, for the charities she supports.” Early on, Lady Mary Fairfax contributed generously to hearing loss research, one of two principal areas at Garvan to benefit from $5.46 million that she has donated to the institute since 2002, says O’Keefe. Indeed, some of her very early contributions ensured the hearing loss program was adequately funded. The other principal area of interest for Lady Mary has been cancer research. “I think, like most people, she was drawn to cancer research because cancer is the scourge of our community,” says Justice O’Keefe. Her early contributions went into prostate cancer research, and since then the research program has expanded to include a number of projects, including trying to find a cancer vaccine. “Garvan is a world-famous institute,” adds O’Keefe. “It’s brought credit to St Vincent’s and it has brought credit to Sydney as a city.” – Heather Catchpole

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Professor Peter R. Schofield Profile

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NeuRA

NE COULD SAY that a chance meeting changed Professor Peter Schofield’s life. During his agricultural science degree at the University of Sydney, an encounter with Professor John Shine in 1981 set him on a path that led him to the Garvan Institute and research on the genetics of mental illness. In the late 1970s, genetics, molecular biology and the cloning of genes were at the cutting edge of science. After graduating from his degree with a university medal, Schofield did his PhD in genetics with Shine at the Australian National University, in a lab group that worked on plant and human genes. Exposed to medical molecular biology, Schofield decided to pursue his newfound interest in receptors (proteins on the cell membrane that allow the cell to ‘talk’ with the other molecules), an interest sparked when Shine sent him to a conference in the U.S. “I realised the human field was an awful lot further ahead than the plant field,” says Schofield. At that point, Shine encouraged him to look broadly for postdoctoral opportunities. Schofield joined Genentech, a biotechnology corporation in California, then worked at the University of Heidelberg in Germany. In 1985, he transitioned into the field of neuroscience, which he felt was “beginning to emerge as an interesting area”. He returned to Australia and in 1993 was appointed a NHMRC senior research fellow at the Garvan, where for many years he

has researched genes that lead to dementia and mental illness. He became head of Garvan’s Neuroscience division in 1999, subsequently taking his position as CEO of Neuroscience Research Australia (NeuRA) in 2004, and has been a conjoint professor at the University of New South Wales since 2000. In his 28-year career, Schofield has received many awards and prizes, most recently a Research Australia Medical Media Award in 2006. His research group is now working to identify genes potentially responsible for bipolar disorder; work that is now possible through, as he describes it, dramatic progress in genetics. Schofield charts this progress by comparing Shine’s PhD on the Shine–Dalgarno sequence, done in 1975, which described the sequencing of just eight nucleotides, with his own PhD (during the early 1980s), for which

Professor Peter Schofield’s research group is working to identify genes potentially responsible for bipolar disorder.

he sequenced approximately 5,000 to 6,000 nucleotides. Today, it’s possible to sequence an individual’s entire genome of three billion nucleotides. Of course, none of this would have been possible if not for the cumulative effect of a greater collaboration between researchers. One of the biggest changes in the application of genetics to clinical research has been the degree of collaborative research. Schofield believes this collaboration will be fundamental for curing debilitating illnesses. “When people ask me ‘what are you working on now?” I say, ‘I’m still working on the genetics of dementia and mental illness. They’re not cured yet!’” Professor Schofield says. “They are big nasty problems and they are going to require a lot of people and a lot of innovative approaches. I still have a lot to do before I retire.” – Therese Chen www.garvan.org.au

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much of it translates to rodents and people. We are able to test our hypotheses in mice, and if a gene or pathway or process functions as we predict, there is a good chance it will also apply to people.” The research has already turned up some unexpected findings. U.S. researchers working with Neely found that a variation of one gene in particular, known as α2δ3, not only reduced sensitivity to acute pain, but also made individuals much less likely to have chronic lower back pain. Using functional MRI (magnetic resonance image) scanners to examine the brains of mice with mutant α2δ3 genes, the

The neuroscience work at Garvan is leading to insights into a variety of illnesses.

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“It’s exciting because using flies in this way allows us to sort through the massive amounts of genetic data very quickly,” he says. “By cross-referencing fly data with human information already in the public domain, we know we’ll be able to pinpoint new therapeutic targets.” Neely and Professor Josef Penninger from the Austrian Academy of Sciences have already identified 580 genes in the fly genome associated with heat perception, and found roughly 400 equivalent genes in people, 35% of which are suspected to be pain genes. Focussing on a molecular signalling implicated

It’s exciting work, with enormous potential to reveal genetic causes that underpin diseases such as anorexia and obesity. in pain sensations, called phospholipid signalling, they identified two enzymes that make phospholipids. When they removed those enzymes from mice, the animals became hypersensitive to heat pain. “Pain affects hundreds of millions of people and is a research field badly in need of new approaches and discoveries,” says Neely. “The fact that evolution has done such a remarkable job of conserving pain genes across species makes our fly data very useful, because

researchers found that the gene controls the way that heat pain signals are processed in the brain. In these mutant mice, the pain impulse arrives in the brain correctly at the thalamus, a first sensory processing centre, but is not properly sent on to the cortex, which normally alerts the animals to the sensation of pain. Instead, the researchers found that areas in the brain responsible for experiencing sight, smell and hearing were being activated. “Our findings help explain the wide variance in how people

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Enabling people to remain happier and healthier in their later years is a key focus of the Neuroscience division.

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experience pain,” Neely says. They also “indicate potential ways of treating acute and chronic pain in the future – by mimicking the effects of the mutated gene”. The research also provided the first genetic insight into synaesthesia, where people experience sounds or written words as colours, or experience tastes, smells and shapes in linked combinations. “The mice we used, with the mutated gene, experienced heat as other perceptions, including vision, sound and smell. We could see their brains lighting up in those areas with MRI scanning. To see if this sensory cross activation, or synaesthesia, was pain specific, we touched their whiskers. It appeared that they could hear, smell and see our touch.” Neely’s approach is also useful for other Garvan researchers, including Herzog’s team, who collaborate with the fly researchers to study eating disorders. It’s exciting work, Herzog says, with enormous potential to reveal genetic causes that underpin diseases such as anorexia and obesity. And it shows how understanding the brain can lead to insights on a wide range of conditions. – Stephen Pincock GARVAN 50-YEAR ANNIVERSARY

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Neural stem cells W

HEN SEARCHING for stem cells to treat Alzheimer’s and Parkinson’s disease, look no further than up your nose. Professor John Shine, former Executive Director and now head of the Neural Stem Cells research group, investigates the growth and development of olfactory stem cells – precursors to the neural cells that give rise to our sense of smell. These cells could one day be used in the treatment of neurodegenerative diseases and hearing loss – research that could be in clinical trials within 10 years, says Shine. Finding the right neural stem cells is a difficult task. They exist in areas of the brain like the hippocampus, but “you don’t want to go and take a biopsy of the middle of the brain,” says Shine. The nose, however, offers a trove of fresh stem cells. Exposed to a harsh external environment, neural cells there are constantly dying off and being replaced by stem cells. “The reason for picking the olfactory system is simply that it is a relatively rich source of existing stem cells that have the capacity to turn into mature neurons.”

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Professor Shine and his research group are investigating ways in which these stem cells can be cultured, multiplied and differentiated into neural cells. In future, patients could use their own cells to treat neurodegenerative disease. At the moment, though, it’s all still “a bit of an art” says Shine. “If it’s Wednesday afternoon you might get 1% of [stem cells] turning into neurons, but on Thursday afternoon that doesn’t work so well.” The Neural Stem Cells group is investigating more reliable and reproducible ways of culturing and growing these cells. Part of this work ties into a broader research program at Garvan into a molecule known as neuropeptide Y, thought to be a central growth factor for neural stem cells. Although a long way off, neural stem cells could trigger a new paradigm of personalised treatments for neurodegenerative disease. “It’s very typical of where the whole of medicine is going in a way,” says Shine, “and no more so than in the area of cell therapy, because your cells are very different to everybody else’s cells.” – Mischa Vickas www.garvan.org.au

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George Smythe

Associate Professor George Smythe Profile

“I

REMEMBER IN primary school, one day when they took us up to see the bigger kids in the science lab cutting up rats, and I thought, ‘gee, that’s what I want to do’,” recalls Associate Professor George Smythe, who retired five years ago from a successful research career based largely at the Garvan Institute. After completing a chemistry degree at the University of New South Wales (UNSW) and postdoctoral research at Arizona State University, Smythe returned to Australia with his family but without a job. Fortunately, an endocrinology position at the Garvan opened in 1970. Initially working with hormone assays with Professor Leslie Lazarus, Smythe suggested the Garvan use mass spectrometry, a technology emerging in the U.S. that could measure the mass of individual molecules and atoms. The Garvan became the home of the first benchtop mass spectrometer in Australia, and Smythe used the technology to measure the ratio and activity of neurotransmitter chemicals in the brain – something that previously could not be done with any accuracy. Working on noradrenaline, Smythe identified its activity and role in the release of pituitary adrenocorticotropic hormone and adrenal cortisol. “Because the method we were using was so accurate and specific, it was difficult for ‘conventional’ wisdom to dispute the results,” he explains. After this breakthrough, many researchers started measuring

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Associate Professor George Smythe was influential in bringing Australia’s first benchtop mass spectrometer to the Garvan Institute in the early ’70s.

neuronal activity in this way, and mass spectrometry became an important tool in neuroscience research. Smythe continued to work in neuroendocrinology, the intersection between neuron activity and hormone release. He discovered rare adrenal gland tumours capable of secreting adrenaline and, in relation to diabetes research, investigated how the brain was involved in the release of glucose. Smythe left the Garvan in 1988 to establish the Ray Williams Clinical Mass Spectrometry Laboratory at St Vincent’s Hospital. In 1995 the unit was moved and incorporated into the Biomedical Mass Spectrometry

Facility at UNSW, where he served as the deputy director. “We invited clinicians to come to us with their problems and see if mass spectrometry could help them,” he says. Smythe worked with one team to identify how nitric oxide affected heart transplant success. He and his colleagues also used mass spectrometry to look at peptides and proteins in the blood that could be used to eventually enable a simple preclinical test for Alzheimer’s disease. “The most enjoyable time of my life was at the Garvan,” he says. “It fulfilled my life-long desire to be involved in research related to health and medicine.” – Tara Francis GARVAN 50-YEAR ANNIVERSARY

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New pathways to cancer treatment Research insights at the molecular level and close ties with clinical practice mean Garvan’s cancer division is changing the way we think about finding a cure.

VERY YEAR, a growing number of Australians develop cancer. In 2009, some 114,000 people were newly diagnosed. By 2020, the annual number of new cases is expected to top 149,000. Cancer remains a leading cause of death in Australia despite new treatments and early detection improving the outlook for many people with malignancies. Scientists at the Garvan Institute of Medical Research study the mechanisms underpinning cancer and work to bring those discoveries

A joint venture of the Garvan and Sydney’s St Vincent’s Hospital, it houses top cancer clinicians from St Vincent’s, and researchers from the Garvan and the University of New South Wales. The centre will connect researchers with the hospital’s best-practice cancer services, accelerating the translation of research into clinical practice. The goal is to develop innovative approaches in personalised medicine and improve outcomes for patients. A classic example of this approach is Dr Alex Swarbrick’s research in breast cancer.

“To develop better treatments for cancer, we need to understand much more about the processes that govern cell division, survival, movement and differentiation.” into the clinical setting where they can benefit patients. “To develop better treatments for cancer, we need to understand much more about the processes that govern cell division, survival, movement and differentiation into the tissues of our body,” says Professor Susan Clark, acting head of the Cancer division and leader of the Epigenetics group. Recently, the Garvan’s cancer researchers have benefited from the opening of the groundbreaking Kinghorn Cancer Centre. 72

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Swarbrick, laboratory head and co-head of the Translational Breast Oncology program, and his colleagues were using a novel antibody in mice to look for a new way to combat an aggressive form of breast cancer. This antibody blocked an important method cells use for communicating with one another, whimsically called the ‘hedgehog signalling pathway’. Hedgehog signalling plays a vital role in healthy embryo development, helping organise a

ball of undifferentiated cells into an organism’s complex structures, layers and divisions. Over the past decade, it has also become clear that aberrant hedgehog signalling is involved in cancers. Hedgehog gene mutations are critical in development of common skin cancers called basal cell carcinomas, and a rare childhood brain cancer, medulloblastoma. In 2008, Swarbrick began collaborating with Associate Professor Sandra O’Toole, a pathologist from the Royal Prince Alfred Hospital in Sydney, to look at hedgehog signalling in breast cancer. They found that in roughly a third of all breast cancers, the hedgehog pathway CONTINUED ON PAGE 75

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JOHN GOLLINGS

Dr Alex Swarbrick and Associate Professor Sandra Oâ&#x20AC;&#x2122;Toole have identified a new way of turning off the cellular cross-talk involved in breast cancer.

At the cellular level, the way cancers develop can be determined by understanding how cells divide, differentiate and survive.

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The Kinghorn Cancer Centre, opened in 2012, connects researchers with best-practice cancer services.

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LAUREN TROMPP

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Professor Susan Clark has pioneered research into the factors that influence the human genome.

Professor SuSAN Clark Profile

OR THE PAST 20 years, Professor Susan Clark has been blazing trails in epigenetics, the biomolecular world ‘above’ DNA. She developed tools to identify sites of DNA modification, and has used these techniques to dissect cancer DNA biology. “We’re looking at how DNA in a cancer cell is organised differently than the DNA in a normal cell,” she says. Attending an agricultural high school, Clark was drawn to the “hands-on” aspects of the life sciences. “I was lucky to have maths and science teachers who were very inspiring and helped me see the beauty of science and the puzzles and challenges that were in front of us, especially in biology.” After undergraduate studies at the Australian National

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University in Canberra, Clark went on to a PhD in molecular biology at the University of Adelaide. There, she applied techniques using restriction enzymes – molecules used to ‘cut and paste’ DNA for cloning and sequencing – to decode the first human DNA gene sequences. The late 1970s and early 1980s “were very exciting times for molecular biology,” she says. Clark continued her research in molecular biology and epigenetics at industry and government institutions. Her research focussed on DNA methylation, a type of DNA modification that influences whether a gene is ‘switched on’ or ‘switched off’ in healthy and cancerous cells. In the early 1990s, Clark and her research group developed the bisulphite sequencing protocol, a method of detecting DNA methylation that has improved cancer diagnosis. The technique is recognised internationally as the best way to detect DNA methylation locally and genome-wide. Clark aspired to work in a medical research organisation where she could be a truly

investigative scientist and make a difference to clinical outcomes. The Garvan Institute was ideal. “You could go on your own quest, develop your own ideas not in isolation, but in an environment where there was a lot of interaction with people who were like-minded.” Clark has been at the Garvan since 2004. She is now acting head of the Cancer division and leader of the Cancer Epigenetics program as well as a professor of medicine at the University of New South Wales. The challenge for an organisation like the Garvan will be maintaining the investigative zeal that first caught Clark’s eye, due to limited funding opportunities nationally for basic research. “We need to be investing in basic biology research, because without a greater understanding of the molecular building blocks, we are not in a position to make the next quantum leap in science that will lead to the design of new drugs, new therapies, and new diagnostic tools,” she says. “We still have such a long way to go before we understand the guiding principles of biology.” – Mischa Vickas www.garvan.org.au

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was switched on. These breast cancers send out hedgehog signals, and nearby normal cells that receive these signals then begin to support tumour growth. The most aggressive breast cancers are characterised by very high levels of hedgehog signalling. But showing that the hedgehog pathway was activated in some breast cancers was only the first step toward developing a new treatment. Next, the researchers needed to show that switching off the pathway could be beneficial. To do this, they sought the help of fellow Garvan researcher Dr Daniel Christ, an expert in designing antibodies for just this kind of job. Creating an antibody to block the hedgehog pathway and providing this in a form that was suitable for delivery to mice was “no mean feat”, Swarbrick says. Some of the mice were given the hedgehog-blocking

PENELOPE CLAY

Garvan’s Dr Liz Caldon investigates cell cycle control in breast cancer.

The Kinghorn Cancer Centre will connect basic researchers with the hospital’s best-practice cancer services, accelerating the translation of research into clinical practice.

Breast cancer cells stained to show the nucleus and highlight the proteins making up the cytoskeleton.

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DARREN SAUNDERS

antibody, while others received an antibody to block another possible molecule involved in cancer, and yet others were given inactive ‘control’ substances. “Within weeks, the growth of

the tumours in some mice had slowed dramatically,” Swarbrick remembers. “But what took us by surprise was that the mice essentially had no metastasis.” That is, cancer hadn’t spread to different areas of the mice’s bodies. The mice experiencing these dramatic improvements were the ones receiving the antibody blocking the hedgehog pathway. The mice’s response to the antibody was “phenomenal”, according to Swarbrick. The researchers are now collaborating with a drug company to develop a pharmaceutical treatment for aggressive breast cancers where the hedgehog pathway is active. “We think blocking hedgehog might be more effective than some other targeted drugs because the normal cells are receiving the

hedgehog signal,” says Swarbrick. “In our approach, you’re really drugging the environment. What we need to do now is figure out which drug combination to use to treat the tumour cells at the same time.” Another researcher at The Kinghorn Cancer Centre, Dr Darren Saunders, is working toward new cancer therapies by targeting the garbage disposal and recycling systems in cells. Since returning to Australia from Canada in 2010, Saunders has been studying the molecular biology and genetics of cancer, aiming to develop new treatments and improve outcomes for patients. In particular, he and his colleagues have been working on new ways to make the most of recent technological developments in cancer research. “These new technologies provide us with fast and powerful new ways of understanding the functions of GARVAN 50-YEAR ANNIVERSARY

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Garvan THANKS the Bill and Patricia Ritchie Foundation Mrs Patricia Ritchie once said that the Garvan shared their family’s values. “I have always believed that if you want to give where it will do the most good, give to the future – that’s why we give to medical research,” she said. Mrs Ritchie first heard about the organisation though a seminar series, and after speaking with Professor John Shine, the Foundation established The Bill Ritchie Post Doctoral Research Fellowship, which over the last 20 years has supported many important research careers in their early stages. “From the start, Pat Ritchie saw the Garvan was an institute with a multiplicity of disciplines,” recalls Richard Croall, the Foundation’s Chairman in its early days. “The legacy left by both Bill and Pat is a tremendous basis for a lot of good to come in the future.” In the early 1990s, founded on the couple’s shared interest in philanthropy, the family’s charitable trust officially became the Bill and Patricia Ritchie Foundation and Patricia Ritchie became the driving force of an astounding legacy of charitable initiatives. She was active in supporting the Mater Hospital North Sydney, where the Patricia Ritchie Centre for Cancer Care and Research, a unique patient care facility with capacity for teaching and research, is based. It wasn’t just medical research that benefited from her vision. Indigenous education was also very close to her heart. Insightful and direct, she was able to see where funds could best be directed to achieve the Foundation’s goals. “She was connected to what was happening in the world and could identify what needed support. That was her real strength,” says daughter Julia Ritchie, the Foundation’s current Executive Director. – Heather Catchpole

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Genetic pathologist Dr Scott Mead with next-generation sequencing equipment installed at The Kinghorn Cancer Centre.

cancer genes, defining biological pathways, and identifying new therapeutic strategies,” he says. “But a major bottleneck in these studies has been analysing the functions of the possible tumour genes and mutations.” To overcome this logjam, his team has been carefully analysing the function of proteins encoded by various cancer-related genes, to help reveal the mechanisms that lead to cancer development and progression. “This work has recently uncovered new insights into how pancreatic and breast

cancer cells reprogram normal metabolic pathways to build new cancer cells,” he says. “We have also found that cancer cells hijack pathways that are involved in breaking down proteins and reusing them within the cell. If we can target those garbage disposal and recycling systems we think there are great opportunities to develop new therapies.” PROFESSOR Chris Ormandy, leader of the Garvan’s Mammary Development group, has unearthed another piece of www.garvan.org.au

PIC CREDIT

penelope clay

Professor Chris Ormandy, leader of the Garvan’s Mammary Development group, has unearthed another piece of fundamental cellular machinery that is askew in breast cancer. fundamental cellular machinery that is askew in breast cancer. Ormandy is interested in ELF5, a transcription factor – a molecule that switches genes on or off. Ormandy and his colleagues discovered ELF5’s remarkable importance in 2008, while examining microscope slides of mouse mammary glands.

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They had been studying the molecular processes that lead to the development of milkproducing cells in mice whose mammary cells lacked a cellsurface receptor for prolactin, the hormone that triggers milk production in mice and humans. The milk-producing sacs and ducts of mouse mammary glands

are stained purple for clearer visibility under the microscope. Normal glands look like bunches of grapes. In this analogy, the grapes are the sacs and the stalks are the ducts. However, glands from mice whose mammary cells were unable to respond to prolactin looked very different. There were plenty of ‘stalks’, but no ‘grapes’. Incapable of receiving the vital hormone’s message, the glands never developed milk-producing cells. The next step of the experiment caused some excitement. The GARVAN 50-YEAR ANNIVERSARY

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researchers were trying to reactivate the effect of prolactin by adding a protein into the mice’s mammary cells. “We had picked out a whole lot of genes that were prolactin regulated,” Ormandy explains. “The next thing was to show that we could rescue the loss of prolactin by putting a single gene back, which is a long shot. Nobody thought we could do it. They all thought that prolactin would activate 50 genes and the concerted action of those 50 genes would be to build the mammary gland.” The Garvan researchers had tried to do this several times with other genes. But on that day in 2008, past failures were forgotten. Ormandy’s team had bred mice with mammary glands that couldn’t detect the message from prolactin, but were expressing ELF5. To their amazement, cells where ELF5 was active developed normally – as if there was no problem with prolactin. “My first thought was ‘wow’,” Ormandy recalls. His second: “I bet this is important in breast cancer.” Fast-forward to 2012, and Ormandy’s group showed that ELF5 causes breast cancer to develop an aggressive subtype that does not respond to standard therapies, such as tamoxifen. Collaborating with Garvan researchers Dr Maria Kalyuga and Dr David Gallego-Ortega, Ormandy showed that ELF5 can change an existing tumour to an oestrogen-insensitive type. This switch often takes place during cancer treatment, and can result in worse outcomes for patients. The team also showed that this mechanism was at work in many cancers where ELF5 alters subtypes of breast cancer to favour the formation of basal cancer types, and that ELF5 is also involved in metastasis. They 78

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are now considering how this could be done using methods that could include small therapeutic molecules in a clinical setting.

Penelope Clay

BREAST CANCER ISN’T the only malignancy under the Garvan’s spotlight. For example, in 2012, Professor Andrew Biankin, head of the Pancreatic Cancer group, and his research team sequenced the genomes of 142 pancreatic cancers, identifying more than 2,000 genes involved in the often-fatal disease. Their work showed pancreatic cancer should not be thought of as one disease – different cancers are CONTINUED ON PAGE 99

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Breast cancer (shown in red, main image) is one of several cancers under the microscope at Garvan.

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The interior of The Kinghorn Cancer Centre, opened in 2012, brings together the cutting-edge science of the Garvan Institute and the compassionate patient care of St Vincentâ&#x20AC;&#x2122;s Hospital.

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caused by different mutations, and each tumour needs to be treated differently based on that spectrum of mutations. Biankin’s work was done under the auspices of the International Cancer Genome Consortium, which aims to find the genetic drivers behind 50 major human cancers. A clinical trial is now underway in which pancreatic cancer treatment will be based on patients’ genetic profiles. Meanwhile, Dr Goli Samimi, leader of the Ovarian Cancer group, is determined to defeat another deadly cancer, one that affects 1,300 women each year in Australia, and leads to 800 deaths. Samimi has been studying ovarian cancer since 1999 and is determined to beat it. In fact, she relocated from the U.S. to the Garvan specifically because of the opportunities and resources the

bloodstream. Those alterations, known as methylation, occur early in the development of a cancer, meaning doctors should be able to use them to detect the presence of a growing tumour while it is still amenable to surgery. To develop their test, the Garvan researchers showed for the first time that it is possible to perform whole-genome sequencing on freefloating DNA in the blood. “That was the first huge hurdle. Nobody had done that before,” Samimi says. “Now that we know it is possible, we can do the analysis to find those changes.” Another recent breakthrough at Garvan relates to prostate cancer, which affects roughly one in nine Australian men. Rather than focussing on genetic changes, the work relates

“Our work, like much of the Garvan’s cancer research, forces us to rethink our understanding of the processes that result in cancer development.” institute offered to aid her cause. The first challenge in improving ovarian cancer survival is detecting the cancer earlier. “Ovarian cancer is a highly fatal disease and the biggest reason is that there’s no early detection for ovarian cancer,” she says. “The majority of women are diagnosed at late stage, when the tumour has spread throughout the body.” Early detection could have a dramatic affect on the number of women who survive. While just 20% of ovarian cancer patients diagnosed with late-stage cancer survive for five years, more than 80% of those diagnosed early will survive that long. That’s why Samimi and her group are collaborating with Professor Susan Clark’s team to develop a blood-based test that can spot tell-tale alterations on fragments of cancer cell DNA circulating in the patient’s

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to ‘epigenetic’ modifications. These are molecular changes that affect the way that our genes are expressed, without changing the DNA sequence. Using new genome-wide sequencing techniques, Professor Susan Clark and her colleagues found a new mechanism of gene ‘deregulation’ in prostate cancer that involves activation of many adjacent genes in large domains across the cancer genome. The activated areas often contain key cancer-related genes, most notably the gene for prostatespecific antigen, which can be used as a marker for the presence of prostate cancer. The study reveals a new way of thinking about epigenetic cancer gene deregulation that might have major ramifications for the treatment of prostate cancer. “Our work, like much of the Garvan’s cancer research, forces us to

Garvan acknowledges the support of The Petre Foundation Daniel and Carolyn Petre established the Petre Foundation in 1999 to support charities and causes throughout Australia. So far, the Foundation has donated more than $10 million to organisations across the country. The Petre Foundation’s decision to support research at the Garvan Institute resulted from personal experience – both Carolyn Petre’s mother and her aunt (her mother’s sister) had died of breast cancer. And with three daughters of their own, the spectre of breast cancer was uppermost in the Petre’s minds. Daniel Petre had learnt a lot about charity while working for many years with Bill Gates as a Microsoft executive. Gates convinced him that if you’re going to do philanthropy, it is critical to only fund efforts that will make a difference. And that meant focussing on the best possible science. The couple researched their options for nine months, and concluded that the Garvan Institute, and in particular Professor Rob Sutherland and his team, were conducting the best world-class breast cancer work in Australia. In 2001 the Petre Foundation donated $2 million to fund a Chair in Breast Cancer Research at the Garvan, under the leadership of Professor Sutherland. More recently, the Petre Foundation has supported prostate cancer research. Prostate cancer kills more men than breast cancer kills women. The Foundation has donated another $2 million to fund a Chair in Prostate Cancer Research at the University of Sydney, with matching funds coming from the University of Sydney Medical School Foundation. The Chair will work collaboratively with the Garvan’s Cancer Research division. The first Chair is to be appointed later in 2013. – Jonathan Nally

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Dianne Lavender

CANCER DIVISION

Garvan is grateful to MRS Virginia kahlbetzer Virginia Kahlbetzer first joined the “Garvan family” in 2001 when she began supporting the Garvan’s cancer division. The following year, Rob Sutherland decided to expand Garvan’s translational research capacity by starting up a program in lung cancer, a greatly neglected area of research in Australia. Over the next 11 years, Mrs Kahlbetzer became the major force behind this initiative and her ongoing generosity was pivotal in growing this research area. In memory of her father, who had died of lung cancer, Mrs Kahlbetzer initially made a five-year pledge to support this work. This funding was used to recruit a new group leader, cancer geneticist Associate Professor Maija Kohonen-Corish and, subsequently, a postdoctoral fellow. In the next few years, this group started attracting grant funding from national and state bodies, and expanded its focus to include both lung and colon cancer. Due to Mrs Kahlbetzer’s vision and generosity, Garvan’s Lung Cancer research team continues to build strong collaborative projects, particularly with clinicians at the Royal Prince Alfred Hospital, to find better treatments for this devastating disease. Following her initial five-year pledge, Mrs Kahlbetzer maintained her commitment with further donations and followed the Garvan’s work with great interest. Her donations often came quite unexpectedly, were most timely and provided enormous encouragement (as well as financial support) for the research team. Sadly, Mrs Kahlbetzer was diagnosed with lung cancer in late 2012, but her commitment to the Garvan’s research continued to the end. Mrs Kahlbetzer died in August 2013 and will be very fondly remembered as a great Garvan friend whose encouragement of Garvan researchers was truly remarkable.

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Associate Professor Maija Kohonen-Corish and Dr Laurent Pangon are studying the role of genes in colon cancer.

rethink our understanding of the processes that result in cancer development,” Clark says. “These kinds of discoveries also provide great opportunities to improve the way we treat cancer.” The work of Associate Professor Maija Kohonen-Corish, leader of the Garvan’s Colon and Lung group, is also challenging conventional paradigms. Not long after she arrived at the Garvan in 2002, Kohonen-Corish was at a seminar where another researcher mentioned a gene known as MCC (‘mutated in colon cancer’). MCC had been known of since the 1990s, but despite its name, it was widely considered not to be a major genetic factor in colorectal cancer. “Out of the blue, someone working in a completely different field mentioned the gene and I thought to myself ‘I’m going to take another look at MCC in colon cancer’,” she recalls. Going on little more than a hunch, Kohonen-Corish looked at whether there were any epigenetic modifications of MCC in colorectal cancer samples. She found that in about half of all colorectal cancers, the gene had been ‘damped down’ by another molecule binding to it, in a process known as methylation. Suddenly, a gene the scientific world had decided was not involved in colon cancer was back in the picture. “MCC is quite rarely mutated, so the name is wrong, but we were the first to look at the epigenetics,” says

Kohonen-Corish. “That was in 2003. I realised that this finding was going to quickly take over the direction of my research.” Since then, Garvan researchers have begun to unpick the network of biological interactions that links MCC and cancer development. They have found the gene has at least three functions that relate to a cell’s ability to repair damage to DNA, its ability to move around short distances and, most importantly, to act as a regulator of certain molecules that are aberrantly activated in colorectal cancer. When the MCC gene is silenced by methylation, the researchers believe, cells are less able to perform these vital functions. Recent studies by other groups internationally support this idea. Other researchers have found that MCC is also implicated in a form of leukaemia and in liver cancer. Looking ahead, the Garvan group suspects that cells where MCC is methylated may be more vulnerable to radiotherapy. If this turns out to be the case, it would help select the most appropriate treatment options for a patient. In the long term, new drug therapies may also target the molecular pathways involving the MCC protein. “Before we can try this, we need to understand the pathways better,” says Kohonen-Corish. “That’s what we’re working on at the moment. We’ve got a long road ahead of us.” – Stephen Pincock www.garvan.org.au

Cancer DIVISION

Monash university

Professor Daly’s work on cell signalling meshed not only with cancer research, but also with investigations at the Garvan into type 2 diabetes.

Professor Roger Daly Profile

ROFESSOR ROGER Daly’s 20-year career at the Garvan may never have happened if it wasn’t for a chance connection at a local pub. “There are two sides of my arrival at the Garvan,” Daly says. While working as a postdoctoral scientist at the Imperial Cancer Research Fund (now known as Cancer Research UK), he spotted an Australian backpacker called Leanne working at a bar just around the corner. “The rest is history. I ended up marrying Leanne and started a relationship with Australia,” he says. The second side of the story is Daly’s recruitment to the Garvan by the director of the Cancer division at the time, Professor Rob Sutherland. “Rob was working on cell cycle control in breast cancer, and we both felt that my work on cancer cell signalling would

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synergise with this,” says Daly. On establishing his own research group at the Garvan, Daly struck up research collaborations and friendships that persist today. “Working at the Garvan Institute provided the opportunity to collaborate in areas which I may not have been able to do if I’d been elsewhere,” he says. One such opportunity was with Professor Greg Cooney, investigating a protein known as GRB14, which they suspected had an inhibitory effect on insulin signalling. Over 15 years, the two researchers characterised the biochemistry of the protein, its function in mice, and, in collaboration with Steve Hubbard from New York, its precise structure when inhibiting the insulin receptor. In 2012, an independent study of a large human population showed that changes in GRB14 were one of the most important risk factors for type 2 diabetes. The Garvan’s emphasis on research that can benefit patients directly has influenced Daly’s latest work. “The Garvan

Institute has always had clinical interactions, which enabled us to look at the clinical relevance of the basic research we were doing. I’m very excited by the possibility of applying our knowledge of intracellular signalling to the development of novel therapeutic strategies for cancer patients, and the identification of biomarkers that aid selection of the optimal therapy for a given patient.” Now head of the Department of Biochemistry and Molecular Biology at Monash University in Melbourne, Professor Daly is taking a cutting-edge approach to characterising how this process goes awry in cancer cells. He sees The Kinghorn Cancer Centre at the Garvan as an important step in developing personalised cancer treatments. “The aim is to have a genomics pipeline, so each patient has their cancer sequenced and that is then used in combination with other patient and tumour characteristics to determine what the optimal therapy would be. It’s very exciting.” – Phillip English GARVAN 50-YEAR ANNIVERSARY

Cancer cancerDIVISION DIVISION

Customised cancer care T

including $25 million from The Kinghorn Foundation, after whom the centre is named. The Kinghorn Cancer Centre is a leader in the burgeoning field of cancer genomics, offering the potential for more personalised medicine using molecular markers to identify patients most likely to respond to specific treatments. “With this new building, I realised we could be the first institute in this country to go next-gen and introduce genomics… the future of medicine,” says Professor John Mattick, Executive Director of the Garvan. – Gemma Black

LAUREN TROMPP

HE KINGHORN CANCER CENTRE is a bastion of translational cancer research, representing both the cutting-edge science conducted at the Garvan Institute and the compassionate, holistic approach to patient care at St Vincent’s Hospital. Strategic development for the centre, located at St Vincent’s campus in Sydney, began in 2006. The Kinghorn Cancer Centre was officially opened on 28 August 2012, under the inaugural leadership of the late Professor Rob Sutherland, best known for his pioneering work at the Garvan on hormone-dependent cancers, such as breast and prostate cancer. A revolutionary concept that will see top clinicians working with researchers at the Garvan and University of New South Wales, the ambitious $128 million project was funded through $70 million from the Australian Government, as well as $58 million from individual donors and organisations,

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LIZ MUSGROVE

Cancer DIVISION

A background in physics grounded Professor Musgrove’s initial research. She has since won wide acclaim for her work on the cell cycle.

Professor Liz Musgrove Profile

HANGING LIVES through cancer research is an ambition that comes early for many scientists. But Professor Liz Musgrove stumbled into medical research “more by accident than design”, she says. “I grew up in an era when science and technology were big news. People were going to the Moon,” she says. Lured by this excitement as a pre-teen, she went on to study physics at the University of New South Wales in her home town, Sydney. Unsure about what to do next – “in those days, the concept of a five-year plan was all a bit foreign” – Musgrove soon accepted a job with a company that made cardiac pacemakers. There, she developed a taste for “the more biological end of physics,” and moved on to run the flow cytometry facilities

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at the Ludwig Institute for Cancer Research, University of Sydney. “It was emerging technology involving lasers and fluidics, so they tended to look for people with a physics or engineering background.” From then on, Musgrove was hooked on cell biology, but soon came to realise that if she wanted a research career she needed a PhD. The Garvan Institute, with its breadth of expertise and sense of collaboration, was a perfect fit. “I’ve always been interested in more collaborative, programmatic science, bringing people with a range of expertise to bear on larger problems,” she says. What’s more, “… somewhere in the building there is someone who knows almost anything about what you need to know,” she adds. Musgrove has won wide acclaim for her work on the cell cycle (when cells divide to make new cells). In her role as head of the cell cycle research group, she studied ways that female sex hormones affect the cell cycle, and how these

mechanisms run out of control in the formation of breast cancer. Professor Musgrove, who has now left the Garvan for Britain, has witnessed a huge change in the types of technologies available for carrying out cancer research. When she began in the field, “Just about any of the standard tools that people use commonly these days hadn’t been developed,” she reveals. Looking forward, she would like to see new discoveries and technologies used in the clinic to help get the right therapy to the right patients. Her work has already gone some way to this end, by helping to identify which patients are likely to respond best to anti-oestrogen therapies, such as tamoxifen. The aim is to avoid patients being placed on toxic therapies that are unlikely to benefit them, and identify which drugs they should be taking instead. It’s an outcome that, for a physics graduate without an initial career plan, is all the more impressive. – Catherine de Lange GARVAN 50-YEAR ANNIVERSARY

Cancer DIVISION The director of the Cancer division for 27 years, Professor Sutherland also gained international renown for his own work on hormonedependent cancers.

VALE Professor Robert Sutherland

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Profile

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ROFESSOR Robert Sutherland was born in Gore, on New Zealand’s South Island, on 18 July 1947. The son of a school teacher and World War II veteran, he went to Ashburton High School before graduating from the University of Canterbury with a Bachelor of Agricultural Science in 1968, followed by a Masters in 1970. He crossed the Tasman Sea to Australia aged 25, having won a scholarship to the John Curtin School of Medical Research at the Australian National University in Canberra, where he completed his PhD in 1974. He then took a postdoctoral research fellowship at the Faculté de Médecine ParisSud in France, where he not only established a lifelong appreciation for fine wines, but also worked under renowned French biochemist and endocrinologist Étienne-Émile Baulieu. Returning to Australia in 1978, Sutherland spent the next seven years as a senior research fellow at the Ludwig Institute for Cancer Research, University of Sydney. In 1982 he married Cheryl Frewin, and in 1985 joined the Garvan Institute as head of the Cell Biology group, which became the Cancer division in 1991. As director of the division for 27 years, Sutherland gained international renown for his work on hormone-dependent cancers, such as breast, prostate and ovarian cancers. In 1986, he demonstrated the mechanism behind the first targeted cancer therapy, called tamoxifen, an

antagonist to oestrogen receptors found in breast tissue. In 2010, he received the NSW Premier’s Award for Outstanding Cancer Research and was also made an Officer of the Order of Australia “for distinguished service to medicine as an international contributor to the research of cancer, the development of Australia’s research capacity and through leadership roles in advisory bodies”. Sutherland mentored more than 50 postgraduate students in his career, including Professor Andrew Biankin, whose PhD Sutherland supervised from 1999 to 2003. Biankin trained as a surgeon at St Vincent’s Hospital before his PhD, and went on to lead the Pancreatic Cancer group at the Garvan. He says among Sutherland’s most important contributions was his

role as a pioneer and champion of translational medicine – integrating research science into medical practice. “He was paradigmchanging and ahead of his time in much of his thinking,” Biankin says. This approach drove Sutherland’s establishment of The Kinghorn Cancer Centre, a joint facility of St Vincent’s Hospital in Sydney and the Garvan Institute. The centre was officially opened on 28 August 2012, a little more than a month before Sutherland, who had dedicated his life and career to cancer research, sadly lost his personal battle with the disease. Despite spending the latter part of his life in Australia, Professor Sutherland, a keen rugby fan, remained a dedicated supporter of the New Zealand All Blacks, and in his later years revived an early interest in racehorses. – Gemma Black www.garvan.org.au

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Professor Andrew Biankin Profile

FTER FINISHING medical school and his surgical training, Professor Andrew Biankin was struck by the realisation that it was “time to get out there and start working,” he says. “I was looking down the path of doing the same thing every day for the next 30 years. And I couldn’t face it.” Instead, he went to the Garvan Institute and sought an interview with Professor Rob Sutherland, the then director of the Cancer division. Sutherland took him on as a PhD student, which Biankin completed before being recruited by Johns Hopkins University in Baltimore in the U.S. for postdoctoral research. He then returned to the Garvan to run the Pancreatic Cancer group. Biankin’s career coincided with the genomics revolution, which opened his eyes to the complexities of cancer. His team, in partnership with Professor Sean Grimmond at the University of Queensland, proposed a project aiming to categorise the genomes of about 400 pancreatic cancers, and was awarded the largest National Health and Medical Research Council grant ever given. The picture that Biankin’s research has painted of pancreatic cancer is that the cancer is heterogeneous, and that it is futile to search for highly recurrent mutations that can be targeted with drugs. “On average, we see similarities in genetic abnormalities only 2% of the time in pancreatic cancer,” he explains, “so you can see how a drug, if targeting a specific genetic

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The ability to change the lives of people with cancer has inspired much of Professor Biankin’s research. As the disease is so heterogeneous, he advocates personalised cancer treatments.

abnormality, would never come out in a clinical trial.” This is why Biankin is so adamant that the way clinical trials take place must change, to allow scientists to be nimbler when it comes to applying their findings, and to make treatments specifically targeted to a patient’s cancer subtype. His approach was put into practice in a bid to save the life of his mentor, Rob Sutherland, when he was diagnosed with pancreatic cancer. Biankin’s team sequenced the tumour, grew the cancer in a mouse “and hit it with about a dozen drugs to see which ones it would respond to”. Unfortunately, they didn’t find any that would work on that cancer, and Sutherland passed away in October 2012.

Biankin is continuing his drive for a personalised approach to cancer treatment at the University of Glasgow, which is building a centre for stratified medical research. Yet he says this was a vision that was established by Professor Sutherland at the Garvan, and led to some incredible outcomes. “We got to the point in the lab where we were working on cancers of patients who were still alive, and in some cases somebody would find something that would have immediate relevance to the patients,” he says. “How many scientists have that opportunity in a research lab? You discover one thing one minute and then two weeks later it’s changed somebody’s life.” – Catherine de Lange GARVAN 50-YEAR ANNIVERSARY

OSTEOPOROSIS and bone biology DIVISION

Reducing the burden of bone disease

ATHERED around a computer screen in mid 2009, a small group of Garvan researchers couldn’t quite believe their eyes. Professor John Eisman and Associate Professor Jackie Center from the Garvan’s Osteoporosis and Bone Biology division had squeezed into Dr Dana Bliuc’s small office to look at the latest results from the Dubbo Osteoporosis Epidemiology

such as vitamin D or hormone therapy. Amazingly, the figures seemed to show that taking bisphosphonates for just a few years gained participants a remarkable five extra years of life. Such a huge benefit seemed like it must be an error. It wasn’t. “It just didn’t make sense,” recalls Eisman, who was the founding director of the Garvan’s Osteoporosis and Bone Biology division, and is now director

“When we first looked at the figures, we thought that there had to be a mistake; that we were missing something.” Study (DOES). Since 1989, Eisman and his colleagues had been running the study to better understand the factors that contribute to a person’s risk of developing osteoporosis. The longest and most comprehensive study of its kind in the world, it has transformed understanding of this debilitating disease. But on that morning four years ago, the trio of researchers were wondering if they’d missed some major factor. The graphs on the screen showed the death rate among people taking bonestrengthening bisphosphonate drugs, and the death rate among people taking other treatments, 88

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of Clinical Translation and Advanced Education. “It was so remarkable.” In Australia, someone is admitted to hospital with an osteoporosisrelated fracture every five or six minutes. Among women over the age of 75, almost half of those with osteoporotic fractures would be expected to die within the next five years. But the death rate in the study dropped to one

in 10 among women who took bisphosphonates. And in younger women, where you would expect up to one in four to die over five years, there were no deaths. “When we first looked at the figures, we thought that there had to be a mistake; that we were missing something,” says Center. The team was so unsure about its findings that it spent the next two years trying to disprove them to confirm there wasn’t some other factor that could account for the benefit. Perhaps the people who took bisphosphonates also tended to be better at maintaining their health? Or did the longer life expectancy have more to do with their general healthiness? Yet try as they might, the researchers couldn’t prove themselves wrong. All further comparisons simply confirmed their findings. Other researchers have since reported evidence that backs up the Dubbo data, although it seems that the Garvan researchers have identified a larger benefit than other groups. For Eisman, Center and their colleagues, the bisphosphonate mystery is just one illustration of how poorly we understand bone diseases such as osteoporosis. It also posed several further questions. First among them was: How exactly could bisphosphonates be extending lifespan? www.garvan.org.au

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Data from one of the world’s largest bone studies, and new genetic research, are helping Garvan researchers tackle some of society’s most debilitating diseases.

Garvan IS GRATEFUL TO Mrs Janice Gibson and the Ernest Heine Family Foundation

“My hypothesis is that higher bone turnover is releasing toxic metals such as lead [from bone] into the body, and that this is reducing life expectancy,” says Eisman. According to this hypothesis, which they plan to test, people taking bisphosphonates would be protected from the toxic

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Every five to six minutes, someone is admitted to hospital with an osteoporosis-related fracture.

them with a radioactive molecule and inject them into mouse models to study their progress. This was a slow process, because researchers used tritium, a very weak isotope that produced a very clear signal. They had to leave tissue samples exposed to X-ray film for several months before they could see a result.

Arthritis and musculoskeletal conditions are the major disabling condition in more than one in three Australians with a disability. effects of lead that had been safely sequestered in their bones. The Garvan researchers are now looking for funding to study this mysterious phenomenon internationally. Meanwhile, another Garvan group, led by Professor Mike Rogers, has been exploring the bisphosphonate enigma from another angle. Until recently, the only way scientists could detect the action of bisphosphonates, which have been widely used to treat bone disease for 40 years, was to label

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These days, researchers can label drugs with fluorescent tags and use sophisticated CT (computed tomography) scanners, microscopes and 3-D fluorescence imagers to watch the process unfold in real time, just like watching a movie. These techniques let them see bisphosphonates adhere to the bone surface where they act on bone cells, and to see where else the drugs go in the body. This is providing clues about

Mrs Janice Gibson and the Ernest Heine Family Foundation are longstanding supporters of medical research in Australia. Their generous support of the Garvan Institute over the past seven years has been vital to the growth and success of its internationally recognised research into osteoporosis and bone disease. In 2007, alerted by a news item that the Garvan’s groundbreaking Dubbo Osteoporosis Epidemiology Study (DOES) was in danger of closing due to a lack of government funding, Mrs Gibson contacted Garvan to learn more about its research into this disease. The result was a three-year commitment by Mrs Gibson and the Ernest Heine Family Foundation – set up in 1994 by Mrs Gibson and her sister, the late Mrs Judith Scott, in honour of their parents Ernest and Grace Heine – to fund this study. DOES is the longest-running and largest study of its kind in the world, and a vital resource for researchers. The Ernest Heine Family Foundation is strategic about its giving and aims to make a significant difference in supporting real outcomes for the community. In keeping with its mission, in 2011 Mrs Gibson and the Ernest Heine Family Foundation significantly increased their commitment to Garvan through a five-year pledge, funding the Mrs Janice Gibson and Ernest Heine Family Foundation Chair in Osteoporosis Research, currently held by Professor Peter Croucher. Under his stewardship over the past 18 months, this program has gone from strength to strength, not only in its quest to understand what causes and drives the development of osteoporosis and the search for cures and treatments, but also in ensuring that both medical practitioners and the general community are kept abreast of developments.

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Lauren Trompp

OSTEOPOROSIS and bone biology DIVISION

Professor Peter Croucher Profile

DESIRE TO DO more research and less administration led Professor Peter Croucher to quit his job as head of the department of human metabolism at the University of Sheffield in Britain, and take up a new role as head of the Garvan’s Osteoporosis and Bone Biology division and the inaugural Mrs Janice Gibson and the Ernest Heine Family Foundation Chair in Osteoporosis Research at the beginning of 2012. “I realised it is such a great institute, with a great group of people, including cancer biologists and immunologists, who were exactly the types of individuals I wanted to work with,” he says. After graduating with a zoology degree at University College Cardiff in 1987, Croucher studied skeletal disease at the University of Wales and molecular biology at the University of Cambridge. At Cambridge’s Laboratory for Molecular Biology, he became involved in research into multiple myeloma, a cancer that causes devastating bone destruction. Recruited to the University of Sheffield, he was involved in the discovery of RANK ligand, a molecule that myeloma cells use to ‘hijack’ the normal processes that maintain our skeletons, and instead use them to cause bone degradation. The research led to the development of an antibody treatment that is in the final stages of clinical testing for treating myeloma. Current Garvan research has resulted in a new technique that can spot individual tumour cells as they arrive in the skeleton, 90

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Professor Croucher’s team is working to understand bone tumour growth and the genes important in our bones’ development.

revealing that they are often dormant for long periods before growing. This might explain why cancers that grow in the bone typically reoccur, despite initially successful treatments. Croucher’s team is working to identify the molecular pathways the tumours use to stay dormant, and use this knowledge to stop their activation and growth. Other work involves a global consortium of researchers who are involved in the Knockout Mouse Project, which aims to produce thousands of mouse strains, each with a different gene rendered inoperative. Many hundreds have already been produced, and Croucher’s team of collaborators from Imperial

College and the Sanger Institute in Cambridge conducted a pilot study to see which of them have something wrong with their skeletons. “We found that 10% have either stronger or weaker bone, suggesting that more genes than we previously thought are important in controlling our bones,” he says. In recognition of this discovery, Croucher’s group was awarded a major grant by the Wellcome Trust to implement this new approach to identify bone-related genes in partnership with his colleagues. We now understand “somewhere between 8% and 10% of the genes that make our skeleton work, so we’ve still got a lot of genes to find,” says Croucher. – Jonathan Nally www.garvan.org.au

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another unexpected action of bisphosphonates – their ability to prolong the survival of cancer patients. “We would like to understand how drugs that target the skeleton also appear to have anti-tumour activity in other tissues,” Rogers says. ONE IN Three Australians will develop some form of musculoskeletal disease during their lifetime. These diseases, which include osteoporosis and osteoarthritis, are painful, disabling and in some cases life-threatening, says Professor Peter Croucher, the Garvan’s inaugural Chair in Osteoporosis, an appointment funded by Mrs Janice Gibson and the Ernest Heine Family Foundation, and head of the Osteoporosis and Bone Biology division. Arthritis and musculoskeletal conditions are the major disabling condition in more than one in three Australians with a disability. In 2004–05, more than $4 billion was spent on treating the conditions. Despite their importance, many of those who develop these diseases will not receive adequate treatment. “This is a major public health issue,” Croucher says, “yet musculoskeletal diseases receive relatively little attention.” His group is trying to address the problem by exploring the complex biological changes that underpin conditions such as osteoporosis, osteoarthritis and cancers that grow in bone, in the hope of developing better treatments. There are six research groups in the Garvan Institute’s Osteoporosis and Bone Biology division, each with a slightly different focus, ranging from basic

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bone biology and the molecular pharmacology of bone, to clinical epidemiology and the translation of scientific understanding into clinical benefit for patients. In 2012, Croucher and his collaborators in Britain took an important leap forward in understanding the genetic underpinnings of bone diseases, courtesy of a remarkable new global effort that aims to breed 20,000 different strains of mice, each lacking a single different gene. Scientists hope that studying this collection of ‘gene knockout’

mice will reveal a wealth of information about all kinds of diseases. What they didn’t expect was that so many of the genes would turn out to be involved in bone strength. “We wanted to see what screening the first 100 knockout mice from the pipeline would tell us about the impact of these genes on bone, and whether our approach was an effective one,” says Croucher. Examining the 100 different strains of mice using the kind of X-ray and CT scanning technology used on human bones, they found that nine strains had alterations to their bone structures. That meant that from 100 genes, nine were important CONTINUED ON PAGE 93

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Anything that can help reduce the number of fractures people have will reduce suffering, extend lives and reduce costs in the health system.

Calculate your fracture risk

NE OF THE most clinically valuable outcomes from the Garvan’s Osteoporosis and Bone Biology division in recent years is a fracture risk calculator for over-60s developed by Professors Tuan Nguyen and John Eisman using data from the Dubbo Osteoporosis Epidemiology Study. The risk calculator uses a combination of an individual’s medical history and demographics to determine their risk of fracturing a bone, including age, sex, bone density, history of falling and previous fractures. “It’s one of the success stories of the Garvan,” says Professor Croucher. The Garvan was the first institute globally to develop such a calculator, and its accuracy has been validated by several studies around the world. See: fractureriskcalculator.com

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OSTEOPOROSIS and bone biology DIVISION

The late Professor Sambrook left an enduring legacy in bone biology research.

VALE Professor philip sambrook AO Profile

ROFESSOR PHILIP Sambrook, who passed away in 2012, was a devoted clinician, talented researcher and avid mountaineer. He first joined the Garvan Institute in 1985 as part of the Osteoporosis and Bone Biology division, and is described by colleague and friend Professor Tuan Nguyen as having been “a wonderful man with sharp intellect and compassion”. But it was Sambrook’s scientific ethos that many remember him for. On asking Sambrook to review one of his papers, Nguyen recalls his amazement at discovering that Sambrook’s attention and precision went as far as the style of the margin on the page. “He calmly explained to me that a paper would exist for a long time as a piece of evidence, and we must make sure that every aspect of the paper is right. I have since learned from Philip that attitude to science.” This ethic was reflected in Sambrook’s extensive research into rheumatology and, in particular, osteoporosis, a ‘silent disease’ of the bones that affects two million Australians. Sambrook’s work on steroidinduced osteoporosis led to new treatments and preventative interventions for this condition. In 1989, Sambrook helped develop the Garvan’s internationally renowned Dubbo Osteoporosis Epidemiology Study (DOES). As part of a team of researchers, Sambrook studied thousands of men and women in order to identify nutritional, 92

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lifestyle and family history risk factors for bone fracture and osteoporosis. In the 1990s, Sambrook and his colleagues at Garvan used DOES to conduct some of the world’s first research into the genetic causes of osteoporosis. The team made the first identification of a gene associated with the condition, and it is now understood that genetics determine more than 70% of bone density characteristics. The joints and bones of thousands of Australians benefited from his time at Royal North Shore Hospital and St Vincent’s Hospital in Sydney, and he shared his knowledge with many students

at the University of New South Wales and the University of Sydney. He was a determined researcher and practitioner, and an insightful educator. Publishing more than 300 peer-reviewed publications, he is described by Nguyen as a “man who contributed to science until the very last days of his life”. In 2008, Professor Sambrook was awarded a Medal of the Order of Australia, for his “compassion, loyalty, teachings, writings and scientific ethos”. “I think Philip has left behind a legacy of service to others,” says Professor Nguyen. – Mischa Vickas www.garvan.org.au

WORKING WITH EISMAN, Professor Tuan Nguyen, leader of the Bone Genetics and Epidemiology group, has also been looking at the genetic underpinnings of bone strength. The team is part of an international collaboration to use the most advanced gene sequencing technologies to find genes associated with an individual’s bone density or fracture risk in more than 13,500 women, including 1,500 women from the DOES and 12,000 women from Iceland and Denmark. Twenty years ago, Eisman and his colleagues identified the first gene associated with osteoporosis when they showed that variations

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iStockphoto

in regulating our skeleton. If the same ratio holds true across the entire genome, then 8% to 10% of all genes may be involved in bones in some way. “What’s even more interesting is that we’ve gone back to cohorts of human patients and looked at those genes, and half of them are associated with bone mass in people too,” says Croucher. It may be that these genes could become the targets of drug therapies to prevent bone loss, he adds. “If you were to block some of them, it may result in higher bone mass and stronger bones. We’ll be making antibodies to those genes to test our results.” Over the next five years, Croucher and his colleagues will be screening the next 800 to 1,000 genes from the mouse pipeline in the hunt for more bone-related genes. “We believe that many genes will be individual players in complex pathways – so they will act as pointers to those pathways, and obviously some pathways will be much more important than others,” he says. “It’s our aim to pinpoint the critical pathways.”

Your risk of bone fracture goes beyond your medical history and environmental factors – age, sex and even your genes all play a role.

in the vitamin D receptor gene affected an individual’s risk for the disease. Since then, the tools scientists have at their disposal for linking genes to diseases have become far more powerful, and vastly cheaper. Nguyen can still remember the night two years ago when the final results of the new study

likely it was to be associated with fracture risk. Nguyen was thrilled. The bars on the Manhattan plot that marked the genes’ correlation with bone problems were all high: the study had picked up a whopping 56 genes linked to fracture risk. “I thought, ‘wow, we did a good job’,” he says with a laugh.

“We would like to understand how drugs that target the skeleton also appear to have anti-tumour activity.” pinged into his email inbox from the coordinating scientists in the U.S. The email contained a pair of attachments. The first was a type of graph that scientists call a Manhattan plot. This bar chart looked vaguely like a crowded highrise cityscape, with each skyscraper representing a particular gene. The higher a gene’s tower, the more

He quickly opened the second attachment, a table listing the identities of all the genes in the study. Jubilation turned to surprise, as more than half of the 56 genes were not ones that he was expecting to find. “There were so many genes,” Nguyen recalls. “And so many that I wasn’t expecting to be there.” GARVAN 50-YEAR ANNIVERSARY

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Dubbo Osteoporosis Epidemiology Study

N JULY 1989, Garvan researchers began a study they hoped would shed some light on a poorly understood condition that affects millions of men and women around the world: osteoporosis. Currently, more than two million Australians are affected by osteoporosis. Broken bones associated with the condition cost the Australian community an estimated $1 billion per year in direct costs. When factors such as carers and lost Professor John Eisman and Janet Watters cutting the 18th birthday cake for DOES in 2007. income are included, those Professor Philip Sambrook, who passed away in 2012. costs rocket to an estimated $7 billion per year. Professors Tuan Nguyen and Jackie Center soon joined DOES, based in a city about 400 km northwest of them, and since then the study has produced more than Sydney, is the world’s longest-running, large-scale 12 PhDs and 100 scientific papers, says Nguyen. “It has epidemiological study of osteoporotic fractures in men been a huge success for Australia.” and women. More than 3,500 men and women aged 60 or older are In the 24 years the study has been running, it has now in the study, and results show osteoporosis is not just garnered international recognition for helping reveal a woman’s disease. While women are initially twice as likely the lifestyle factors that contribute to improvement as men to have a first fracture, the risk of a man’s second or deterioration of our bones, and the impact of those fracture substantially increases to the point where it is the changes on quality of life and survival. same as in women. More recently, data showed that women “It is one of the most remarkable things we’ve – but not men – with more abdominal fat are at less risk of done,” says Professor John Eisman, director of Clinical bone fracture. This may explain why global rates of fracture Translation and Advanced Education at the Garvan. are declining at the same time as obesity is increasing. Eisman initiated the study with rheumatologist

Still, the identification of the new genes was a great advance. For Nguyen, the new genome data on fracture risk offered a chance to improve the fracture risk calculator he’d developed with Eisman (see ‘How to calculate your fracture risk’, p91). That work is now underway, and there’s good reason to hope that adding genetic information will substantially improve the calculator, Nguyen says. Anything that can reduce the number of fractures people have will reduce suffering, extend lives and reduce costs in the health system, notes Eisman. Every fracture a person sustains signals an 94

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increased risk of further fractures as well as a higher risk of death. Despite this, about 80% of women and 90% of men who sustain a fracture do not receive treatment to reduce their risk of breaking more bones in the future, he notes. “Over recent years we have come to appreciate that people are simply not getting good care.” In 2012, Eisman led the development of a consensus across 36 countries for better managing secondary bone fractures, which the participants dubbed ‘Making the first fracture the last fracture’. The expert

task force, including 63 clinical care opinion leaders, developed a toolkit for reducing secondary fractures based on a summary of the evidence for cost-effective interventions. It also highlighted those approaches that appear not to work, including those based on patient or community education. The results were published in the Journal of Bone and Mineral Research in October 2012. Fighting this inadequate care has become Eisman’s passion. “It’s an area where people don’t get treatment, around the world,” he says. “This is where my major effort is now.” – Stephen Pincock www.garvan.org.au

Lauren Trompp

OSTEOPOROSIS and bone biology DIVISION

In his 40-year career, Professor John Eisman has revolutionised our understanding of bone biology.

HEN PROFESSOR John Eisman started researching osteoporosis almost 40 years ago, the condition was mainly associated with older women with broken hips or dowagers’ humps. Nobody understood how common or serious osteoporosis truly was. Although Sydney-raised, Eisman completed his PhD in endocrinology in 1975 at the University of Melbourne, researching calcium regulation. He started meeting patients with weakened bones, who were suffering fractures. “We had not a single evaluated treatment that had been shown to work,” he recalls. After his PhD, Eisman held research positions in the U.S. and Switzerland before returning to Australia in 1978 to practise as an endocrinologist in Melbourne and then back in Sydney in 1984 at St Vincent’s Hospital. He was appointed director of the Garvan’s Osteoporosis and Bone Biology division at the same time – a position he held until 2011. In 1989, he initiated the Dubbo Osteoporosis Epidemiology Study

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Professor John Eisman AO Profile examining men and women aged 60 and older in the regional centre of Dubbo in New South Wales. It revealed, among other data, that osteoporosis is common among men, who suffer about a third of all fractures. It also showed that each fracture increases the likelihood of another, and that every fracture is associated with an increased risk of premature death. Over the past 40 years, researchers including Eisman have developed effective bone density scans and medications that can reverse the risks associated with osteoporosis – but society needs to catch up with the science, says Eisman. Other than having a fracture mended, just 10%–20% of patients around the world receive effective treatment for their underlying condition.

A big part of the problem is the mistaken belief that osteoporosis only happens to frail, elderly women, which is why Eisman prefers to use the term ‘bone failure’ to describe osteoporosis. As well as conducting twin studies to reveal the large part played by genetics in osteoporosis, Eisman and his Garvan colleagues have participated in each of the major multinational genome-wide association studies. Eisman was also instrumental in identifying the first gene associated with osteoporosis, and is using next-generation sequencing techniques with patients in Dubbo to uncover the genes responsible for bone density. When he’s not working, Professor Eisman enjoys art – particularly sculpture. This perhaps isn’t surprising, given his dedication to one of the finest physical structures of all. “How many buildings are still standing after 60 to 70 years? That’s our skeleton – it’s still going strong then, because it’s constantly being improved and repaired. It’s absolutely amazing.” – Gemma Black

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Lauren Trompp

OSTEOPOROSIS and bone biology DIVISION

A world expert on the genetics of osteoporosis and bone fracture, Professor Nguyen finds Garvan’s big question approach to research “exciting”.

Professor TUAN NGUYEN Profile

ROM DIFFICULT beginnings, having arrived in Australia from Vietnam as a refugee, Professor Tuan Nguyen has become a world expert on the epidemiology and genetics of osteoporosis and bone fracture. And despite landing a professorship in the U.S. directly from his PhD studies, Nguyen and his wife decided to return to Australia. It was here that Professor John Eisman – described by Nguyen as a “very good persuader” – convinced him to join the Garvan Institute. That was more than 20 years ago. “People ask me: ‘How can you work in the same place for 20 years? Isn’t it boring?’ But every week you are exposed to new things. It’s exciting!” Nguyen says. 96

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Part of this excitement comes from the encouragement given by management at the institute to ‘ask big questions’. One of the biggest questions Nguyen has tackled draws on results from the Dubbo Osteoporosis Epidemiology Study. Nguyen estimates a dozen PhD theses have been produced from the data accrued in the 24-year study. However, he is quick to stress that he and his group are interested in more than just scientific data. “We get money from taxpayers, so we have to do something for them. We have to make a difference to the person on the street,” says Nguyen. To achieve this goal of translational research, his research group developed a predictive model of bone fracture that incorporated five risk factors: age, sex, bone density, the number of falls a person had recently, and any history of fracture. But rather than just publish the model in an academic journal, they also implemented

it as an online calculator hosted on the Garvan’s website (see fractureriskcalculator.com). Professor Nguyen is also interested in personalised medicine, a goal he shares with the Garvan. He argues that most people who experience bone fracture have a normal bone density, but may have a very high risk due to other factors, such as low muscle mass, a dangerous environment, or carrying high-risk genes. The research group is now focussed on incorporating genetic factors into these predictive models by taking advantage of the ever-shrinking cost of genome sequencing. “Back in the 1990s when we started a genome-wide study, each patient cost more than $1,000 for only 500 markers,” he says. “Now I can do 500,000 markers for less than $1,000. And that’s amazing. The application of bioinformatics and biostatistics to translate this huge amount of information into individualised diagnosis, prevention and treatment is the future.” – Phillip English www.garvan.org.au

THE FUTURE

Lauren Trompp

Professor John Mattick says his most important job is attracting the most gifted people to the Garvan, and promoting that cross-pollination of ideas which has led to so many medical breakthroughs.

The future of medicine The Garvan is perfectly positioned to lead the new wave of genetic advances that will transform the nature of medicine, says institute Executive Director John Mattick. But its power is still in its people. Written by Stephen Pincock.

N THE 50 YEARS since Professor Les Lazarus, then a young clinician– scientist and later the institute’s first Executive Director, first walked through the doors of the fledgling Garvan Institute of Medical Research, the scientific world has changed almost beyond recognition. Wave after wave of discovery has yielded fundamental advances in our knowledge of human biology, leading to improved treatments and new management of a myriad of diseases. Thanks to the work of Garvan researchers and their colleagues

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around the world, healthcare professionals can now harness significantly more effective treatments for common diseases such as asthma, diabetes, cancer, osteoporosis and arthritis. Yet

disease and other forms of dementia, are yet to be unravelled. Their increasingly devastating impact on society means the role of research institutes like the Garvan is more vital today than

“The Garvan’s mission has always been to make significant contributions to medical research that will change the direction of science and medicine, and have major impacts on human health.” much more remains to be done. The causes and pathways of diseases that affect a growing number of people, including obesity, diabetes, Alzheimer’s

ever, says the institute’s Executive Director, Professor John Mattick. “In a sense, we’ve become the next generation victims of our successes. Because we have GARVAN 50-YEAR ANNIVERSARY

THE FUTURE

defeated or are well advanced in defeating many of the diseases that often took life prematurely, like infectious disease and cancer, we are now facing the next wave: the diseases of lifestyle and ageing. “The Garvan’s mission is and has always been to make significant contributions to medical research that will change the direction of science and medicine, and have major impacts on human health,” Mattick says. “So, our focus will increasingly be on understanding the major diseases that afflict our society – cancer, immunological diseases, diabetes and obesity, osteoporosis and neurological diseases.” Thanks to the rapid recent advances in genomic technology, scientists today can understand the molecular basis of disease much faster and more inexpensively than in the past. Already, the ability to study the particular mutations found in individual tumours –

the nature of medicine, he says. Over the next two decades, making treatment choices as well as risk minimisation strategies based on these genomic approaches will become commonplace as we move toward better informed, personally focussed medicine. Within 10 years, 20 at the most, everyone who chooses will have their genome sequenced and incorporated into their personal health records. This will allow a much better use of scarce healthcare resources and major improvements in health economics, as well as national wellbeing and productivity. “The Garvan will lead the nation in this transition,” states Mattick. FROM ITS EARLIEST days, the Garvan has had two closely related objectives: to understand the processes that underpin human biology, and to take that understanding into new ways of

Centre, to enable the analysis of the mutations that cause different types of cancers and other genetic diseases, which will greatly inform both treatment and research. This infrastructure will form a platform for the development of genomic medicine over the next decade and beyond. “Today, the gap between a research discovery and its clinical application is smaller than ever. These new technologies will not only allow us to better understand the diseases which occupy our attention, but also provide a direct route back to improved diagnosis and treatment in the clinic,” Mattick explains. FORTY YEARS AGO, researchers at the Garvan were working to develop life-saving insulin infusion techniques to treat complications of type 1 diabetes, amongst other groundbreaking research. John Mattick was still an intellectually curious

“Moving into that future, the institute should be focussed on maintaining a community of clear thinking, creative and courageous individuals who take considered risks … to try to make real progress into the darkness.” which cause the cells to proliferate uncontrollably – is allowing doctors to prescribe the right drugs to block those mutations. “Science and medicine is at an inflection point. Just over a decade ago, it cost a billion dollars to generate the first human genome sequence. Today we can do it for a few thousand. And the cost is rapidly falling,” says Mattick. “This means that we can now start to analyse and understand our individual differences. We can use the same technologies to look at the changing patterns of gene structure and expression during our lifetime and during the development of complex diseases.” As new genomic tools become even more accessible, they will lead to a complete transformation in 98

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preventing or treating disease. Those twin goals will become ever more closely entwined, thanks in large part to the genomic revolution, says Mattick. The state-of-the-art Kinghorn Cancer Centre is an embodiment of that desire to apply leading edge technologies and scientific insights directly to the care and treatment of patients. Genome sequencing will soon become routine in cancer research and the standard in clinical care, allowing doctors to identify the individual characteristics of a patient’s tumour and treat it with specifically targeted therapies. To that end, the Garvan is establishing the country’s first Centre for Clinical Genomics within The Kinghorn Cancer

but vocationally uncertain undergraduate at the University of Sydney, where there was little he liked more than listening to jazz, body surfing or sailing around Sydney Harbour. Mattick today is one of the country’s most eminent biologists and stands at the helm of a much larger ship – a world-class institute with a workforce of around 600 people, who publish hundreds of scientific papers each year. Although improvements in technology clearly play a part in scientific advancements, he has no doubt that his priorities lie with the institute’s living, breathing assets. “Great institutes are built on great people, and apart from trying to steer this ship in the right direction, my most www.garvan.org.au

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JOHN GOLLINGS

The striking interior of The Kinghorn Cancer Centre reflects the meeting point of clinical excellence and scientific innovation, a hallmark of the way research at the Garvan Institute has been conducted for half a century.

LAUREN TROMPP

important job is to attract and retain the most gifted people.” Research institutes such as the Garvan attract some of the most intellectually remarkable and altruistic people in the nation, he says. “These are the people who invent the future. Intellectually, the Garvan is the light on the hill. “Moving into that future, the institute should be focussed on maintaining a community of clear thinking, creative and courageous individuals who take considered risks in their research to try to make real progress into the darkness – to make conceptual breakthroughs and real improvements in clinical practice.” In coming decades, Mattick believes the Garvan is well placed to contribute to the next grand challenge of science – understanding the human brain. “The big advances over the next two to three decades are going to come from investigating with progressively higher resolution how our genomic idiosyncrasies influence our individual differences, and then the molecular mechanisms by which the body alters physiology to the environment. “Of all the organs in the body, the brain is the one that has been set up to reprogram its circuitry in response to our environment and experience,” Mattick says. “To understand our own brain will be perhaps the most magnificent achievement of human intelligence. We have a long way to go. But I think we’re just getting to the point where our technologies are advanced enough to do it, and I expect that the Garvan Institute will be a key part of that revolution in the decades to come.”

GARVAN 50-YEAR ANNIVERSARY

In 50 years, the Garvan Institute of Medical Research has grown from a small St Vincentâ&#x20AC;&#x2122;s Hospital clinical research unit to an internationally renowned medical research centre attracting the worldâ&#x20AC;&#x2122;s best scientists. Working in a uniquely collaborative environment and focussed on basic research as well as the clinical translation of research discoveries, the institute has gone from strength to strength from its humble beginnings. The vision of many philanthropists have helped it to grow, and the institute continues to be inspired by the ethos of the Sisters of Charity, whose founding donations, along with a donation by the daughter of James Patrick Garvan, Mrs Helen Mills, enabled the institute to become a reality in 1963. Having achieved its half century, in this book the Garvan reviews the significant events, discoveries and people that have influenced its standing today, and looks forward to the innovations to come in the future. Garvan Institute of Medical Research 384 Victoria Street Darlinghurst, Sydney NSW 2010, Australia www.garvan.org.au