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Annual Report 2006<br />
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01 > Overview // AR 2006<br />
Our vision >><br />
>> to your health<br />
The <strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong> will continue to grow as<br />
a world leader in medical research with the power to improve<br />
the health of all mankind.<br />
Our “Bench to Bedside” philosophy will ensure that<br />
our research outcomes are rapidly translated into better<br />
prevention strategies, treatments and healthcare for all.<br />
The <strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong> is one of the largest<br />
medical research institutes in Australia with over 400 staff<br />
conducting research into a wide range of important human<br />
disorders affecting both adults and children.<br />
Our research spans infectious and immune diseases; cancer<br />
and leukaemia; liver and metabolic diseases; eye and brainrelated<br />
disorders and heart and respiratory disorders.<br />
Closely affiliated with both <strong>Westmead</strong> Hospital and<br />
the University of Sydney, our research extends from the<br />
laboratory to the patient, using the basic tools of molecular<br />
and cell biology, genetic epidemiology, imaging technology<br />
and clinical research.<br />
This ‘Bench to Bedside’ approach enables greater translation of<br />
research from biomedical discovery to the development of new<br />
prevention strategies, diagnostics and more effective treatments.
02 03 > Overview // AR 2006<br />
Contents<br />
Chairman’s Report<br />
OVERVIEW<br />
RESEARCH REPORT<br />
Medical research is driven by a hypothesis. A scientist begins<br />
their project with a critical assumption or idea. While science<br />
Furthermore WMI researchers devised a test which assists in<br />
identifying the appropriate treatment for multiple sclerosis<br />
can be serendipitous, presenting unanticipated results, it is<br />
patients. They have created a quick and non-invasive<br />
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Chairman’s Report – 3<br />
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Director’s Report – 4<br />
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Messages – 5<br />
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Research Highlights – 6<br />
Infection and Immunity – 10<br />
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57<br />
Cancer – 14<br />
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57<br />
Liver and Metabolic – 16<br />
57<br />
Neuroscience and Vision – 18<br />
57<br />
N59 Cardio-respiratory – 20<br />
International collaborations – 22<br />
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N53<br />
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Infection & Immunity – 30<br />
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Cancer – 37<br />
Liver and Metabolic – 43<br />
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57 Neuroscience and Vision – 45<br />
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Cardio-respiratory – 48<br />
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Staff – 50<br />
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Publications 2006 – 54<br />
OR6<br />
the researchers dogged pursuit of knowledge that advances<br />
our medical frontiers.<br />
Like any investigation, medical research, is a step-by-step<br />
process. It can be painstaking, entailing the collection and<br />
interpretation of endless data, over many years. A researcher<br />
will test, and re-test results before announcing an outcome.<br />
Research at the <strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong> (WMI) is<br />
focused on outcomes; outcomes, which will directly benefit<br />
patients and assist health care practitioners provide better<br />
treatments and prevention strategies.<br />
This year the <strong>Institute</strong> celebrated its tenth anniversary. It<br />
has been a decade of outstanding achievement. The diverse<br />
research work conducted at the <strong>Institute</strong> and its contribution<br />
to better healthcare outcomes is recognized internationally.<br />
Since its formal establishment just over a decade ago the<br />
<strong>Institute</strong>’s researchers have lead or contributed to a number<br />
of significant medical research breakthroughs. WMI is widely<br />
acknowledged for its contribution to the discovery of the first<br />
gene found to cause melanoma. WMI researchers are world<br />
leaders in HIV research, tracing and trying to prevent the<br />
way HIV enters the body. Australia’s only successful clinical<br />
islet cell transplantation unit for curing Type 1 diabetics, was<br />
established by WMI researchers and this unit is still one of<br />
only a few in the world.<br />
diagnosis for brain infections, including brain abscess and<br />
meningitis and worked tirelessly to understand the nature of<br />
a liver disease now commonly known as NASH.<br />
Through its longitudinal, Blue Mountains Eye Study, WMI<br />
researchers have identified the most common causes of<br />
blindness in the elderly. And this year the <strong>Institute</strong> established<br />
Australia’s first major collaborative breast cancer tissue bank<br />
– a central library of both clinical and molecular data for use<br />
by all Australian researchers.<br />
Support of this high caliber medical research is critical.<br />
Without it researchers cannot continue to look for cures and<br />
better treatments.<br />
I would like to thank those who do support and continue to<br />
support the <strong>Institute</strong> including the <strong>Millennium</strong> Foundation<br />
Board and its staff, the WMI Advisory Board and Council<br />
of Governors, Sydney West Area Health Service and the<br />
University of Sydney.<br />
Finally I would like to congratulate the <strong>Institute</strong> staff on<br />
their achievements over the past decade and wish them every<br />
success in 2007.<br />
Mr Paul Bell<br />
Advisory Board and Council of Governors – 24<br />
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Organisation Structure – 25<br />
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<strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong> at a glance – 60<br />
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Funding – 26<br />
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Science is a process.<br />
Director’s Report<br />
< 04 05 > Overview // AR 2006<br />
Messages<br />
This year, the <strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong> reached a<br />
significant milestone celebrating a decade of excellence in<br />
medical research.<br />
Ten years ago, we were a small group of 60 researchers,<br />
covering four major research areas. Since then we have grown<br />
to be one the largest medical research institutes in Australia,<br />
with five primary research divisions and over 400 staff and<br />
postgraduate students.<br />
Over the past ten years, our researchers have competed with<br />
the best biomedical research in the world but still maintained<br />
a focus on outcomes. The <strong>Institute</strong>’s motto ‘bench to bedside’<br />
remains at the core of our work. Our research utilizes the<br />
common and rapidly advancing technologies of cell biology<br />
and genetic epidemiology. We share ideas and technology,<br />
collaborating on new research directions for new diagnostics,<br />
treatment and therapies. Many of our discoveries are being<br />
transferred to the frontline of health care services and new<br />
biotechnology.<br />
As Director of the <strong>Institute</strong>, I am privileged to acknowledge<br />
the efforts of all of the Centres’ leaders and their staff who<br />
conduct both basic and clinical research and are recognized<br />
internationally in both endeavours. This year the <strong>Institute</strong><br />
received 14 NHMRC project grants in addition to our three<br />
ongoing NHMRC Program Grants and 3 NHMRC Centres<br />
of Clinical Research Excellence. The breadth of the research is<br />
impressive, interactive and covers a diverse range of disorders<br />
and diseases. The funded projects will examine the molecular<br />
determinants of progression and treatment in melanoma,<br />
genes underlying dermatitis and asthma, transport of<br />
Herpes Simplex virus in nerve cells, host factors affecting<br />
hepatitis C, nuclear receptors in liver disease, the molecular<br />
mechanisms of scarring of kidneys, the mechanisms of<br />
induction of high blood pressure by snoring, amongst others<br />
and eye disease in children. There is an encouraging degree<br />
of cross collaboration in the use of biomedical and genetic<br />
epidemiologic research techniques amongst the groups<br />
involved in these apparently diverse topics.<br />
In addition Associate Professor Philip O’Connell led a team<br />
which was awarded $16M over 4 years to establish the<br />
Australian Centre for Pancreatic Islet Transplantation. This<br />
is a translational centre which has already cured selected<br />
patients with diabetes through transplantation of islets, a<br />
perfect example of bench to bedside research.<br />
The expertise of the Brain Dynamics Centre, under the<br />
leadership of Associate Professor Lea Williams was recognized<br />
this year when they received a Clinical Centre of Research<br />
Excellence award to establish a Centre for Anxiety and<br />
Neuroscience and an Australian Research Council grant to<br />
conduct further research into the risk markers for depression.<br />
These successes are based on the legacy of the research<br />
pioneers of <strong>Westmead</strong> Hospital. In particular Professor Peter<br />
Castaldi who we recognized this year with the inaugural<br />
’Castaldi Oration’. Professor Castaldi was a driving force<br />
behind the establishment of this <strong>Institute</strong> and I would like to<br />
reiterate the <strong>Institute</strong>’s appreciation of his continuing support<br />
and guidance. Professor Peter Doherty, Nobel Laureate<br />
and Patron of the <strong>Institute</strong> gave a most erudite entertaining<br />
oration on “The continuing threat of infectious diseases”.<br />
Finally, to Mr Paul Bell, Chairman of the WMI Advisory<br />
Board and Mr Pat Wilde, The <strong>Millennium</strong> Foundation<br />
President, thank you. Both Boards whom you represent<br />
operate on a volunteer basis, and have worked tirelessly over<br />
the past decade to raise much-needed funds and support<br />
for the institute. Your efforts are appreciated by not only the<br />
Executive but all here at WMI.<br />
Professor Tony Cunningham<br />
From the Chief Executive,<br />
Sydney West Area Health Service<br />
The vision of Sydney West Area Health Service is to provide<br />
quality health care to the people it serves. Fundamental to<br />
this objective is the support and enhancement of medical<br />
research and innovation.<br />
From the outset medical research has been a key part of the<br />
<strong>Westmead</strong> campus. The campus was developed on a highly<br />
effective model - a tertiary teaching hospital, combining first<br />
class clinical care with teaching and medical research.<br />
Over the past decade the <strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong> has<br />
grown to become one of Australia’s leading research institutes.<br />
Its primary objective of translating research outcomes in to<br />
improved diagnostics and more effective prevention and<br />
treatment strategies assists SWAHS in meeting our goal of<br />
improving the health of our community through excellence<br />
in healthcare.<br />
I applaud the dedication and innovation of <strong>Westmead</strong><br />
<strong>Millennium</strong> <strong>Institute</strong> researchers and wish them every success<br />
in the next decade.<br />
Professor Steven Boyages<br />
From the Vice-Chancellor,<br />
University of Sydney<br />
The University of Sydney has been allied with <strong>Westmead</strong><br />
since it was established in the late nineteen seventies. As a<br />
university teaching facility it is a first class campus. For almost<br />
three decades it has displayed an unrivalled ability to blend<br />
academia with the practicalities of healthcare delivery.<br />
From the outset its professors and doctors have embraced<br />
both basic science and clinical medicine while at the same<br />
time emphasising the translation of research into better<br />
health outcomes. When the <strong>Institute</strong> was formally established<br />
ten years ago, this research philosophy was firmly entrenched<br />
Since then WMI researchers have contributed to the field<br />
of medical research in a number of different ways. Not<br />
only does their work contribute enormously to medical<br />
knowledge, but their mentoring and support of PhD,<br />
Masters and Honours students ensures the continued growth<br />
of a critical mass of research excellence.<br />
Over the past decade the University of Sydney has been<br />
proud to support the world-class medical research at<br />
<strong>Westmead</strong> and as we continue our partnership, wish its staff<br />
every success.<br />
Professor Gavin Brown AO FAA CorrFRSE
06 07 > Overview // AR 2006<br />
Research Highlights<br />
In July, the <strong>Institute</strong> celebrated ten years of research. The<br />
centrepiece of the celebration was the Inaugural Castaldi<br />
Oration delivered by 2005 Australian of the year and<br />
Nobel Laureate, Professor Peter Doherty. The oration, was<br />
established to honour former Area Health Service Board<br />
Chairman and WMI Advisory Board Member, Emeritus<br />
Professor Peter Castaldi AO. More than 200 guests attended<br />
the event including the Right Honourable Gough Whitlam<br />
and NSW Health Minister John Hatzistergos.<br />
The <strong>Institute</strong> received more than $14 million in NHMRC<br />
funding during 2006, the largest amount awarded to<br />
any medical research institute in NSW. Thirteen highlycompetitive<br />
grants were awarded to the institute’s diverse<br />
range of projects including research covering diagnosis,<br />
treatment and prevention of liver disease, paediatric eye<br />
disorders, ovarian, breast and colon cancer, renal and kidney<br />
failure, serious viral infection, cardiac arrhythmia and<br />
respiratory disorders including asthma and sleep apnoea.
08 09 > Overview // AR 2006<br />
Research Highlights<br />
Infection and Immunity<br />
The Nuclear Magnetic Resonance spectroscopy team, lead by<br />
Professor Tania Sorrell had an extremely successful year with<br />
funded by both the federal government and the JDRF aims<br />
to identify factors that cause graft damage and to develop a<br />
safer immunosuppressive regimen.<br />
Liver and Metabolic<br />
Dr Poustchi was the recipient of a Young Investigator<br />
award at the Asia Pacific Digestive Disease Week in Cebu,<br />
The Brain Dynamics Centre capped a successful year with<br />
the opening of their newly refurbished facilities. The Baroness<br />
Susan Greenfield officially opened three new laboratories.<br />
the completion of studies showing that biochemical profiles<br />
of different fungi can be identified using NMR spectroscopy<br />
and which can be used for their clinical diagnosis. The work<br />
also showed that resistance to medicines used in therapy can<br />
also be rapidly determined using this technology.<br />
<strong>Institute</strong> researchers together with Professor Adrian Mindel<br />
conducted the first nationwide survey of adult infection<br />
with Herpes Simplex viruses types 1 and 2 (which cause<br />
oral and genital herpes respectively) conducted outside the<br />
USA. Such studies will provide the baseline information for<br />
future deployment of vaccines against genital herpes expected<br />
within the next five years.<br />
Responding to the urgent national need for knowledge on<br />
avian flu, infectious diseases researchers investigated ways<br />
to rapidly and accurately identify the presence of the avian<br />
virus in people. The virus researchers received two NHMRC<br />
strategic grants to work on a portable diagnostic system that<br />
could show the presence of flu virus H5N1 in a human<br />
sample within two hours. A highly sensitive technique for<br />
detection of potential resistance to antiviral drugs was also<br />
developed.<br />
The pioneering immunological clinical research of the<br />
pancreatic islet cell transplantation group resulted in<br />
them being chosen to lead an Australian wide research<br />
consortium. The aim of the research is to develop pancreatic<br />
islet transplantation as a mainstream therapy for patients<br />
with difficult to control diabetes. The new study, which was<br />
The Molecular Genetics of Allergy Group, lead by Dr<br />
Graham Jones made significant process in the understanding<br />
of the genetics and function of a new gene, PHF11, and<br />
its involvement asthma and eczema. The group identified<br />
genetic variants in PHF11 that increase the risk of developing<br />
asthma and eczema. It also showed for the first time that<br />
PHF11 controls the expression of other genes expressed in a<br />
subset of immune cells called T-cells.<br />
Cancer<br />
Melanoma researchers lead by Professor Rick Kefford<br />
and A/Professor Graham Mann commenced a research<br />
program investigating the molecular determinants of the<br />
risk, progression and treatment response in melanoma. The<br />
NHMRC funded program will be conducted over the next<br />
five years.<br />
The Genomics and Genetic Epidemiology group completed<br />
the Australian Melanoma Family Study (AMFS), with<br />
the University of Melbourne’s MEGA Centre and the<br />
Queensland Cancer Fund Epidemiology Research Unit.<br />
This is one of the world’s largest population-based studies<br />
of melanoma. Approximately 1100 people who developed<br />
melanoma before age 40 or unaffected controls were enrolled<br />
in the study, plus thousands of their family members.<br />
The Breast Cancer Tissue Bank, a simple but vital research<br />
tool, began sample collection this year. Patients operated on<br />
in NSW hospitals were invited to donate tissue to the bank.<br />
Researchers across Australia are able to access the bank.<br />
Philippines 2006, for related research on insulin resistance<br />
and responses to antiviral therapy in patients with Chronic<br />
hepatitis C.<br />
In the area of insulin resistance and liver disease, Dr Ian<br />
Cua a Clinical Research Fellow won the Unit’s second<br />
Young Investigator Award at the Asian Pacific Association<br />
for the Study of the Liver meeting (March 2006) in Manila,<br />
Philippines, for his studies on the role of adipokines in<br />
mediating insulin resistance in hepatitis C.<br />
Neuroscience and Vision<br />
Researchers in the Centre for Vision Research in conjunction<br />
with the University of Sydney, used data from the Blue<br />
Mountains Eye Study to investigate dietary fat and its<br />
relationship to this eye disease. They found that people who<br />
consumed one serve of fish a week had a 40% lower risk of<br />
developing the early form of age-related maculopathy (ARM)<br />
and people who consumed three serves of fish a week had a<br />
75% lower risk of developing the more severe form of ARM.<br />
A PhD project titled: Conscious and Nonconscious Emotion<br />
processing: An integration of fMRI and ERPs was recognized<br />
by the award of best PhD thesis for this year (winning the<br />
Tasman Lovell medal in Psychology). It identified the neural<br />
signature of conscious and nonconscious processing of fear<br />
and happiness.<br />
Cardio-respiratory<br />
During 2006 LECRR researchers completed a major<br />
epidemiologic study that identified heavy snoring as a risk<br />
factor for the presence of carotid artery wall atherosclerosis<br />
(plaque). Since dislodgement of carotid artery wall plaque is a<br />
cause of stroke, this finding suggests that heavy snoring alone<br />
poses a significant health threat.<br />
A project conducted by the Centre for Heart Research<br />
involved the creation of a chronic ovine (sheep) model of<br />
atrial flutter using purely percutaneous (through the skin)<br />
means. Previous models required open heart surgery. With<br />
the aid of new 3D electro-anatomical imaging, the group was<br />
able to reliably induce atrial flutter in sheep, similar to the<br />
abnormal heart rhythms experienced by humans. Gene and<br />
stem cell therapy to treat such disorders of the conduction<br />
system of the heart will commence in late 2007.
10 11 > Overview // AR 2006<br />
Infection and Immunity<br />
We are examining important viruses and bacteria and how they interact<br />
with the immune system. We are also looking at how to manipulate the<br />
immune system for transplantation.<br />
s<br />
s<br />
The Infection and Immunity division is investigating serious<br />
infectious diseases and pathogens, oral infection, organ<br />
transplantation, autoimmunity and other immune disorders.<br />
The Centre for Infectious Diseases and Microbiology<br />
conducts research on the identification, treatment and<br />
prevention of serious infectious diseases. It also provides<br />
training and education to health care professionals, patients<br />
and the community in managing the spread of these diseases.<br />
A major research area is concentrating on Cryptococcus,<br />
a fungus that causes meningitis and other brain and lung<br />
infections. Researchers aim to define how the organism enter<br />
s<br />
11<br />
Peptide C<br />
the body and triggers the disease to develop new treatments<br />
against it.<br />
Work over the past year has provided further insight into<br />
how a recently discovered enzyme, phospholipase B (PLB),<br />
enables Cryptococcusto to penetrate a patient’s tissue.<br />
As investigations progress, researchers hope to use PLB<br />
as a target for new drug treatments that may eliminate<br />
cryptococcal infection and several other important fungibased<br />
diseases.<br />
Research in new antifungal drug treatments has led to the<br />
identification of three classes of drugs that may inhibit the<br />
effect of PLB. One of these drugs, Miltefosine, is already<br />
being used in developing countries to kill a parasite that causes<br />
leishmaniasis. Laboratory tests have also shown Miltefosine to<br />
kill a number of fungi, including those resistant to available<br />
drugs. The centre aims to improve Miltefosine’s effect while<br />
reducing some of its current side effects. Collaborations are<br />
being sought overseas to conduct a trial of Miltefosine to<br />
treat cryptococcosis, which has become a major problem for<br />
patients with AIDS in developing countries.<br />
B<br />
A<br />
With the support of a five-year NHMRC Centre of Clinical<br />
Research Excellence (CCRE) grant (2005-09), research<br />
continues to improve outcomes for immunocompromised<br />
patients with blood malignancies. One new strategy aimed<br />
at bone marrow transplant patients is investigating the effects<br />
of vaccinating bone marrow donors’ cells so that immunity<br />
can develop before the transplant takes place, reducing the<br />
recipient’s risk of infection following the procedure.<br />
This year, the centre began the Community Respiratory Virus<br />
Project to understand how coughs, flu, colds, bronchitis or<br />
pneumonia are being transmitted in the hospital wards to<br />
patients with blood malignancies or who are undergoing<br />
transplants. Results so far have been very positive with some<br />
transmission patterns being identified between patients, their<br />
families and staff. This has led to strict protocols being set<br />
(including a flu vaccination program for patients and their<br />
families) to prevent the spread of flu and other respiratory<br />
viruses. An education program developed for patients and<br />
their families has successfully incorporated information about<br />
the impact of these infections upon the patients.<br />
Over the past year, researchers working in rapid diagnostics<br />
have characterized a new antibiotic resistant gene relevant to<br />
serious infections in Australian intensive care units (ICUs).<br />
Using newly created procedures for analysis, researchers<br />
hope to simultaneously identify bacteria causing disease and<br />
the genes associated with their resistance. These advanced<br />
diagnostic methods will mean strategies can be implemented<br />
faster than currently possible to prevent bacteria from<br />
being transmitted to ICU patients, and treatments can be<br />
administered more rapidly in the event of infection.<br />
The Centre for Transplant and Renal Research is<br />
internationally reputed for its investigations into causes,<br />
treatments and cures for progressive renal disease and<br />
transplantation.<br />
More than 150,000 Australians have Type 1 diabetes (also<br />
known as juvenile or insulin-dependent diabetes). These<br />
patients are at risk of developing serious complications<br />
including kidney failure. If diabetic control can be improved<br />
then the incidence of these complications can be reduced.<br />
The centre proposes a radically new treatment where blood<br />
sugar levels are nomalised by transplanting the insulin<br />
producing cells, rather than using the imperfect treatment of<br />
insulin injections.<br />
s<br />
s<br />
21<br />
The centre is continuing to make important breakthroughs<br />
in this field of study, which includes investigations of<br />
human pancreatic islet cell transplantation to patients and<br />
the production of alternative sources of islet cells through<br />
xenotransplantation – the transplantation or grafting of cells,<br />
tissues and organs from one species to another.<br />
Researchers at the centre were the first to establish a successful<br />
clinical pancreatic islet cell transplant program in Australia<br />
proving that infusing patients with these cells provides<br />
much better control of diabetes than the traditional insulin<br />
injection therapy.<br />
COOH
12 13 > Overview // AR 2006<br />
The positive benefits lasted only a few years, and the<br />
centre is now leading a larger Australian consortium, with<br />
substantially increased Federal Government funding, which<br />
is being administered by the Juvenile Diabetes Research<br />
Foundation. The aim is to examine anti-rejection treatments<br />
that may reduce the risk of islet cell grafts failing. The<br />
researchers hope to develop safer and more effective processes<br />
for islet transplantation and to have a better understanding of<br />
what happens to the graft after it has been transplanted.<br />
Dovetailing this field of research is the centre’s pioneering<br />
work aimed at creating a limitless supply of insulin producing<br />
cells using modified pigs as the source. In collaboration with<br />
a numbers other researcher groups the centre is investigating<br />
ways to design pancreatic islet cells that can be taken from<br />
pigs that will be more resistant to the human immune system.<br />
The Centre for Virus Research is a world leader in research<br />
on human immunodeficiency virus (HIV) and the herpes<br />
group of viruses including herpes simplex virus (HSV),<br />
cytomegalovirus (CMV), and Varicella Zoster virus. The<br />
Centre’s main focus is to identify how these viruses infect<br />
patients to develop ways to diagnose, treat or prevent them and<br />
their transmission in the international and local community.<br />
In 2006 an estimated 40 million people were infected with<br />
HIV worldwide. The centre has helped identify how HIV<br />
infects patients via host cells called dendritic cells, which are<br />
found in the lining of the genital tract. In women, this lining<br />
is thinner and less protected than in men. Understanding<br />
how these early interactions occur is encouraging the<br />
development of ‘microbicides’ or decoys, which may stop<br />
the virus from entering cells of the genital tract. The Centre<br />
is now collaborating with a biotechnology firm to develop<br />
novel candidate microbcides.<br />
Centre researchers are also using sophisticated techniques<br />
to study how HIV induces changes in hundreds of human<br />
genes that simultaneously occur within a single infected<br />
dendritic cell. Other important work is directed at how a<br />
group of people infected with a weaker strain of HIV have<br />
been able to naturally control it. Recently, this work has<br />
led to the discovery of defensive proteins, which appear to<br />
control HIV in these patients.<br />
Cytomegalovirus affects about 60 per cent of the population.<br />
It is usually controlled in healthy people, but can be fatal<br />
in immunosuppressed people such as those who have<br />
undergone bone marrow or solid organ transplants.<br />
Researchers have been defining the mechanisms that keep<br />
CMV dormant and the chemical interactions that trigger its<br />
activation. This work has led to the discovery and patent of a<br />
type of interleukin-10, a protein that inhibits key functions<br />
of immune cells.<br />
Shingles is a painful condition affecting many elderly<br />
individuals caused by re-emergence of dormant Varicella<br />
virus years after causing chicken-pox. An exciting research<br />
project is underway that may provide insight into the<br />
molecular immune processes which allow this and then<br />
control the re-emergence. With ethics permission, autopsy<br />
material from patients who have passed away at the time of<br />
a shingles episode are being used to identify such immune<br />
mechanisms in the hope of improving the success rate of<br />
current vaccine (about 60 per cent).<br />
The centre has already pioneered work showing how herpes<br />
simplex virus travels in nerves between the site of infection<br />
on the skin and the site of dormant infection near the spinal<br />
cord. When the virus is activated, it travels back to the skin<br />
surface to present as cold sores or genital herpes. The Centre<br />
is unraveling mechanisms that trigger this viral activity to<br />
produce blocks that may stop the outbreaks. Negotiations<br />
with a US biotechnology firm are underway to fund this<br />
research in return for licensing one of the centre’s patents.<br />
Research into HSV type 2 is significant because it causes<br />
genital herpes and enhances HIV by up to three times. The<br />
vaccine Simplirix, which was developed some years ago<br />
based on discoveries made by the centre, is being retrialled<br />
in the US with availability forecast within about three years.<br />
Simplirix has shown to be about 75 per cent effective against<br />
genital herpes infection in women who have never previously<br />
had HSV. Centre researchers are examining how immune<br />
processes control virus infection in an attempt to improve the<br />
vaccine to protect previously infected women and also men.<br />
In particular, work on how immunity to HSV type 1 (which<br />
usually causes cold sores) can control HSV type 2 is about to<br />
be patented.<br />
The <strong>Institute</strong> of Dental Research investigates the causes<br />
of major oral diseases to design new and better treatment<br />
options for patients. As both tooth decay and chronic gum<br />
infection (periodontal disease) are major health burdens for<br />
Australian communities, the <strong>Institute</strong>’s work is critical.<br />
Ongoing research into the microbiology of progressive tooth<br />
decay has identified a particular group of bacteria that attack<br />
the tooth nerve in the final stages of decay. Researchers are<br />
currently investigating new diagnostic methods that can be<br />
used in the dental surgery to predict the invasion by these<br />
bacteria, so that more conservative approaches to treatment<br />
may be applied. For the patient this may mean retaining<br />
the living tooth rather than undergoing more complex and<br />
invasive therapies, which often leave the tooth susceptible to<br />
fracture leading to even more complicated treatments at a<br />
later stage.<br />
The <strong>Institute</strong> is also developing a new anti-bacterial<br />
compound that may be able to target specific diseases or<br />
bacteria in the mouth and gums so that protective bacterial<br />
flora (good bacteria) are not destroyed during treatment.<br />
Current therapies still rely on broad-spectrum antiseptics or<br />
antibiotics, which wipe out good and bad bacteria present<br />
in the mouth. While tests are at an early stage, the eventual<br />
outcome may see low-cost treatments such as toothpastes or<br />
mouthwashes containing the specific anti-bacterial available<br />
in supermarkets.<br />
The <strong>Institute</strong> for Immunology and Allergy Research<br />
investigates diseases caused by abnormal functioning of the<br />
immune system. This includes many major unsolved diseases<br />
that plague communities worldwide. The <strong>Institute</strong>’s research<br />
programs focus on three main themes: autoimmune disease<br />
such as multiple sclerosis (MS); allergy disorders such as<br />
eczema and asthma, and why individuals vary so much in<br />
their response to infection with HIV and hepatitis C viruses.<br />
Collaborative research on the genetics of severe eczema and<br />
asthma in children has led to the discovery of a link between<br />
these diseases and several genes that are important for normal<br />
immune function called TIM-1, TIM-3 and PHF11.<br />
Researchers know TIM-1 and TIM-3 are expressed on the<br />
surface of specific types of immune cells and relay messages<br />
inside the cell, leading to cell activation through the turning<br />
on or off of specific genes. The <strong>Institute</strong> has now made<br />
important advances in understanding how PHF11 operates,<br />
showing that it is present deep inside a cell and directly<br />
controls the switching of genes on or off. Researchers are<br />
now investigating whether these genes interact to influence<br />
susceptibility to disease. Although still at an early stage,<br />
this research may guide the development of new drugs and<br />
topical therapies.<br />
Major research is also being conducted on a gene crucial to<br />
the immune system’s healthy functioning called Interleukin<br />
7 receptor alpha chain or CD127. In 2003, the <strong>Institute</strong> was<br />
the first to publish findings that a genetic variant of CD127 is<br />
important in the development of MS. The researchers believe<br />
this is due to its role in generating regulatory T cells, which<br />
stop the immune system from attacking the body’s own<br />
tissue and have submitted at patent application for improved<br />
therapy based on this discovery. Three international research<br />
groups have recently confirmed this discovery making<br />
CD127 only the second clearly established genetic risk factor<br />
in MS after HLA (a cell’s identification markers). As a result,<br />
CD127 has become one of the hottest areas of research into<br />
MS strengthened by the potential to design treatments to alter<br />
the abnormalities found in the gene’s function.<br />
In other research, the <strong>Institute</strong> was awarded an Australian<br />
Research Council Linkage Project grant to collaborate with<br />
the pharmaceutical company Biogen IDEC to investigate<br />
why up to one-third of MS patients fail to benefit from<br />
interferon, the disease’s main treatment therapy.<br />
NHMRC grant funding is also supporting research between<br />
the <strong>Institute</strong> and the Storr Liver Unit to investigate the<br />
genetics of hepatitis C. About 35 per cent of individuals fully<br />
recover from the hepatitis C infection due to their immune<br />
system clearing the virus from their body. The remaining<br />
65 per cent of patients fail to clear the virus and may go<br />
on to form cirrhosis and liver cancer. Based on these data,<br />
researchers are examining the factors in patients’ genetic<br />
makeup that determine disease outcomes when infected by<br />
the virus.
14 15 > Overview // AR 2006<br />
Cancer<br />
00.005.0483 00.005.0484<br />
The Cancer division conducts groundbreaking laboratory<br />
and clinical investigations into cancers common to<br />
Australians to improve prevention and treatment strategies<br />
and to establish new cures.<br />
The <strong>Westmead</strong> <strong>Institute</strong> for Cancer Research bases its<br />
research on the notion that if discoveries can be made to<br />
understand the faults in the wiring of cancer at a molecular and<br />
cellular basis - and how this differs from the make up of healthy<br />
cells - then medical science can develop ways to correct the<br />
defects.<br />
One of the difficulties researchers face is a lack of suitable<br />
human cancer research models. An outstanding success this<br />
year has been the development of a three-dimensional model<br />
of normal breast tissue. This model is enabling researchers<br />
to grow tiny spheres of cells taken from breast tissue in a<br />
highly organised structure, which is more closely aligned<br />
physiologically to the human system than traditional cell culture<br />
or animal models.<br />
In using the model, researchers are unraveling the process of<br />
how breast cells become cancerous through the actions of<br />
the ovarian hormones oestrogen and progesterone. Major<br />
advancements are already in play with researchers identifying<br />
pathways these hormones control within the normal breast<br />
cells. As work progresses, researchers hope to identify the<br />
normal breast cell targets that control the interaction between<br />
the ovarian hormones and cancerous cells to produce suitable<br />
prevention strategies.<br />
00.005.0490 00.005.0485 00.005.0487 00.005.0486 00.005.0459 00.005.0458<br />
46<br />
The <strong>Institute</strong> hosts the newly opened Breast Cancer Tissue<br />
00.005.0463<br />
46<br />
Bank. The bank has begun collecting breast cancer tissue<br />
samples from hundreds of women with breast cancer across<br />
NSW. This is a major achievement made possible through the<br />
cooperation of clinicians and patients. Data from the samples<br />
will be carefully linked back to the women’s follow up treatment<br />
and outcomes and researchers from all over Australia will have<br />
access to the bank to improve investigations into the disease.<br />
Cancer researchers Rick Kefford and Graham Mann are the<br />
determine the genetic signatures that make particular melanoma<br />
tumours behave aggressively using modern gene expression<br />
and microarray technology. Researchers hope to develop new<br />
treatments that target molecular faults within the cells to improve<br />
diagnosis and prognosis of this disease, enabling clinicians to give<br />
patients better treatment and advice.<br />
00.005.0482 00.005.0481<br />
Of all human cancers melanoma is most resistant to current<br />
therapies and it is an area where researchers are also using gene<br />
expression analysis (examining how genes operate within a cell)<br />
to produce better treatment outcomes for patients. The <strong>Institute</strong><br />
is investigating features in the few melanomas that are sensitive<br />
to treatment as a basis for developing techniques to breakdown<br />
the disease’s resistance to chemotherapy.<br />
Ovarian cancer is the most lethal gynaecological cancer. Each<br />
year, more than 1,000 women in Australia are diagnosed and<br />
more than 800 women die from the disease. Overall survival<br />
rates are low with only about 45 per cent of women free of the<br />
malignancy after five years.<br />
00.005.0465 00.005.0466<br />
51<br />
00.005.0462<br />
Most ovarian cancers are initially sensitive to chemotherapy.<br />
However, the most common outcome for women with this<br />
disease is for it to return within a couple of years and, when<br />
the patient relapses, the cancer is most often resistant to<br />
chemotherapy. There are however, a small group of patients<br />
that respond extremely well to chemotherapy and are essentially<br />
cured. Researchers in the Gynaecological Cancer Research<br />
Group are trying to identify why some patients respond so<br />
much better to treatment than others in the hopes of developing<br />
new therapies based on gene targeting.<br />
They have already identified one gene that may be used to<br />
increase response to chemotherapy and this work has led to an<br />
international patent. The researchers have found tumours that<br />
express a lot of this gene tend to do worse, and that this gene<br />
is over-expressed in ovarian cancer cells which are resistant to<br />
treatment. (Expression is the process of a gene’s DNA sequence<br />
being converted to proteins within cells.) The group is now<br />
investigating methods to decrease the gene’s expression using<br />
a novel technique called siRNA, which specifically targets the<br />
Most cancers are due to genetic changes that accumulate in the cells with<br />
leading chief investigators on a five-year NHMRC Program gene. The aim is to then apply conventional chemotherapy<br />
age, but in 5 to 10 per cent of cases, patients have a family history of multiple<br />
Grant and a Cancer <strong>Institute</strong> NSW Translational Program grant, to improve a patient’s response to treatment. Pre-clinical<br />
cases of early-onset cancer. Many patients are enrolled in collaborative,<br />
both of which commenced in 2006. These cement long-standing experiments are underway with a commercial partner being<br />
00.005.0491 00.005.0492 00.005.0488 00.005.0489 00.005.0460 00.005.0461 collaborations with 00.005.0468 the Sydney Melanoma Unit 00.005.0469 – the largest sought to 00.005.0516 develop methods to target this 00.005.0517 gene. The group is also 00.005<br />
genetic-epidemiological studies investigating the familial aspects of cancer.<br />
28 26<br />
melanoma treatment centre in the world. The programs aim to investigating other genes with similar characteristics to possibly<br />
extend the treatment base.<br />
00.005.0464 00.005.0515
16 17 > Overview // AR 2006<br />
Liver and Metabolic<br />
HO<br />
3<br />
A<br />
5<br />
The Liver and Metabolic division researches aspects of<br />
liver disease that affect patients in Australia with a focus<br />
on hepatitis B and C, fatty liver disease and liver cancer.<br />
The Storr Liver Unit researchers conduct many exciting<br />
projects. The unit has been investigating the molecular causes<br />
of fatty liver disease (FLD) and ways to reduce its increasing<br />
prevalence. Of all liver disease, FLD is the most common<br />
in Australia. It occurs through an accumulation of fat in the<br />
liver and is closely linked to overweight, obesity and diabetes<br />
- about 70 per cent of Australians are overweight or obese<br />
and diabetes affects about one in five Australians.<br />
Researchers have been examining the importance of bile acids<br />
to the origin and progression of FLD. The molecule NF-kB<br />
has also been shown to trigger inflammation and damage in<br />
patients with FLD. Importantly, the unit has also established<br />
a link between obesity and hepatic fibrosis (liver scarring),<br />
B<br />
6<br />
C<br />
Cholestorol<br />
D<br />
17<br />
which can eventually lead to cirrhosis or end stage liver<br />
disease. Patients with FLD have increased levels of leptin, a<br />
hormone secreted by fat cells and attributed to have a major<br />
role in regulating the appetite and metabolism. The Unit<br />
has now identified how leptin acts on certain cells found in<br />
the liver called Kupffer cells, to release proteins, which then<br />
activate the cells responsible for fibrosis.<br />
The Storr Liver Unit is also conducting a two-year Lifestyle<br />
Intervention study for fatty liver disease, which is the world’s<br />
first and largest clinical trial aimed at reducing overweight<br />
and obesity levels in these individuals. The study is based<br />
on a behaviour modification program designed to break<br />
down the psychological barriers that prevent patients from<br />
maintaining a healthy lifestyle. More than 170 patients have<br />
been recruited for the trial. Results at three months already<br />
show improvements in physical activity, weight, liver tests and a<br />
reduced risk of diabetes in those who received the intervention.<br />
not being screened, rendering the trial redundant. Despite<br />
professional concerns over the stress that diagnostic screening<br />
may cause, patients preferred this to not knowing if they had<br />
cancer. A screening protocol has now been implemented.<br />
It has shown that malignant tumours were detected at an<br />
earlier stage when they were smaller and easier to treat,<br />
suggesting that screening protocols are appropriate for this<br />
disease.<br />
In other research, the Storr Liver Unit has been looking<br />
at the role of bile acids in drug metabolism. There is huge<br />
individual variation in how patients respond to drugs.<br />
Traditionally, drug doses in treatments such as chemotherapy<br />
are administered using the same dose for all persons.<br />
However, while one patient may have little response another<br />
may develop serious side effects. Exploring molecules called<br />
nuclear receptors within the liver, researchers have been<br />
trying to understand differences in individual variations<br />
in these drug responses, in an effort to develop more<br />
‘personalised’ medicine.<br />
The unit is also conducting novel work in the area of human<br />
genome mapping in individuals who have been treated for<br />
hepatitis C. Researchers are in the preliminary stages of<br />
understanding how to scan the entire genetic code of these<br />
individuals to work out why some respond to hepatitis C<br />
treatments and others do not. These investigations seek to<br />
identify whole genome differences between the two groups<br />
of individuals with the ultimate aim of reading a patient’s<br />
molecular signature to administer better treatment regimens.<br />
If successful, this technology could eventually be used for<br />
many disease treatments.<br />
Propionyl-CoA<br />
NADP + H +<br />
O 2<br />
7`-hydroxylas<br />
NADPH + H +<br />
O 2<br />
2 CoA-SH<br />
The rate at which drugs are cleared from the body can vary substantially<br />
between individuals and have a major influence on the effectiveness and<br />
toxicity of treatments. Researchers are exploring molecules called nuclear<br />
receptors within the liver trying to understand differences in individual<br />
drug responses.<br />
In another world first, the unit recently abandoned a<br />
OH<br />
proposed randomised controlled trial to address doubts over<br />
the benefits of liver cancer screening. An overwhelming<br />
majority (95 per cent) of patients chose to be screened over<br />
C – S – CoA<br />
O
18 19 > Overview // AR 2006<br />
Neuroscience and Vision<br />
Our researchers have commenced studies on the genetic epidemiology<br />
of psychiatric disorders. The ultimate aim of these studies is to identify a<br />
genetic predisposition to various brain disorders at a very early stage.<br />
The Neuroscience and Vision division is investigating the<br />
causes of emotional disorders, mental illness and visual<br />
disorders, using a combination of imaging technology,<br />
molecular biology and epidemiology.<br />
The Brain Dynamics Centre is a world leader in<br />
interdisciplinary brain and mental health research.The centre<br />
focuses on major mental illnesses including schizophrenia,<br />
depression, attention deficit hyperactivity disorder (ADHD)<br />
and related behavioural disorders (such as conduct disorder),<br />
anxiety disorder, particularly post traumatic stress disorder<br />
(PTSD), and more recently conversion disorders.<br />
Finding suitable treatments for these disorders has been<br />
difficult for clinicians since their origins are still largely<br />
unknown. This has motivated researchers to make use of all<br />
available diagnostic techniques - genotyping, EEG, MRI,<br />
psychometrics - to quantify brain dysfunction at all scales.<br />
This, in turn, informs quantitative and conceptual models<br />
of disorders. Researchers at the centre have also developed<br />
new methods to analyse the data. For the first time they<br />
have a complete map or model showing how the brain<br />
functions physically and chemically to be able to navigate<br />
abnormal changes in the brain. Researchers can use the<br />
brain map to understand how individuals may respond to<br />
different therapies, ultimately leading to more accurate and<br />
personalised treatments being prescribed faster.<br />
In another breakthrough this year, research has identified<br />
key cognitive and biological markers of ADHD. They have<br />
also identified which of these markers are improved with<br />
stimulants such as Ritalin. These are important findings<br />
because they provide an objective test to assess which children<br />
are likely to respond best to stimulants. A new trial is now<br />
underway to test which children may respond to nonstimulant<br />
medication.<br />
Researchers have also shown that biological changes in the<br />
brain occur with PTSD and predict response to psychological<br />
treatments. In addition, researchers have learnt biological<br />
changes in the brain are a major factor in anorexia nervosa,<br />
a chronic eating disorder affecting mostly young women.<br />
Testing pre and post treatment is again determining which<br />
biological markers improve with medical treatment. This<br />
research also offers insights into whether medication may be<br />
of help for some individuals with anorexia.<br />
While the causes of schizophrenia are still unknown, the<br />
researchers have identified candidate cognitive and biological<br />
markers of this condition. Cognitive remediation is being<br />
trialled for the first time in Australia to target specific<br />
problems such as poor memory or information processing.<br />
The Centre for Vision Research investigates the causes of<br />
vision impairment to reduce the impact these conditions<br />
have on people’s lives. The centre has been conducting visual<br />
impairment studies in older and younger people for more<br />
than a decade. Researchers are concentrating on several<br />
themes including the genetic and nutritional influences on<br />
eye diseases.<br />
Recently, a 10-year examination on a group of more than<br />
3,650 people was completed as part of the landmark Blue<br />
Mountains Eye Study. Using baseline photographs taken of<br />
patients’ retinal vessels, researchers have been able to show<br />
the diameter of retinal arteries is strongly related to blood<br />
pressure levels now and into the future, making it a strong<br />
marker for cardiovascular disease risk. Researchers have also<br />
confirmed the retinal veins are markers associated with disease<br />
such as diabetes, and can also indicate if a patient smokes and<br />
whether they have generalised inflammatory problems.<br />
Researchers involved in the Blue Mountains Eye Study have<br />
also investigated the role fish high in omega-3 fatty acids play<br />
in affecting factors leading to cardiovascular disease. Those<br />
who ate moderate amounts of fish had better retinal factors<br />
at the study’s commencement and had reduced risk of heart<br />
attack and stroke 10 years on.<br />
A separate study has shown individuals who ate a diet with<br />
a higher glycaemic index (the speed of which glucose is<br />
absorbed in the blood) are more prone to cataracts and<br />
macular degeneration. Similarly, those with signs of macular<br />
degeneration who ate higher amounts of fish high in omega-<br />
3 fatty acids could slow the disease’s progression.<br />
The centre has expanded its investigations into the causes of<br />
short-sightedness to include children from Singapore. Myopia<br />
levels in south-east Asian countries have grown exponentially<br />
in the past 50 years. Ninety per cent of university graduates<br />
in Singapore are short sighted as are young people joining the<br />
armed forces. A study comparing myopia levels in children<br />
in Sydney and Singapore with similar Chinese backgrounds<br />
and age-related profiles showed the Sydney children had very<br />
low rates of the condition (3 per cent), while the children in<br />
Singapore had much higher rates (29 per cent). Researchers<br />
believe the time children generally spend playing outdoors<br />
directly correlates to myopia levels.
20 21 > Overview // AR 2006<br />
Cardio-respiratory<br />
Laboratory and clinical studies are combined by respiratory researchers<br />
hoping to identify breathing and sleep disorders linked to or resulting from<br />
a disease or injury.<br />
The Cardio-respiratory division combines laboratory<br />
research and clinical studies to enhance our understanding<br />
of common cardio and respiratory disorders like abnormal<br />
heart rhythms and sleep disorders.<br />
The Centre for Heart Research is focused on finding better<br />
treatments for patients with abnormal heart rhythms and to<br />
cures these conditions.<br />
Ventricular trachycardia (VT) is a debilitating condition that<br />
causes the heart to beat rapidly, affecting the heart’s pumping<br />
chambers or ventricles. It usually occurs when the heart<br />
muscle has sustained damaged from previous heart attacks<br />
and can cause sudden death.<br />
VT is treated using a defibrillator, a device which triggers a<br />
painful electric shock to normalise the heartbeat. A therapy<br />
can be applied which modifies abnormal electrical activity<br />
responsible for VT, reducing the need for patients to undergo<br />
the electric shocks. This method uses radiofrequency ablation<br />
to heat the heart tissue using electrical energy to destroy<br />
small regions responsible for VT. To locate these areas more<br />
effectively, researchers are working on a three-dimensional<br />
mapping system, which is based on satellite navigation<br />
technology, to guide clinicians directly to the scarred areas.<br />
Researchers are also developing a novel catheter, which<br />
is positioned within the patient’s heart to indicate where<br />
abnormal electrical activity is originating from. This can be<br />
done from a single abnormal heartbeat, which is a major<br />
improvement on previous methods. The ultimate aim for<br />
researchers is to perfect these innovations so patients with VT<br />
may be cured of the condition.<br />
Researchers have also been working on improving outcomes<br />
for patients with atrial fibrillation (AF), rapid heart-beating in<br />
the upper heart chamber, which leads to stroke in about 15<br />
per cent of people aged over 75 years.<br />
Technology developed in France to isolate electrical triggers that<br />
cause AF is being offered to <strong>Westmead</strong> Hospital patients as an<br />
alternative to medication or open-heart surgery. Researchers at<br />
the centre are working to improve the 70 per cent efficacy of<br />
this treatment and to improve the procedure’s success rate.<br />
Among other projects, researchers have begun collaborating<br />
with <strong>Westmead</strong> Hospital’s cardiothoracic unit to investigate<br />
ways of refining the artificial mitral valve used to replace the<br />
diseased valve in patients.<br />
The Ludwig Engel Centre for Respiratory Research aims to<br />
improve the quality of life for patients with respiratory and<br />
sleep-related respiratory diseases.<br />
The centre primarily researches the causes, consequences<br />
and potential new treatments of the obstructive sleep apnoea<br />
syndrome, a disorder affecting about 800,000 Australians.<br />
Other research areas include cystic fibrosis, asthma and<br />
chronic obstructive pulmonary disease.<br />
Patients with sleep apnoea experience repeated episodes<br />
of throat blockage during sleep, which stops them from<br />
breathing for short periods of time. The disorder results<br />
from snoring and obstructed breathing and is linked to<br />
hypertension, heart failure, heart attacks as well as stroke.<br />
Over the past year, researchers have been looking at the<br />
role heavy snoring may play in triggering stroke. Vibrations<br />
caused from heavy snoring travel in tissues surrounding<br />
the airways to the carotid arteries found in the neck, which<br />
supply blood to the brain. Researchers are investigating<br />
whether this may exacerbate atherosclerosis (hardening) in<br />
the carotid arteries eventually leading to stroke.<br />
Clinical studies yet to be published on a group of 110<br />
patients with varying degrees of heavy snoring and mild sleep<br />
apnoea showed heavy snoring was associated with a 10- to<br />
17-fold increase in the risk of carotid artery vascular disease.<br />
As research continues, approaches to treatment may alter to<br />
include more regular screening of carotid arteries in patients<br />
who snore heavily and increased research into preventative<br />
therapies for the condition.<br />
Studies over the past year have also assessed the efficacy of<br />
a rehabilitation program designed to minimise hospital<br />
admissions and improve quality of life and wellbeing in<br />
patients with chronic obstructive lung disease. The program<br />
uses a combination of aerobic exercise, education, clinical<br />
support and medication optimization. This successful<br />
combination has been shown to add 60 metres to patients’<br />
walking distance and reduce hospital admission rates over<br />
two years following completion of the program and improve<br />
general wellbeing.
22 23 > Overview // AR 2006<br />
International Collaborations<br />
Medical research today is an international activity and some<br />
research projects like the sequencing of the human genome<br />
are only made possible by international co-operation.<br />
From the outset the <strong>Institute</strong> has formed international links<br />
and partnerships with research institutes, hospitals and<br />
universities across the globe.<br />
UNITED KINGDOM<br />
Cambridge<br />
Dundee<br />
Glasgow<br />
Leicestershire<br />
London<br />
Manchester<br />
In 2006, our research projects span the world’s continents,<br />
from Moscow to Manila to Minneapolis. These<br />
collaborations allow our researchers to contribute and gain<br />
valuable research knowledge.<br />
While we participate on this international stage we also<br />
work closely with our Australian based research partners.<br />
Together this assists us in achieving our goal of better<br />
prevention strategies, treatments and healthcare for all.<br />
MIDDLE EAST<br />
Taran - Iran<br />
Tel Hashomer (near Tel Aviv)<br />
ASIA<br />
Beijing<br />
Manila<br />
Singapore<br />
Tokyo<br />
USA<br />
Baltimore<br />
Boston<br />
Cambridge (Massachusetts)<br />
Chicago<br />
Denver<br />
Houston<br />
Michigan<br />
New York<br />
Philadelphia<br />
San Diego<br />
San Francisco<br />
Seattle<br />
Washington DC<br />
EUROPE<br />
Geneva<br />
Hamburg<br />
Madrid<br />
Moscow<br />
Nijmegen (Netherlands)<br />
Paris<br />
Perugia<br />
Rome<br />
Rotterdam<br />
Wuppertal (Germany)<br />
Zurich<br />
SOUTH AFRICA<br />
Alberton<br />
Durbinw<br />
Sydney<br />
NEW ZEALAND<br />
Auckland
24 25 > Overview // AR 2006<br />
Advisory Board and Council of Governors<br />
Organisation Structure<br />
WMI ADVISORY BOARD<br />
ADVISORY BOARD<br />
GOVERNORS<br />
Chair – Mr Paul Bell<br />
DIVISIONS AND GROUPS<br />
INFECTION & IMMUNITY<br />
Mr Paul Bell<br />
Chairman<br />
R2<br />
Professor Gavin Brown AO<br />
Vice-Chancellor, University of Sydney<br />
Professor Peter Castaldi AO<br />
57<br />
57<br />
57<br />
57<br />
8<br />
8<br />
8<br />
Professor Tony Cunningham<br />
Director, <strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong><br />
8<br />
8<br />
57<br />
8<br />
05<br />
N53<br />
R2<br />
57<br />
Mr Philip Chronican<br />
57<br />
57<br />
Group Executive, Westpac Institutional Bank<br />
8<br />
57<br />
X<br />
57<br />
57<br />
N53<br />
N53<br />
57<br />
57<br />
57<br />
57<br />
57<br />
8<br />
57<br />
57<br />
57<br />
57<br />
57<br />
57<br />
57<br />
Professor Jeremy Chapman<br />
Network Director, Acute Interventional Medicine<br />
Sydney West Area Health Service<br />
Mr David Greatorex AO<br />
Mr Jim Bosnjak OAM<br />
Chairman, Bosnjak Investment Group<br />
N59<br />
57<br />
57<br />
Dr Peter Farrell<br />
Chief Executive Officer, ResMed Australia<br />
Professor Ian Gust AO<br />
N53<br />
DIRECTOR<br />
Prof Tony Cunningham<br />
CHIEF OPERATING OFFICER<br />
Mr Mark Dado<br />
OPERATIONS<br />
Manager, Mr Glenn Holden<br />
FACILITIES AND<br />
GRANT ADMINISTRATION<br />
Manager, Mr Mark Smith<br />
FINANCE<br />
Manager, Mr Mark Wissam<br />
Centre for Infectious<br />
Diseases and Microbiology<br />
Director, Professor Tania Sorrell<br />
Centre for Transplant and<br />
Renal Research<br />
Director, Transplantation<br />
A/Prof Phillip O’Connell<br />
Director, Nephrology<br />
Prof David Harris<br />
Centre for Virus Research<br />
Director, Prof Tony Cunningham<br />
<strong>Institute</strong> of Dental Research<br />
Director, Prof Neil Hunter<br />
<strong>Institute</strong> for Immunology<br />
and Allergy Research<br />
Director, Prof Graeme Stewart<br />
LIVER & METABOLIC<br />
Storr Liver Unit<br />
Co-Acting Director,<br />
Prof Jacob George<br />
Co-Acting Director,<br />
Prof Christopher Liddle<br />
NEUROSCIENCE & VISION<br />
Brain Dynamics Centre<br />
Director, A/Prof Lea Williams<br />
Centre for Vision Research<br />
Director, Prof Paul Mitchell<br />
PR2<br />
N59<br />
PR2<br />
57<br />
Mr James Wakim<br />
Managing Director, Arab Bank Australia<br />
Mr Patrick Wilde<br />
President, The <strong>Millennium</strong> Foundation<br />
R4<br />
N59<br />
R2<br />
R2<br />
OR6<br />
R2<br />
R2<br />
57<br />
Professor Janice Reid<br />
Vice-Chancellor, University of Western Sydney<br />
R2<br />
HUMAN RESOURCES<br />
Manager, Ms Amanda Clout<br />
PR AND COMMUNICATIONS<br />
Manager, Ms Gayle McNaught<br />
Information Technology<br />
CANCER<br />
<strong>Westmead</strong> <strong>Institute</strong> for<br />
Cancer Research<br />
Director, Prof Rick Kefford<br />
CARDIO-RESPIRATORY<br />
Centre for Heart Research<br />
Director, Dr Pramesh Kovoor<br />
Ludwig Engel Centre for<br />
Respiratory Medicine<br />
Director, A/Prof John Wheatley<br />
N53<br />
R4<br />
OP4<br />
R2<br />
R2<br />
OR6<br />
Manager, Mr Ian Magee<br />
Science Council<br />
Chair, A/Prof Christine Clarke<br />
R4
26 27 > Overview // AR 2006<br />
Funding<br />
Infrastructure Grants 2,651,483<br />
Funding Organisations<br />
During 2006 the <strong>Institute</strong> received research funding from the following major organisations. We thank them for their support.<br />
Allergan Australia Pty Ltd<br />
Leukaemia Foundation<br />
National Health and Medical Research Council Grants 7,814,750<br />
Other Grants 8,412,863<br />
Other Income 2,055,313<br />
Total 20,934,409<br />
American Health Assistance Foundation<br />
Anthony Rothe Memorial Trust<br />
Australia and New Zealand Intensive Care Foundation<br />
Australian Centre for HIV and Hepatitis Virology Research<br />
Australian Cystic Fibrosis Research Trust<br />
Australian Dental Research Foundation<br />
Australian Health Ministers’ Advisory Council<br />
Australian Research Council<br />
Australian Rotary Health Research Fund<br />
Australian Society for Psychiatric Research<br />
Biogen Idec Australia<br />
Cancer <strong>Institute</strong> NSW<br />
Cure Cancer Foundation<br />
Eli Lilly Australia Pty Ltd<br />
Janssen-Cilag Pty Ltd<br />
Juvenile Diabetes Research Foundation<br />
Juvenile Diabetes Research Foundation International<br />
Kidney Health Australia<br />
Multiple Sclerosis Research Australia<br />
National Breast Cancer Foundation<br />
National Health and Medical Research Council<br />
National Heart Foundation of Australia<br />
National <strong>Institute</strong>s of Health (USA)<br />
NSW Office of Science and Medical Research<br />
Pfizer Australia Pty Ltd<br />
Red Cross Blood Transfusion Service<br />
Robert W Storr Bequest<br />
Roche Products Pty Ltd<br />
Sanofi-aventis Australia Pty Ltd<br />
Schizophrenia Research <strong>Institute</strong><br />
The Australian Lung Foundation<br />
The Cancer Council New South Wales<br />
The Cardiac Society of Australia and New Zealand<br />
The <strong>Millennium</strong> Foundation<br />
University of Sydney<br />
University of Sydney Cancer Research Fund
28 29 ><br />
Research Report // AR 2006<br />
Research Report
.<br />
< 30 31 > Research Report // AR 2006<br />
Infection and Immunity<br />
Centre for Infectious Diseases and Microbiology<br />
Fungal pathogenesis<br />
The group has shown that specialised lipid domains<br />
(“rafts”) in the cell membrane of the fungus Cryptococcus<br />
neoformans, which causes severe meningitis, serve as sites<br />
of attachment of a key enzyme, phospholipase B (PLB).<br />
This enzyme is attached to the raft by an anchor. When<br />
released from the anchor, free PLB1 facilitates penetration<br />
of Cryptococcus into lung and brain. We are now studying<br />
how the production and release of PLB1 is regulated and<br />
the mechanism by which it is released from the membrane.<br />
This fundamental knowledge will lead to new understanding<br />
of cryptococcal biology and help us to identify new<br />
target molecules for development of drugs to treat fungal<br />
infections. This work was received with great interest by the<br />
international cryptococcal research community.<br />
Antifungal drug development<br />
The group has an NHMRC project grant to make and test<br />
new chemical compounds that act on enzymes produced by<br />
fungi, which are important in virulence (and hence initiation<br />
of disease). Led by synthetic chemist, Dr Kate Jolliffe, 50<br />
novel compounds in 2 chemical classes have been made and<br />
tested against a range of fungi that cause disease in humans.<br />
Particular interesting is one class of compound related to<br />
a marketed drug, miltefosine, which was developed as an<br />
anti-cancer drug and is now used for treatment of a parasite<br />
infection (leishmaniasis). We will be undertaking further<br />
modification and testing of the most promising compounds<br />
in 2007.<br />
Bacterial pathogenesis, antibiotic resistance and<br />
novel diagnostics<br />
The group was the first to identify and have since<br />
characterised the genetic basis of newly arrived transmissible<br />
resistance to carbapenem antibiotics and the CTX-M<br />
type ESBLs newly arrived in Australia, including novel<br />
gene variants. The group has defined the basis for most<br />
major antibiotic resistance genes relevant in ICU in<br />
Australia, and begun to incorporate these into novel highspeed<br />
multiplexed assays in collaboration with industry<br />
partners. Assays developed for rapid detection of S. aureus,<br />
MRSA, and influenza (including H5N1 “bird flu”) are<br />
now entering clinical trials. Our work has been presented<br />
in major international conferences (eg ICAAC) and<br />
journals (eg Lancet Infections Diseases, Nature Reviews<br />
Microbiology). New areas include bacteriophage therapeutics<br />
(in collaboration with industry), novel immunofluorescence<br />
methods (funded by ARC, in collaboration with Macquarie<br />
University) and quorum-sensing inhibitors (funded by ARC,<br />
in collaboration with BioSignal/ UNSW).<br />
Nuclear magnetic resonance spectroscopy<br />
This has been a very successful year, with the completion of<br />
studies showing that biochemical profiles of different fungi<br />
can be identified by NMR spectroscopy and hence be of<br />
diagnostic value, and that resistance to medicines used in<br />
1<br />
NH 2<br />
1<br />
2<br />
2<br />
therapy can also be rapidly determined using this technology.<br />
The work has been published in the top international<br />
antibiotics journal and was presented at the leading<br />
international meeting on mycology (ISHAM), in Paris, in<br />
June 2006.<br />
Improved outcomes in immunosuppressed<br />
haematology patients<br />
This is a large Centre of Clinical Excellence Program now<br />
in its second year. So far research highlights have included<br />
a study of the occurrence, transmission and prevention of<br />
community respiratory virus infections in patients with<br />
cancer of the blood. Importantly the group has shown that<br />
protection of patients is improved by routine vaccination<br />
against influenza and education of patients, their carers,<br />
and staff about the importance of hand washing and other<br />
infection control measures. Several important ethics studies<br />
are underway, assessing patients understanding of informed<br />
consent for treatments that they receive, their response to<br />
living with cancer, and the effect of isolation during times of<br />
very low function of the immune system (in order to prevent<br />
serious infections). Other key programs are proceeding<br />
in vaccine research and the development of faster tests for<br />
diagnosis of infections, in order prevent, or to improve<br />
outcomes of serious infections through more rapid diagnosis<br />
and thus commencement of treatment.<br />
3<br />
6<br />
s<br />
s<br />
s<br />
10<br />
Centre for Transplant and Renal Research<br />
Pancreatic islet cell transplantation<br />
Following the units pioneering clinical trial of pancreatic islet<br />
transplantation they have been chosen to lead an Australia<br />
s<br />
11<br />
Peptide C<br />
wide consortium with the aim of developing pancreatic islet<br />
transplantation as a mainstream therapy for patients with<br />
difficult to control diabetes. The original trial involved six<br />
patients with severe metabolic complications from their<br />
diabetes. Five of the six had marked improved metabolic<br />
outcomes after successful pancreatic islet transplantation<br />
and three patients no longer required insulin injections for<br />
substantial periods of time. This trial identified progressive<br />
loss of islet graft function and complications from the<br />
anti-rejection drugs as the major impediments to it more<br />
widespread application. The new study, which has been<br />
funded by the Federal Government and the JDRF aims to<br />
identify factors that cause graft damage and to develop a safer<br />
immunosuppressive regimen.<br />
Pancreatic islet xenotransplantation research<br />
Currently pancreatic islet cell transplantation is the only<br />
known cure for Type 1 diabetes. If this therapy is to be<br />
more effective sources of insulin producing cells other than<br />
B<br />
A<br />
organ donors needs to be found. In collaboration with<br />
researchers in Melbourne and Adelaide we are investigating<br />
the use of pig pancreatic islet cells for future transplantation<br />
in human patients. The group’s current research is focused<br />
on understanding the mechanisms of early islet cell loss.<br />
This appears to be due to a combination of clotting and<br />
early cellular rejection. Our data suggests that producing<br />
pigs whose islet cells express several human proteins that<br />
regulate clotting and rejection may be sufficient to allow<br />
this tissue to be used safely in patients. This information<br />
has been used to develop a new line of pigs that have been<br />
genetically modified so that they may be better suited to<br />
clinical transplantation. Australia is the world leader in pig<br />
transgenesis and this ambitious collaborative project between<br />
four research institutes is making substantial progress in the<br />
development of pig islet cell xenotransplantation.<br />
Transplantation immunity and tolerance<br />
The aim of this group is to better understand the<br />
mechanisms of rejection of pancreatic islet xenografts<br />
and to develop novel strategies for suppressing this<br />
immune response. The group has made several findings in<br />
understanding the role macrophages play in the rejection<br />
of pig islet grafts. In particular they have shown that<br />
macrophages have a surprisingly specific and sophisticated<br />
recognition response for identifying pig tissue. At present<br />
work in this area is focusing on understanding the molecular<br />
mechanisms responsible for this recognition. In particular<br />
we have focused on a group of macrophage receptors called<br />
toll receptors and have found that they have an important<br />
role in regulating macrophage recognition of pig tissue.<br />
The group is also investigating novel strategies to induce<br />
tolerance to transplanted islet tissue and to further reduce<br />
the requirement for long-term immunosuppression. In<br />
particular they are focusing on the role of a regulatory T cell<br />
called CD4CD25+ T cells. They have found that these cells<br />
are capable of inducing tolerance to islet allografts and have<br />
begun investigating their role in maintaining tolerance to pig<br />
islet cells.<br />
Chronic allograft nephropathy research<br />
The aim of this group is to increase knowledge about the<br />
mechanisms for the long-term loss of renal transplant.<br />
Current treatment strategies are very good at preventing<br />
acute cellular rejection but over time renal transplants are<br />
s<br />
20<br />
s<br />
21<br />
still lost to a complex process known as Chronic Allograft<br />
Nephropathy. The group has been at the forefront of this<br />
research internationally and by studying protocol biopsies<br />
has identified several novel factors responsible for this<br />
chronic graft loss. The focus of the group is to understand<br />
the molecular mechanisms responsible for this loss<br />
using a genome wide analysis of biopsy specimens using<br />
genomics or gene chips. This had allowed us to identify<br />
early mechanisms of graft fibrosis and glomerulosclerosis.<br />
Which in turn has allowed us to understand better the<br />
early pathology that ultimately leads to chronic allograft<br />
nephropathy. Ultimately it will assist us to develop a<br />
diagnositic test that predicts those patients that will develop<br />
this condition and to design new treatments. In the last 6<br />
months we have been successful in obtaining funding from<br />
the National <strong>Institute</strong>s of Health in the US to take part in<br />
a large multicentre study that will identify the genomics of<br />
Chronic Allograft Nephropathy.<br />
COOH
32 33 > Research Report // AR 2006<br />
Renal failure research<br />
include using soluble receptors as decoys binding to the virus<br />
role in subverting human gene machinery in different cell<br />
partially effective vaccine candidate has been developed<br />
This research is focused on novel therapies for reducing<br />
as well as direct antagonism of the HIV binding receptors.<br />
types. The Retroviral Genetics lab also runs services for drug<br />
(partly based on our previous work) but is not yet licensed.<br />
kidney inflammation in chronic kidney disease. New<br />
approaches to treatment that are currently being tested<br />
in animal models of human kidney disease include the<br />
administration of protective cells (regulatory macrophages<br />
and regulatory T lymphocytes) which reduce inflammation<br />
and structural and functional injury. In addition, vaccination<br />
using genes of molecules that drive the inflammatory<br />
response is also being tested. We have exciting preliminary<br />
results in models of diabetic nephropathy, suggesting that<br />
this approach not only slows the progression of diabetic<br />
kidney disease, but also reduces the severity of diabetes itself,<br />
and also reduces diabetic complications occurring in other<br />
organs including eyes and heart. These novel approaches are<br />
bringing new understanding to the processes that underlie<br />
the progressive nature of kidney disease, and have the exciting<br />
potential of use for treating human kidney disease.<br />
Centre for Virus Research<br />
HIV molecular pathogenesis<br />
The HIV molecular pathogenesis group’s primary focus is to<br />
understand the very early interactions of the HIV virus with<br />
host cells of the body, predominantly human dendritic cells<br />
(DCs). These are the first cells to come into contact with<br />
HIV within the genital tract.<br />
In 2006 our group revealed that HIV induces partial<br />
maturation of DC and in doing so the virus may utilise<br />
the migratory capacity of DC to gain access to T cells in<br />
the lymph nodes. The group continues to investigate the<br />
mechanisms by which HIV subverts the maturation of<br />
DC and the effect this may have on the initiation of an<br />
appropriate immune response.<br />
The global gene changes that HIV induces in dendritic<br />
cells continue to be investigated using DNA microarray<br />
technology, and investigations are now being broadened to<br />
include the effects that HIV has on the proteins regulating<br />
the expression of interferons.<br />
Other investigations conducted in the laboratory involve<br />
investigating ways to prevent infection of DCs particularly<br />
those in skin and genital mucosa. The methods employed<br />
Preliminary studies indicate that these can be effective<br />
inhibitors. The ultimate goal is to reduce or even prevent viral<br />
trafficking at a very early stage of infection.<br />
HIV protein functions and interactions group<br />
The main interest of this group is to understand the function<br />
of several HIV proteins and their interaction with cellular<br />
proteins on a molecular level. The long-term aim is to<br />
identify novel antiviral therapeutics.<br />
During 2006, the research projects conducted by the group<br />
included understanding the role and function of the small<br />
HIV protein Vpr in viral isolates from AIDS patients,<br />
investigation of the role of the cytoplasmic tail of the<br />
envelope HIV glycoprotein 41, and a collaborative study to<br />
determine the role of DNA methylation in HIV replication.<br />
Retroviral genetics laboratory<br />
The Retroviral genetics laboratory focuses on several different<br />
aspects of HIV pathogenesis. We are working on the innate<br />
and adaptive immune factors which are found in untreated<br />
HIV+ patients with non-progressive disease.<br />
The main goal of this group is to understand what guides<br />
the path to non-progressive HIV disease in a subset of HIV+<br />
individuals and can these natural factors, which provide them<br />
protection, find some use as therapeutic agents/vaccines.<br />
We are adopting a variety of immunological, virological,<br />
proteomic and protein chemistry techniques to identify and<br />
characterize these novel factors from patients who have lived<br />
with HIV for more than 20 years.<br />
Another aspect of this study is genomics where we are<br />
gathering information based on the cell surface markers<br />
and whole human genome (>47,000 genes) to understand<br />
how HIV guides different stages of HIV disease in different<br />
hosts and in different cell types within the same host at the<br />
level of manipulating cellular phenotype and human gene<br />
machinery.<br />
Other studies in the lab are also directed at understanding<br />
HIV infection of the brain in relation to cellular infiltration<br />
across the blood brain barrier, HIV recombination,<br />
emergence of novel HIV strains, their pathogenesis and their<br />
resistance and epidemiologic testing of HIV in Australia.<br />
Cytomegalovirus research<br />
Human cytomegalovirus (CMV) is a medically important<br />
virus which infects 50-90% of the population. Whilst<br />
infection is usually mild in healthy individuals, it is a frequent<br />
cause of serious, life-threatening disease in neonates and<br />
immunosuppressed individuals such as solid organ and bone<br />
marrow transplant recipients, and in people with HIV AIDS.<br />
After initial (primary) infection, the virus is not completely<br />
cleared by the host’s immune system. Rather, the virus is<br />
able to establish a life-long latent infection, during which<br />
time the virus remains in the body but does not grow or<br />
cause disease. Periodically, the virus may reawaken from this<br />
latent state by a process called reactivation, resulting in the<br />
production of new infectious virus. Reactivation from the<br />
latent state in immunosuppressed individuals is thought to be<br />
the major cause of serious disease in these people, but despite<br />
the importance of latency and reactivation to the success of<br />
this virus as a human pathogen, these areas of the life cycle of<br />
CMV remain very poorly understood.<br />
The CMV research group is working to discover how the<br />
virus operates during the latent phase of infection. The<br />
group has applied a variety of molecular and cell biology<br />
approaches, including the use of microarray technologies,<br />
to identify both viral genes and human genes that play<br />
important roles during CMV latent infection of human cells.<br />
These studies have provided important insights into how<br />
the virus functions during latency. Identifying the critical<br />
virus and host cell components of latency and reactivation<br />
will provide a rational basis for the design of drugs and<br />
therapies to limit the consequences of CMV disease in<br />
immunosuppressed individuals.<br />
HSV immunology<br />
Herpes Simplex virus (HSV) causes two common infections,<br />
cold sores (HSV1) and genital herpes (HSV2). Its infection<br />
can sometimes result in encephalitis and neonatal herpes.<br />
Genital herpes enhances acquisition up to threefold. A<br />
The HSV immunology group is focused on discovering<br />
and developing new vaccine candidates and has also been<br />
studying the interaction between HSV and immune cells like<br />
dendritic cells (DC) and T lymphocytes.<br />
Dendritic cells (DC) are the most potent antigen presenting<br />
cells to stimulate T lymphocytes and classified as myeloid<br />
dendritic cells (mDC) and plasmacytoid dendritic cells<br />
(pDC). Langerhans cells are another type of DC residing<br />
in epidermis, which are presumed to play a primary role in<br />
herpes lesions. Such Langerhans cells have been shown to be<br />
infected in herpes lesions. How HSV infects these cells in<br />
vitro and alters their function is now being studied. pDCs<br />
are supposed to be restricted to blood and lymph nodes.<br />
However during 2006, the group used confocal microscopy,<br />
to identify pDC in the skin of genital herpes lesions but are<br />
not infected by HSV2.<br />
In herpes lesions CD4 lymphocytes are the first to enter<br />
and partly control HSV infection preparing the way for<br />
later infiltration by CD8 lymphocytes which clear up the<br />
infection. Some peptides in glycoprotein D (gD) of HSV2<br />
were identified as strong immunostimulatory antigens for<br />
CD4 T lymphocytes. Some of these “epitopes” are recognised<br />
by CD4 lymphocytes of people infected with HSV1 as well<br />
as HSV2, providing a rationale for why infection with one<br />
of these two viruses can protect against the other. Some of<br />
these peptides were conjugated to lipid (in collaboration with<br />
Professor David Jackson, University of Melbourne). The<br />
immunogenicity of the lipopeptides were improved 2-3 fold.<br />
We are currently examining the mechanism of these effects.<br />
Viral transport and assembly<br />
Herpes Simplex virus (HSV) enters the body via the skin<br />
before entering the termini of nerve cell processes. It is<br />
transported along these processes to the body of the nerve<br />
cell. HSV lies dormant within these nerve cell bodies near<br />
the spinal cord in most people. Intermittently the virus<br />
reactivates and is transported back down the nerve cell<br />
processes to the skin where it causes blisters and ulcers or is<br />
shed without causing symptoms.
34 35 > Research Report // AR 2006<br />
One aim of the group is to determine how HSV is assembled<br />
on to identify the first VZV encoded anti-apoptotic gene<br />
Oral bacteria and infective endocarditis<br />
porphyrin macrocycle and therefore must obtain this from<br />
within cells at the molecular level. Recent work has identified<br />
ORF63. To further our understanding of VZV with human<br />
Streptococcus gordonii is a primary coloniser of oral<br />
tissue sources, usually from haem-proteins that may also<br />
crucial molecular interactions required for viral assembly.<br />
nerve cells the group has developed a novel model of VZV<br />
microbial biofilms. This organism is considered to be<br />
supply iron. Research at the institute has identified the so-<br />
Such information on viral assembly will allow development<br />
infection of intact human explant ganglia. The group has<br />
beneficial in the oral environment but pathogenic when it<br />
called HA2 receptor as a porphyrin receptor important in the<br />
of inhibitors of this process which may be candidates for use<br />
shown for the first time that VZV can infect intact human<br />
colonises heart valves as this results in infective endocarditis.<br />
acquisition and surface storage of haem. In recent work this<br />
as antivirals for control of recurrent herpes simplex.<br />
ganglionic cells and this is a novel way of studying the<br />
There is considerable interest in attempting to engineer<br />
receptor mechanism was effectively used to selectively target<br />
The group also aims to examine the mechanism(s) involved in<br />
the entry, axonal transport, assembly and exit of HSV-1 from<br />
neurons. The group’s studies have shown how HSV can travel,<br />
assemble and exit from specialized sites along human nerves.<br />
Another aim of the group is to determine how HSV and<br />
HIV are transported within cells at the molecular level.<br />
Recent discoveries have shown how virus transport in cells<br />
is dependent on interactions between specific viral proteins<br />
and cellular “motor proteins” and how in the case of HSV<br />
the virus escapes from nerves to infect skin and cause disease.<br />
Such information on viral transport will allow development<br />
of inhibitors of this process which may be candidates for use<br />
as antivirals for control of recurrent herpes simplex or HIV.<br />
Varicella zoster virus<br />
Despite its significant impact on the community, little is<br />
known about the molecular basis of the Varicella zoster<br />
virus (VZV), due in part, to VZV only infecting humans.<br />
To more closely examine the interaction of VZV with host<br />
cells, the group has established several models of infection<br />
using human cell-types which are targets for infection and<br />
are relevant to those that suffer from either Varicella or herpes<br />
zoster/PHN because each of these cell types are likely to play<br />
different, but essential roles in the disease process. These<br />
include human fibroblasts (skin cells), neurons (nerve cells)<br />
and specialized immune cells (T cells and dendritic cells).<br />
The group has recently shown that human nerve cells<br />
infected with VZV do not undergo programmed cell death<br />
(apoptosis). This is an important finding because it suggests<br />
the nerve cell damage observed when VZV reawakens from<br />
its “silent” state in nerve cells to cause shingles is not due<br />
to programmed cell death. Another implication from this<br />
observation is that VZV encodes a function to interfere with<br />
the death response in human nerve cells, thus providing<br />
a possible mechanism by which the virus can establish<br />
and maintain its life-long dormant infection. We went<br />
interaction of this virus with human nerve cells.<br />
These features of intact ganglionic infection can now be<br />
studied in further detail to better define the molecular<br />
mechanisms that underlie VZV infection of ganglionic cells.<br />
For example, this model provides a means to rapidly test<br />
viral gene mutant viruses and new candidate vaccine strains<br />
containing targeted gene disruptions to define viral genes that<br />
may play critical roles in VZV neurotropism and to examine<br />
in detail the outcome of infection of both neurons and nonneuronal<br />
cells with respect to apoptosis and cell function.<br />
<strong>Institute</strong> of Dental Research<br />
Proteomics and structural genomics of oral pathogens<br />
The difficulty in preventing dental caries results from the<br />
need to devise a strategy to eliminate key cariogenic species<br />
without disrupting the overall complexity of the protective<br />
biofilm community on teeth. Solving this problem is at<br />
the forefront of research at the institute. The completion of<br />
a comprehensive series of comparative proteome studies,<br />
involving both planktonic and biofilm grown cells, has<br />
highlighted a number of biochemical events that are unique<br />
for the survival of the cariogenic pathogen, Streptococcus<br />
mutans, that proliferates under acidic conditions in dental<br />
plaque. Genes implicated in these adaptive responses,<br />
including alteration in acid tolerance and biofilm formation,<br />
are being systematically examined using a functional<br />
genomics approach. By defining the critical events associated<br />
with the survival and proliferation of S. mutans under<br />
conditions that lead to enamel dissolution, researchers at<br />
the <strong>Institute</strong> are gaining the necessary knowledge to develop<br />
a comprehensive strategy for intervention, thus allowing<br />
appropriate susceptible biochemical events to be targeted to<br />
control or eliminate disease.<br />
this bacterium to be both non-pathogenic and to resist<br />
displacement by oral pathogens such as Streptococcus<br />
mutans. In vitro gene expression technology has identified the<br />
gom locus comprising a regulon of 15 open reading frames<br />
implicated in bacterial growth, beneficial adhesion to the tooth<br />
surface, and pathogenic colonisation of heart valves. Analysis<br />
of this locus by researchers at the institute has focused on a<br />
group of novel glycosidases within the gom locus with the<br />
3D-structure of the first of these, GcnA, recently having being<br />
solved at high resolution. Current research is directed at the<br />
selective inhibition of this glycosidase as well as to determining<br />
the structure and function of other products of the gom locus<br />
including two related glycosidases that are also implicated in<br />
infective endocarditis.<br />
Polymicrobial aetiology of caries progression<br />
In studies at the institute, some eighty bacterial species<br />
were detected within the polymicrobial consortia of carious<br />
dentine that overlies the pulp following an extension of the<br />
enamel lesion of dental caries. However, recent studies have<br />
shown that pulpal infection, arising from end-stage disease, is<br />
far more selective. By using fluorescence in situ hybridisation<br />
(FISH), the complex consortia of bacteria associated with<br />
carious dentine has been shown to mass at the periphery of<br />
the soft tissue, with only a few species invading. Currently,<br />
the structural framework and spatial arrangement of bacterial<br />
invasion is being mapped. While clinically important from<br />
a dental perspective, this process also provides a rare insight<br />
into the dynamics of polymicrobial infections that impact<br />
severely on human health, particularly chronic infections.<br />
Targeted control of oral pathogens<br />
Competition for iron is considered to be a central event in<br />
many infections. A number of pathogenic bacteria have<br />
acquired complex mechanisms to sequester iron, often from<br />
haem. The periodontal pathogen, Porphyromonas gingivalis,<br />
is unusual in that it has lost the capacity to synthesise the<br />
and inhibit this bacterium with custom synthesised modified<br />
porphyrin-antibiotic conjugates. More recently, a number of<br />
other haem binding proteins that are located on the surface<br />
of the organism have been identified and are being studies<br />
in order to expand the range of targets for inhibition by<br />
exploiting those aspects of porphyrin storage and transport<br />
that are unique to P. gingivalis.<br />
Determinants of oral infection in high-risk<br />
aboriginal communities<br />
Anaerobic Gram negative bacteria have been determined<br />
to be numerically important in relation to the early onset<br />
and high incidence of periodontal disease in an Aboriginal<br />
community. Research at the institute has suggested that<br />
early mucosal colonisation of infants with pathogenic<br />
porphyromonads act as release sites for transmission of these<br />
organisms within families. Biotyping of Porphyromonas<br />
gingivalis strains based on variations in the lysine-gingipain<br />
gene indicated skewing of biotype distribution in the<br />
Aboriginal community compared with that observed in<br />
metropolitan cohorts. Further evidence for the presence<br />
of characteristic discriminatory flora within the Aboriginal<br />
community was obtained by microbial population analysis<br />
based on molecular phylogeny. These observations have<br />
provided a basis for ongoing dissection of the microbial risk<br />
factors for oral infection that prevail in such a high risk group<br />
and underpin proposed strategies to break the cycle of disease<br />
by preventing transmission to infants. Additionally, there is<br />
no information to determine whether disease susceptibility<br />
amongst Aborigines reflects organisms that have been<br />
associated with Aboriginal people for millennia or if there<br />
is a pathogenic influence from organisms acquired, most<br />
probably, from Anglo-Saxon settlers. As there is little genomic<br />
information for these mucosal pathogens, assessment of the<br />
origin and heterogeneity of organisms within communities<br />
is being assessed by analysis of a matrix of highly conserved<br />
house-keeping genes. This will both establish the relative
36 37 > Research Report // AR 2006<br />
diversity of strains of the organism within the community<br />
the optimal design of vaccines that require T lymphocyte<br />
the expression of genes in Th1 cells. Furthermore, genetic<br />
and also probe the question of separation or overlap with<br />
responses, and for using lymphocytes for immunotherapy.<br />
polymorphisms in PHF11 that are highly associated with<br />
similarly studied organisms from Anglo-Saxon sources, with<br />
isolates from other ethnic groups providing outlier controls.<br />
Role of oral bacteria in immune development in marsupials<br />
At birth, the highly under-developed Tammar wallaby,<br />
Macropus eugenii, climbs through a saliva coated channel<br />
in the fur of its mother from the urogenital tract to the<br />
pouch which has also been cleaned by the licking action of<br />
the mother. For the first three months of its development<br />
the neonate is attached to a teat in the pouch and is<br />
totally dependent on its surrounding environment for<br />
immunological protection since it does not possess mature<br />
lymphoid tissue and therefore lacks immune competence.<br />
It is well recognized in eutherian mammals that bacteria<br />
play a pivotal role in maintaining the health of mucosal<br />
surfaces and in aiding immune development. While<br />
preliminary studies have shown that the bacterial microflora<br />
of the Tammar wallaby pouch young changes with time,<br />
the exact nature of these microbial changes, has not been<br />
elucidated. In collaboration with Macquarie University,<br />
researchers at the <strong>Institute</strong> are engaged in using advanced<br />
molecular phylogenetic methods to identify those bacteria<br />
that are transmitted to the neonate and the role oral bacteria<br />
play in both protecting the neonate from infection and in<br />
influencing mucosal development and maturation of the<br />
immune system.<br />
<strong>Institute</strong> for Immunology and Allergy Research<br />
Immunobiology and apoptosis<br />
The group has discovered a key role for death-inducing<br />
cytokines (Tumour Necrosis Factor, TRAIL and Fas Ligand)<br />
in controlling these processes. Understanding how death<br />
cytokines control lymphocyte homeostasis is important as it<br />
provides information about how autoimmune diseases such<br />
as Multiple Sclerosis (MS) arise, and provides key insights<br />
into how immunomodulatory therapies exert their efficacy.<br />
Death cytokines like TRAIL are already being developed<br />
for use in humans with cancer, but our findings may open<br />
the way for their expanded use in new therapy regimes<br />
for diseases like MS. Our findings are also important for<br />
Death cytokines are also part of the immune response to<br />
virus infection, and consequently most viruses have evolved<br />
specific mechanisms by which they evade the effects of these<br />
cytokines. Smallpox, for example, controls these processes<br />
through the production of a viral death-receptor homologue.<br />
Our research on the poxvirus death receptor protein has<br />
revealed a completely new mechanism of evasion of TNFreceptor<br />
signalling. The minimal domain in this protein that<br />
is required for inhibiting TNF-receptor signalling is also<br />
present in TRAIL-Receptors, and a mini protein encoding<br />
only this domain can ameliorate arthritis in mice. For this<br />
reason, we are currently investigating how the expression<br />
of this domain by TRAIL-receptor proteins alters TRAIL<br />
biology, and how it might be used to prevent autoimmune<br />
inflammation in diseases such as Multiple Sclerosis.<br />
Molecular genetics of allergy<br />
The goal of this group is to establish a research program<br />
that links genetic studies with functional molecular and<br />
cell biological assays to understand how heritable genetic<br />
polymorphisms change gene function in human allergic<br />
disorders.<br />
To investigate the molecular genetics of human allergy, the<br />
group has assembled a well-characterised family-based cohort<br />
of children affected by severe atopic eczema. Researchers are<br />
now investigating the genetics and function of genes that are<br />
involved in T-cell activation.<br />
In an NHMRC supported project, the group has confirmed<br />
that the PHF11 gene at chromosome 13q14 is a major<br />
gene associated with asthma, eczema and atopy and has<br />
now completed the first functional study of PHF11. They<br />
found that PHF11 is localised to the nucleus and the<br />
expression of PHF11 was several fold higher in Th1 T-cells<br />
cells when compared to Th2 cells. Knock-down of PHF11<br />
using shRNA resulted in a significant decrease in the basal<br />
expression of interferon-gamma and interleukin-2 in Th1<br />
cells, both of which are critical Th1-type genes. Further<br />
functional analysis has identified an interaction between<br />
PHF11 and the NF-_ B transcription factor in modulating<br />
atopic eczema in our cohort reduce PHF11 RNA in Th1<br />
cells. This suggests that genetic variation in PHF11 may<br />
contribute to the imbalance between Th1 and Th2 cells that<br />
characterises atopic disorders. In another project the group<br />
published an association study linking genetic variants in<br />
the Th2-specific TIM-1 gene and childhood atopic eczema.<br />
They are following this study up with additional genetic and<br />
functional studies of the related Th1-specific T-cell receptor,<br />
TIM-3.<br />
Multiple sclerosis genetic research<br />
This group was the first to identify common polymorphisms<br />
in the gene CD127 and test their association with MS.<br />
They have subsequently shown a variant was associated<br />
with the primary progressive form of the disease. Two<br />
international groups, using very large cohorts, have now<br />
confirmed CD127 as the first non-HLA region gene to have<br />
its association with MS widely replicated. The group has<br />
studied the functional significance of the CD127 haplotypes<br />
and demonstrated they have different splicing features and<br />
respond differently to stimulation in different immune cell<br />
types. Manipulation of immune cells using this information<br />
is part of a provisional patent application for MS treatment<br />
held by the institute.<br />
The group has continued its international collaborations with<br />
Cambridge University and through them the International<br />
MS genetics consortium, which is shortly to publish the<br />
largest ever genome screen in MS. It has also begun an<br />
Australian MS genetics collaboration, called ‘Ausgene’, with<br />
researchers in Victoria, Queensland and NSW.<br />
The group continues to develop links with Industry and has<br />
an ARC Linkage Grant (2006-2008) in combination with<br />
BiogenIdec, to investigate pharmacogenomic aspects of the<br />
use of interferon beta. It also provides Australia’s neutralizing<br />
antibody testing service for this drug.<br />
Cancer<br />
<strong>Westmead</strong> <strong>Institute</strong> for Cancer Research<br />
Breast cancer research<br />
The Breast cancer research group is investigating the role of<br />
the ovarian hormones oestrogen and progesterone in the<br />
development of the normal breast, and in breast cancer.<br />
Ovarian hormones are fundamental regulators of normal<br />
cell growth and differentiation and are also crucial to the<br />
development and progression of breast cancer. Progesterone<br />
has a pivotal role in normal female reproduction in the<br />
uterus, ovary, mammary gland and brain, and the number<br />
of cellular pathways regulated by progesterone reflects the<br />
complexity of its physiological role.<br />
The progesterone receptor (PR), which mediates the effects<br />
of progesterone in target tissues, is expressed as two proteins,<br />
which have very different activities. Progesterone receptors<br />
transduce the signals of cyclically fluctuating progesterone<br />
levels in the body. For four decades or more of reproductive<br />
life, alternating peaks of progesterone and oestrogens exert<br />
profound effects on reproductive function, especially on the<br />
development and function of the breast.<br />
Some years ago the Breast Cancer Research Group identified<br />
a change in expression of two forms of the progesterone<br />
receptor, PRA and PRB, in cancer. Their work in 2006 has<br />
focused on further identifying the cellular consequences of<br />
this change. Gene expression profiles have shown a distinct<br />
shift in the ability of a cell to respond to progesterone<br />
when the two forms of the PR are imbalanced, and this<br />
is associated with clear changes in signalling pathways<br />
important in maintenance of normal cell biology.<br />
These studies are being extended by the development of new<br />
culture systems, in which these signalling pathways in the<br />
normal human breast can be interrogated. Normal breast<br />
tissue in this culture system maintains the ability to respond,<br />
in physiologically relevant ways, to progesterone, and the<br />
pathways by which this hormone influence the normal breast<br />
are now being unravelled in ongoing studies.
38 39 > Research Report // AR 2006<br />
0.005.0484<br />
0.005.0486 research facilities 00.005.0459 at <strong>Westmead</strong>. The Bank 00.005.0458<br />
was created to<br />
provide a resource of breast cancer biospecimens and clinical<br />
46<br />
0.005.0489<br />
26<br />
The mechanisms through which PR controls gene expression<br />
have also been explored in 2006, with the demonstration<br />
that receptors aggregate with other key components of<br />
transcriptional machinery when they are activated. Studies in<br />
2006 demonstrated that these aggregations were functionally<br />
significant, and identified some of the key functional<br />
components of these aggregates. This aggregation process<br />
is disrupted in human cancers, and ongoing studies in the<br />
group are aimed at identifying the functional consequences<br />
of its disruption in cancer. Most breast cancers are thought to<br />
be initiated at puberty, and develop throughout reproductive<br />
life. Although the vast majority of breast cancers are detected<br />
after menopause, the influence of cyclical ovarian hormones<br />
on their biology is profound. The studies from the Breast<br />
Cancer Group aim to throw new light on the fundamental<br />
question of how ovarian hormones influence breast cancer<br />
initiation and progression.<br />
Breast cancer tissue bank<br />
WMI has led the establishment of the Breast Cancer Tissue<br />
Bank with funding from the NHMRC, Cancer <strong>Institute</strong><br />
NSW and the National Breast Cancer Foundation. The<br />
headquarters of the Bank are located within the clinical and<br />
data to support breast cancer research throughout Australia.<br />
Under the management of WMI a network of centres from<br />
across New South Wales collected tissue for the Bank during<br />
2006.<br />
Materials in the bank are processed and stored using<br />
international best practice methodologies to preserve the<br />
integrity of the specimens and increase their value to research<br />
scientists. Access to human tissue is essential for translating<br />
00.005.0463<br />
46<br />
00.005.0482 00.005.0481<br />
00.005.0465 00.005.0466<br />
51<br />
00.005.0462<br />
has important implications for determining the risk of genetic-epidemiological studies investigating the familial<br />
developing melanoma and possibly the treatment strategy aspects of cancer. As many high-risk individuals have now<br />
for patients carrying altered copies of the p16INK4a protein. been identified, the group established a risk-management<br />
Furthermore, it is likely that unidentified p16INK4a clinic in 2006 that facilitates co-ordinated, multidisciplinary<br />
functions (other then regulation of cell proliferation) may care of women at high risk of breast and ovarian cancer, as<br />
add to its role as melanoma susceptibility gene. The Cell well as providing further opportunities for research. The<br />
Cycle research group is investigating the role of p16INK4a in study of Magnetic Resonance Imaging of the breasts of highrisk<br />
women in NSW has commenced at <strong>Westmead</strong> and the<br />
novel biomolecular pathways.<br />
group is now accumulating data to determine its usefulness<br />
The BRAF oncogene is switched on in most melanomas<br />
in comparison to standard mammographic screening. The<br />
but intriguingly also in 80% of benign moles. Most moles<br />
Service has completed the collaborative study of breast ductal<br />
never transform into melanomas and their melanocytes are<br />
lavage specimens, investigating its use as a surveillance tool in<br />
normally growth arrested. Thus, although aberrant activation<br />
women at high risk of breast cancer.<br />
of BRAF plays a role in melanoma, normal melanocytes<br />
apparently respond to active BRAF by growth arrest and The group continues to participate in the international<br />
only additional genetic alterations allow these cells to become GOG-199 study, aimed at assessing the usefulness of<br />
malignant. The Cell Cycle research group is exploring the screening versus preventive surgery in women at increased<br />
mechanisms responsible for this BRAF-induced growth risk of cancer of the ovary and fallopian tubes. The group<br />
arrest, which is clearly critical in protecting against melanoma has also continued its role in the study of tamoxifen in breast<br />
formation. These investigations will also resolve the molecular cancer prevention for those at higher risk based on family<br />
events necessary to transform a normal melanocyte into a history. In addition, the group has continued to collaborate<br />
melanoma.<br />
in the investigation of the psychosocial aspects of genetic<br />
Melanoma cancers are notoriously resistant to chemotherapy.<br />
00.005.0464 00.005.0515 00.005.0467 00.005.0514<br />
Through its research, the Cell Cycle team has confirmed<br />
that cells in which p14ARF and p16INK4a are active are<br />
more sensitive to chemotherapy. The impact of activated<br />
BRAF on chemosensitivity is currently being investigated.<br />
All these molecules are critical in the genesis of melanoma.<br />
Therefore defining each of their functions is essential to the<br />
development of a rational approach to targeted therapy for<br />
this destructive disease.<br />
Familial cancer research<br />
Most cancers are due to genetic changes that accumulate in<br />
00.005.0460 00.005.0461 00.005.0468 00.005.0469 00.005.0516 00.005.0517 00.005.0518<br />
current research knowledge into clinical practice and in turn<br />
basic researchers can utilise information derived from human<br />
specimens to drive further investigation into the molecular<br />
basis of disease.<br />
Data and specimens stored in the Bank are available to<br />
all Australian researchers following scientific review of the<br />
proposed project.<br />
Cell cycle research<br />
In Australia, melanoma is the third most common cancer<br />
in men and women with over 3,000 cases per year and an<br />
overall lifetime risk of 3.7%. We know now that cancer is<br />
caused by genetic changes, or mutations, in cells. However,<br />
the precise sequence of mutations required to transform a<br />
dormant melanocyte into a melanoma remains unresolved.<br />
In recent years the group’s work has contributed to the<br />
identification of several critical pathways crucial to this<br />
process. In particular, the p16INK4a/p14ARF locus, which<br />
encodes the tumour suppressor proteins p16INK4a and<br />
p14ARF, is altered in 39% of melanoma-prone families and a<br />
single base change that activates the BRAF oncogene is found<br />
in 50-70% of melanomas. The Cell Cycle Research Group<br />
is investigating how these proteins work and which cellular<br />
targets they interact with.<br />
This team recently proposed that the p14ARF protein<br />
mediates the attachment of the small modifying protein,<br />
SUMO, to a number of target proteins in a process called<br />
sumoylation. Sumoylation regulates cellular activity of<br />
these target proteins by altering their function. The group is<br />
exploring the effects of p14ARF induced sumoylation, and<br />
the consequences of p14ARF mutation on the functioning of<br />
these proteins.<br />
Some studies have reported that p14ARF can induce<br />
programmed cell death, known as apoptosis, possibly by<br />
activating the master apoptosis gene p53. The Cell Cycle<br />
group has clarified that p14ARF induces apoptosis only<br />
when co-expressed at normal physiological levels in cells<br />
with a functional p53 gene; it cannot induce apoptosis by<br />
itself. p14ARF is also known to stabilize proteins such as p53<br />
by blocking the attachment of the small modifier protein<br />
ubiquitination which acts as a degradation signal. The<br />
effect of melanoma associated p14ARF mutations on the<br />
degradation of essential proteins is also being investigated.<br />
The p16INK4a tumour suppressor is frequently altered in<br />
high risk melanoma families, and these altered p16INK4a<br />
proteins may affect the function of the remaining<br />
normal copy of p16INK4a. This important hypothesis is<br />
currently being investigated by the Cell Cycle group and<br />
the cells with age, but in 5 to 10 per cent of cases, patients<br />
have a family history of multiple cases of early-onset cancer,<br />
that suggests the presence of an inherited gene mutation that<br />
greatly increases their risk of cancer.<br />
The clinical arm of the Familial Cancer Research Group<br />
operates a service where individuals with a strong family<br />
history of breast, ovary, bowel cancer or melanoma, can be<br />
assessed for genetic susceptibility. In conjunction with this<br />
clinical service, many patients are enrolled in collaborative,<br />
testing for cancer susceptibility by participating in studies of<br />
decision aids and counselling tools for patients considering<br />
genetic testing.<br />
In 2006 the group established pilot telemedicine programs in<br />
several rural centres to evaluate the usefulness of this clinical<br />
tool to improve rural genetic health services.<br />
The group’s laboratory provides a testing service for<br />
individuals in the families described above, primarily<br />
for mutations in the BRCA1 and BRCA2 breast cancer<br />
susceptibility genes. In addition, there is some screening<br />
for susceptibility to melanoma. The laboratory’s research<br />
program has been successfully directed towards improved<br />
screening for BRCA1 and BRCA2 mutations and<br />
continues to focus on improvements to screening and the<br />
understanding of the gene mutations that are detected by<br />
screening.<br />
Gene expression in cancer<br />
Mutations in the tumour-suppressor gene BRCA1 are a<br />
common factor in many breast cancers. The Gene Expression<br />
laboratory is studying the effect of cancer mutations on
40 41 > Research Report // AR 2006<br />
specific proteins in the cell, with emphasis on cellular<br />
and to improve our understanding of the mechanisms that<br />
clinical outcome and, eventually, improve the survival of<br />
disease in patients with haematological malignancy.<br />
alterations that lead to breast and colon cancer. The group<br />
is investigating how such mutations disrupt the normal<br />
function of the BRCA1 protein.<br />
determine how a patient will respond to chemotherapy.<br />
The normal process of ovulation is known to play a part<br />
in early events leading to ovarian cancer. The Group has<br />
patients with ovarian cancer. In all, more than 1800 patients<br />
have been recruited to the study, surpassing expectations and<br />
data analysis is underway.<br />
In the last 12 months, the group has continued to develop<br />
its clinical program of cytomegalovirus (CMV) specific<br />
cytotoxic T cell administration to patients with impaired<br />
The BRCA1 protein senses DNA damage. It monitors<br />
dividing cells, and in response to DNA damage, initiates<br />
gene repair processes in the cell nucleus so the errors are not<br />
transmitted to new cells. BRCA1 has a partner, BARD1;<br />
their interaction helps facilitate the DNA-repair process.<br />
Previously the group discovered that the BRCA1 and<br />
BARD1 proteins, in their unbound state, are normally free to<br />
shuttle between the nucleus and cytoplasm, but when bound<br />
together they become confined to the nucleus, an essential<br />
step in activating the complexed proteins for their crucial role<br />
in DNA-repair and cell-survival.<br />
They have also identified a class of BRCA1 gene mutations<br />
that display an unexpected influence on the BRCA1 proteins<br />
that carry this mutation. The mutant BRCA1 proteins are<br />
positioned differently inside the cell, and are prevented from<br />
entering the nucleus and complexing with BARD1. This<br />
finding provides another mechanism for changes in DNA<br />
repair elicited by BRCA1 gene mutations in breast cancer.<br />
In 2006 the laboratory discovered that the BARD1 protein<br />
locates at cellular mitochondria, implicating a pathway for<br />
control of cell death or cell survival.<br />
The group is also investigating two genes that appear to<br />
play key roles in colorectal cancer: beta catenin and the<br />
tumour-suppressor gene APC. A very large protein, APC<br />
- like BRCA1 - shuttles between the cytoplasm and the<br />
nucleus, where it performs its tumour-suppressor function.<br />
The ultimate aim of this research is to discover new pathways<br />
that control the action of proteins like BRCA1 and APC<br />
in normal cells, and to develop drugs or other reagents that<br />
correct defects in these pathways in cancer cells.<br />
Gynaecological cancers<br />
Ovarian cancer is the most lethal gynaecological malignancy.<br />
The Gynaecological Cancer Research Group has a program<br />
of research which aims to improve our understanding of the<br />
progression from healthy ovarian epithelial cells to cancer<br />
used laser capture micro-dissection to dissect out individual<br />
epithelial cells from normal ovaries, to studying normal<br />
patterns of gene expression during the ovulatory cycle, using<br />
mice as a model system. They used expression microarrays<br />
to identify all active genes in normal cells, and then use<br />
changing patterns of normal gene expression as a standard to<br />
detect aberrant gene expression patterns in malignant human<br />
ovarian cells. Genes that normally regulate cell proliferation<br />
and apoptosis (programmed cell death) are obvious suspects<br />
for contributing to malignant transformation. The group has<br />
identified several novel candidate genes that may be involved<br />
in the initial steps leading to ovarian cancer.<br />
Most ovarian cancers are initially sensitive to chemotherapy,<br />
but eventually develop resistance. Currently there was no<br />
way to predict which ovarian cancers would become resistant<br />
to chemotherapy, nor any way to modulate gene expression<br />
to restore drug sensitivity. The group has identified a set of<br />
genes whose expression levels differ between resistant and<br />
drug-sensitive cells. They have found that one of these genes<br />
is higher in tumours from patients that have a worse clinical<br />
outcome. The <strong>Institute</strong> has a patent on the discovery, and is<br />
now seeking compounds to reduce expression of this gene,<br />
that could be used in combination with platinum drugs to<br />
treat ovarian cancer.<br />
The Australian Ovarian Cancer Study is a major<br />
collaborative project involving WICR, the Queensland<br />
<strong>Institute</strong> of Medical Research (QIMR), and Melbourne’s<br />
Peter McCallum Cancer Centre (PeterMac), and over 20<br />
hospitals across the country. It aimed to recruit 1000 ovarian<br />
cancer patients and create a library of biospecimens at the<br />
PeterMac, for analysis to identify genes involved in ovarian<br />
cancer. QIMR researchers have collected comprehensive<br />
epidemiological data on patients to help identify<br />
environmental and life-style risk factors, while the WICR<br />
group are monitoring the individual patients for a minimum<br />
of five years, recording all details of their treatment and its<br />
outcome. The data will be correlated with risk-factor data<br />
and tumour-gene profiles to identify factors that will predict<br />
Leukaemia cell biology group<br />
The Leukaemia Cell Biology Group is investigating the<br />
role of bone marrow stromal cells in acute lymphoblastic<br />
leukaemia (ALL). ALL is the most common childhood<br />
cancer. Although responsive to chemotherapy 25% of<br />
children and 65% of adults will relapse following treatment<br />
and less than 10% of relapsed patients will survive for 5 years.<br />
New treatments for ALL are necessary to improve outcomes<br />
for these patients.<br />
ALL arises in the bone marrow from cells that normally<br />
develop into B cells (antibody producing cells). ALL cells<br />
are highly dependent on the bone marrow stroma for their<br />
growth and survival and bone marrow stroma protects ALL<br />
cells from the effects of chemotherapy. The leukaemia cell<br />
biology group has been investigating ways in which the bone<br />
marrow supports ALL cells with the aim of disrupting this<br />
supportive and protective function.<br />
The group has identified SDF-1 as a major factor that<br />
supports ALL cells. Drugs that can block the effects of SDF-<br />
1 move ALL cells out of the bone marrow making them<br />
more susceptible to chemotherapy. These drugs inhibit the<br />
growth of ALL cells in the laboratory and in a mouse model<br />
of human leukaemia. These drugs were particularly effective<br />
at minimizing the spread of ALL to other tissues including<br />
the liver and kidney.<br />
The group has also studied the way in which SDF-1<br />
tells ALL cells to grow and survive. By targeting these<br />
mechanisms, even more potent agents have been identified.<br />
It is anticipated that these drugs will enhance the effectiveness<br />
of currently used chemotherapy agents with minimal toxicity.<br />
If successful, these agents will decrease the total dose of<br />
chemotherapy required to treat standard risk patients and<br />
help increase the cure rates in patients with a poor prognosis.<br />
Leukaemia cell therapies<br />
The Cell Therapies group focuses on investigating the use of<br />
targeted cells for the treatment of infectious and malignant<br />
immune systems. The group is currently running its<br />
second clinical trial of CMV specific T cell administration<br />
for patients recovering after allogeneic bone marrow<br />
transplantation. The initial trial using a CMV peptide to<br />
stimulate donor T cells accrued 9 patients. No acute adverse<br />
events were observed and increases in CMV specific T cells<br />
in circulation following infusion were observed. No patient<br />
in the trial required pharmacotherapy for CMV infection or<br />
reactivation.<br />
A considerable amount of effort has been expended in the<br />
last 12 months on gaining approval for a gene therapy trial<br />
of CMV that will expand entry criteria into the trial and will<br />
result in a broader target specificity of CMV antigens. The<br />
trial commenced accrual late in 2006 and has already accrued<br />
8 patients with 4 patients receiving T cell infusions from<br />
their donors. No adverse events have been noted and no<br />
pharmacotherapy for CMV has been required as yet in any<br />
patient receiving T cells.<br />
We are also studying the generation in vitro of T cells<br />
specific for the viral illness varicella zoster that commonly<br />
affect immunocompromised individuals. Using a clinical<br />
vaccine preparation for antigen stimulation, the group has<br />
been able to stimulate growth of a population of T cells<br />
whose specificity is currently being assessed. It is hoped that<br />
this process can be incorporated into generation of CMV<br />
specific T cells to give a tri-virus specific culture product that<br />
will recognise CMV, adenovirus (derived from the vector<br />
encoding the CMV protein pp65) and varicella zoster virus.<br />
Translational oncology<br />
The aim of the Translational Oncology group is to focus<br />
research on clinically important issues in oncology and to<br />
assist clinical application of basic laboratory research through<br />
examination of information and samples from patients with<br />
cancer.<br />
In 2006, the group continued to work to identify measures<br />
that may assist determination of optimal chemotherapy
42 43 > Research Report // AR 2006<br />
doses for patients. This is an important issue since the rate at<br />
which drugs are cleared from the body can vary substantially<br />
between individuals and have a major influence on the<br />
effectiveness and toxicity of treatment.<br />
In a collaborative project with the Family Cancer group and<br />
the Kathleen Cuningham Consortium for Research into<br />
Familial Breast Cancer (kConFab), Translational Oncology<br />
also reported a study in 2006 that described the pathology<br />
features of breast cancer in carriers of variants in a gene that<br />
has been implicated in increased breast cancer risk; ataxia<br />
telangiectasia mutated (ATM). This was of interest because<br />
certain types of familial breast cancer are associated with<br />
particular pathologic features although these were not seen in<br />
carriers of ATM variants.<br />
Another major project that Translational Oncology is<br />
involved with is establishment of a Breast Cancer Tissue<br />
Bank in centres across New South Wales that will make<br />
breast cancer tissue specimens available for research Australiawide.<br />
Supported by funding from the National Health<br />
and Medical Research Council, National Breast Cancer<br />
Foundation and Cancer <strong>Institute</strong> NSW this initiative will<br />
form important infrastructure for future translational breast<br />
cancer research.<br />
Genomics and genetic epidemiology<br />
The Genomics and Genetic Epidemiology Group focuses<br />
on identifying the genes that strongly affect cancer risk<br />
and discovering how that genetic risk interacts with the<br />
environment to cause cancer. Hundreds of families of people<br />
with a strong family history of melanoma have supported the<br />
groups projects over the last twenty years and their samples<br />
continue to be used intensively to identify new melanoma<br />
genes. Over 2006 they were used in three searches involving<br />
22 research groups of the international melanoma genetics<br />
consortium (GenoMEL) and several million dollars’ funding<br />
from the European Union and the US National <strong>Institute</strong>s of<br />
Health. They cover each of the main high-throughput ways<br />
of identifying new disease genes: genetic linkage, genetic<br />
association and candidate gene analysis.<br />
The group also completed the Australian Melanoma Family<br />
Study (AMFS), with the University of Melbourne’s MEGA<br />
Centre and the Queensland Cancer Fund Epidemiology<br />
Research Unit. This is one of the world’s largest populationbased<br />
studies of melanoma, enrolling over 1100 people who<br />
developed melanoma before age 40 in Melbourne, Sydney<br />
and Brisbane, or unaffected controls, plus thousands of their<br />
family members. Early-onset melanoma can be indicative of<br />
increased susceptibility, but little is known about what genes<br />
contribute to risk in this setting. The AMFS has shown that<br />
HO<br />
3<br />
A<br />
5<br />
B<br />
6<br />
C<br />
in at least some cases (2%) a gene that is commonly mutated<br />
in familial melanoma is responsible: the CDKN2A (p16)<br />
tumour suppressor gene. The group has also showed that<br />
the risk caused by these mutated genes in the population is<br />
not as high as it is in people with a strong family history of<br />
melanoma.<br />
As part of her successful PhD Nadine Kasparian reported<br />
some of the first research anywhere in the world that has<br />
Cholestorol<br />
studied perception of melanoma risk and the psychological<br />
consequences of high melanoma risk in melanoma families.<br />
These are collaborations with Prince of Wales Hospital and<br />
the University of Sydney.<br />
Both the NHMRC and Cancer <strong>Institute</strong> NSW Program<br />
Grants have enabled the group to start wide-ranging studies<br />
with collaborators at the Sydney Melanoma Unit, directed<br />
at understanding the genetic abnormalities in melanomas<br />
themselves. The goals of these high-throughput studies<br />
of gene and protein expression are to understand how<br />
apparently similar melanomas can have such different clinical<br />
behaviour, whether a greater propensity to relapse after<br />
surgery, or differing responsiveness to drug and biological<br />
treatment, for example. Since the SMU is the largest<br />
melanoma treatment and clinical research centre in the<br />
world, these are intended to be benchmark studies of these<br />
issues and will be the main focus of the group in 2007-8.<br />
HO<br />
H<br />
17<br />
D<br />
OH<br />
OH<br />
Liver and Metabolic<br />
Storr Liver Unit<br />
The role of leptin in the pathogenesis of hepatic fibrosis<br />
The mechanisms by which the hormone leptin, which<br />
Propionyl-CoA<br />
NADP + H +<br />
circulates in increased concentrations in obese individuals,<br />
exerts its pro-fibrogenic (scarring) effects on the liver are<br />
O 2<br />
NADPH + H +<br />
currently unclear. In this project we examined the expression<br />
of pro-fibrogenic genes and proteins in cultured rat hepatic<br />
7`-hydroxylase<br />
stellate cells (HSCs; the main cellular source of scar tissue<br />
in the liver) following exposure to leptin. We were able<br />
to demonstrate that leptin did not directly enhance HSC<br />
activation. In contrast, there were remarkable increases in<br />
pro-fibrogenic gene and protein expression in HSCs after<br />
these cells were cultured in the medium of Kupffer cells that<br />
had been previously exposed to leptin. Furthermore, we<br />
found that the effect of leptin on Kupffer cells was mediated<br />
by increasing the production of connective tissue growth<br />
O<br />
factor (CTGF) and transforming growth factor beta. 2 Both<br />
C – S – CoA<br />
O<br />
2 CoA-SH<br />
these cytokines are potent stimulators of fibrosis in hepatic<br />
stellate cells. We have taken these data further and have now<br />
characterized the intracellular molecular basis by which leptin<br />
exerts its affects. This project has demonstrated that Kupffer<br />
cells play an important role in leptin-mediated liver fibrosis<br />
and provide a novel molecular mechanism by which obesity<br />
causes scarring of the liver and cirrhosis.<br />
Molecular mechanisms for the development of fatty liver<br />
disease in humans<br />
Non-alcoholic fatty liver disease (NAFLD) is the commonest<br />
cause of progressive liver damage in Australia leading to<br />
cirrhosis and liver cancer in some individuals. To date,<br />
altered lipid (fat) homeostasis has been shown to contribute<br />
to the accumulation of liver fat, but the mechanisms by<br />
which a fatty liver is converted to one with liver damage<br />
(steatohepatitis) has not been fully elucidated. In this project,<br />
researchers from the Storr Liver Unit sought to identify<br />
the molecular determinants leading to the progression to<br />
steatohepatitis. We therefore examined the expression of<br />
a number of critical nuclear receptors (NXRs) and key<br />
genes regulating carbohydrate, cholesterol and bile acid<br />
metabolism, synthesis and transport within the liver. In<br />
addition, we examined the expression of key inflammatory<br />
cytokines and pro- and anti-apoptotic cell death genes.<br />
This study was unique in that it was conducted on minute<br />
quantities of human liver tissue removed at the time of liver<br />
biopsy. Our results indicated that several nuclear receptors<br />
NADP +<br />
(LXR, PXR, FXR and CAR) which regulate key genes for<br />
bile acid synthesis and export were up-regulated in patients<br />
with steatohepatitis compared with healthy controls.<br />
Likewise, the expression of key cell death genes (BAD, BID,<br />
BAX) and those which mediate liver inflammation, were<br />
increased in livers from patients with steatohepatitis. These<br />
data are consistent with our novel proposal that alterations<br />
in nuclear receptor expression are a critical mediator of liver<br />
HO<br />
damage in patients with non-alcoholic steatohepatitis.<br />
The role of bile acids as a mediator of liver injury in an<br />
animal model of fatty liver disease<br />
In this study, we attempted to further characterise the<br />
several steps<br />
OH<br />
7-Hydroxychole<br />
molecular and cellular basis for the development of nonalcoholic<br />
steatohepatitis (NASH) by studies using an animal<br />
model that was developed at the Storr Liver Unit. NASH<br />
is characterized by the presence of hepatic steatosis (fat),<br />
liver injury, inflammation and variable fibrosis (scarring).<br />
The mechanisms which initiate hepatitis in a fatty liver<br />
are important, and at present unknown. In this research,<br />
analogous to our human studies, we sought to examine the<br />
role of nuclear receptors and key genes regulating bile acid and<br />
cholesterol metabolism, synthesis and transport within the<br />
liver of animals with NASH. Our results demonstrated that<br />
bile acids were significantly increased early in the development<br />
of NASH in mice. By day 5, we noted major changes in<br />
nuclear receptors and their downstream targets and of genes<br />
which regulate bile acid synthesis and export. Taken together<br />
these data strongly suggest that nuclear receptors and their<br />
ligands (bile acids and oxysterols) may be important mediators<br />
of liver injury in our nutritional model of NASH. It is hoped<br />
that linking these molecular studies in animals with a fatty<br />
liver, to that in humans with NASH will permit a better<br />
understanding of NAFLD and suggest novel treatments.<br />
NADP<br />
O<br />
2 CoA<br />
Prop<br />
Cholyl-CoA
44 45 > Research Report // AR 2006<br />
Dysregulation of normal muscle function and its<br />
contribution to the development of fatty liver disease.<br />
The liver plays a central role in processing macronutrients<br />
in response to the influx of nutrients and hormones such<br />
as insulin. While the liver maintains fasting blood glucose<br />
concentrations, skeletal muscle and fat tissue are the major<br />
sites of insulin stimulated glucose disposal. Furthermore,<br />
muscle is intricately involved in whole body lipid (fat)<br />
homeostasis. In these additional studies, we examined<br />
changes in the expression of key genes regulating energy<br />
uncoupling, lipid oxidation and glucose transport in the<br />
muscle and liver of mice that develop NASH when fed a<br />
diet deficient in the compounds methionine and choline<br />
(MCD). Our results indicated that lipid oxidation in muscle<br />
is reduced during MCD feeding, thereby delivering a higher<br />
lipid load to the liver and contributing to the development<br />
of hepatic steatosis. Thus, there appears to be a complex and<br />
intricate link between the liver and muscle with regard to<br />
lipid homeostasis that may in part explain lipid accumulation<br />
in the livers of persons who develop fatty liver disease.<br />
The role of the hormone adiponectin and its receptors in<br />
hepatic fibrosis<br />
Liver injury from any cause can lead to hepatic fibrosis, a<br />
process which is mediated by the hepatic stellate cell (HSC).<br />
Adiponectin, a recently characterised hormone secreted<br />
by fat cells with anti-inflammatory and anti-atherogenic<br />
properties may serve as a novel protein in the modulation<br />
of liver fibrosis. Researchers at the Storr Liver unit became<br />
interested in this protein when we noted that low levels<br />
of adiponectin were associated with the development of<br />
NASH in humans. In contrast, high levels of this hormone<br />
appear to be protective for the development of a fatty<br />
liver. We therefore sought to characterise the modulation<br />
of adiponectin receptors which mediate the function of<br />
adiponectin during the activation of HSCs to a profibrogenic<br />
cell type. While this project is in its infancy, we have<br />
demonstrated significant decreases in the expression levels<br />
of the AdipoR1 but not the AdipoR2 receptor during the<br />
activation of HSCs. In contrast, when HSCs were treated<br />
with the cytokine transforming growth factor beta, the<br />
expression of AdipoR2 was up-regulated. Our results indicate<br />
that differential modulation of adiponectin receptors occurs<br />
in vitro during HSC culture and in response to profibrogenic<br />
cytokines. These changes in receptor expression may play<br />
an important role in modulating the fibrogenic response<br />
of the liver to chronic injury. Further studies are therefore<br />
underway to determine the molecular basis of these effects<br />
and to determine if modulation of these receptors in the liver<br />
can lead to reductions in hepatic fibrosis in patients with fatty<br />
liver disease.<br />
Molecular pharmacology research<br />
The Molecular Pharmacology group, lead by Professor Chris<br />
Liddle is engaged in research into the mechanisms regulating<br />
the metabolism and transport of both xenobiotic compounds<br />
(such as therapeutic drugs) and endobiotics (such as lipids,<br />
cholesterol and bile acids) within the liver. Nuclear receptors<br />
are key intracellular proteins that “sense” the presence of<br />
these molecules and they have been working to exploit these<br />
receptors as targets to develop new treatments for a range<br />
of liver diseases. Parts of this work are being performed in<br />
collaboration with the laboratory of Professor Ron Evans at<br />
the Salk <strong>Institute</strong>, La Jolla, California. In collaboration with<br />
the Cancer Pharmacology Unit at Concord Hospital we<br />
have been investigating the altered metabolism of drugs that<br />
frequently occurs in patients with advanced cancer with a<br />
view to developing interventions that will allow such patients<br />
to be able to receive the benefit of full doses of vital cancer<br />
chemotherapy. Our recent work in the field of regulatory<br />
mechanisms in drug metabolism has led to the generation<br />
of two patents, which have been successfully licensed to the<br />
pharmaceutical industry. Royalties arising from these patents<br />
now provide significant ongoing funding for research projects<br />
with the Storr Liver Unit.<br />
Neuroscience and Vision<br />
Brain Dynamics Centre<br />
Brain connectivity projects<br />
These projects are focused on understanding the mechanisms<br />
of how the brain binds information into a coherent whole,<br />
and determines what is significant and important, and what<br />
is not. Understanding the mechanisms of integrative brain<br />
function is important for identifying the causes of disorders<br />
of mental health.<br />
A second focus of these projects is on the role of age and<br />
sex differences. Major psychiatric disorders have striking<br />
differences in their prevalence in males versus females, and<br />
peak ages of onset, such that understanding these factors is<br />
important for understanding the processes of mental illness.<br />
A PhD thesis on this topic will be completed this year.<br />
Towards a continuum of orienting and defensive responses<br />
This ARC Discovery project is focused on identifying the<br />
neural mechanisms underlying how we determine what is<br />
significant in the environment, and process it accordingly.<br />
The ability to discriminate what is significant and important<br />
from what is not is crucial to effective information processing.<br />
Thus, a breakdown in the mechanism of significance<br />
processing may underlie major psychiatric disorders.<br />
PhD research in this area was awarded the Tasman-Lovell<br />
medal this year for the best project.<br />
Development of integrative markers of brain function<br />
This is another ARC linkage project and is focused on<br />
integrating genetic information with cognitive, emotional<br />
and neuroimaging measures to identify evidence-based<br />
biological markers of complex brain function. Biological<br />
markers are important tools for identifying predisposing<br />
factors to disease, diagnosis, treatment evaluation, and the<br />
monitoring of disease progression.<br />
Emotion processing in adolescence and application to<br />
conduct disorder<br />
This project is focused on understanding the biological<br />
basis of emotion processing in adolescence, which is a peak<br />
period for the onset of emotional and behavioural disorders.<br />
These results will provide a platform for identifying specific<br />
disturbances in emotion-related brain function in children<br />
and adolescents with conduct disorder.<br />
Results to date show a striking change in brain function<br />
profile for salient emotions of fear and happiness from<br />
childhood (6-7 years) to adolescence (8-13) years to later<br />
teenage years (14-15 years), when the profile becomes more<br />
like that of an adult<br />
Identifying the ‘signature’ for ADHD and<br />
treatment predictions<br />
This project has used tests of emotion cognition and brain<br />
function to identify objective markers of ADHD and<br />
response to stimulants in ADHD. These markers were found<br />
to classify over 80% of ADHD adolescents.<br />
Posttraumatic stress disorder (PTSD) biological markers<br />
and treatment response<br />
This project aims to develop the most effective treatments for<br />
acute and chronic PTSD. Cognitive behavioural treatments<br />
(CBT) are the current first line treatment of PTSD, but<br />
response can be heterogeneous. This project aims to identify<br />
the most effective elements of CBT treatment of PTSD.<br />
The group conducted a randomized controlled trial on<br />
103 participants with PTSD to examine the most effective<br />
combination of treatment elements for PTSD. Specifically,<br />
the group examined whether cognitive therapy (CT)<br />
enhanced treatment response to exposure-based therapies<br />
(prolonged (PE) and invivo (IV) in an 8-week CBT program<br />
conducted in the Clinic for Traumatic Stress at BDC.<br />
Acute stress disorder treatment efficacy<br />
This study examined the relative efficacy of cognitive therapy<br />
(CT) and exposure treatments in acute trauma populations<br />
(within 3-4 weeks of trauma) in a randomized controlled<br />
trial. Results indicate that early intervention following trauma
46 47 > Research Report // AR 2006<br />
is highly effective in reducing PTSD symptoms. Importantly,<br />
both cognitive therapy and exposure-based therapies are<br />
highly successful in reducing PTSD symptoms compared to a<br />
wait-list control, but PE has greater treatment gains than CR.<br />
Markers of PTSD<br />
The research team is continuing to explore the relationships<br />
between autonomic arousal and neural function in response<br />
to emotional signals and in the context of cognitive tasks.<br />
They have pioneered new integrative analysis techniques<br />
for SCR-fMRI data. They are also examining responses to<br />
positive facial signals in PTSD to explore the integrity of<br />
the reward/approach systems in PTSD. We are examining<br />
structural MRI data to identify specific impairments in brain<br />
regions (particularly anterior cingulate and hippocampus) in<br />
PTSD. Finally, we are integrating autonomic, genetic, spatial<br />
and temporal neural measures (fMRI and EEG) to examine<br />
integrative theoretical models of PTSD.<br />
Depression - objective markers for depression<br />
In Australia, it has been estimated that depression costs<br />
our economy $3.3billion in lost productivity each year,<br />
highlighting the urgent need for valid markers of the illness<br />
and successful treatment. This research, funded by NHMRC<br />
and ARC, is focused on using measures of emotion,<br />
cognition and brain function to identify objective markers<br />
of depression and response to anti-depressant treatment.<br />
Results to date identify distinct brain changes that predict<br />
development of depression.<br />
Pfizer fellowship and NISAD: “Missing links: connectivity<br />
and schizophrenia”<br />
The Centre has focused on young people who have recently<br />
experienced their first-episode of psychosis. The ultimate aim<br />
is to identify the causes of the disorder, and how it might be<br />
prevented or better treated in the future. The project<br />
of normal connectivity revealed in the project reported<br />
under the Cognitive Neuroscience Unit. Schizophrenia<br />
patients showed a reversal of the normal connectivity<br />
between amygdala-frontal networks for processing<br />
stimulus significance.<br />
The inability to ‘bind’ perceptions and cognitions into<br />
a coherent whole in schizophrenia may involve the<br />
networks for determining significance. The findings<br />
support the Centre’s model of schizophrenia as a disorder<br />
of neural connectivity.<br />
Structural brain alterations in schizophrenia<br />
This is a PhD research project which used high-resolution<br />
(~1mm3) images of the brain provided by structural MRI<br />
(sMRI). The same first episode group was studied to provide<br />
a means to link information across projects.<br />
First episode schizophrenia patients showed a loss of grey<br />
matter in the frontal, parietal and temporal cortices, as well<br />
as cerebellum, at the time of their first presentation to mental<br />
health services, relative to matched healthy controls.<br />
In addition, these reductions in grey matter followed a<br />
different pattern of relationship to neural activity to that in<br />
healthy controls. In healthy subjects, grey matter declined<br />
slightly (consistent with neural pruning) and EEG activity<br />
(indexing neural activity) followed a similar pattern. In<br />
schizophrenia, however, there was a preservation or even<br />
increase of EEG activity, particularly for the slow wave Theta<br />
band. This dissociation in schizophrenia is consistent with a<br />
disorganization of pruning, and may be a factor in the cause of<br />
schizophrenia in late adolescence. The increase in EEG activity<br />
may reflect increases in synchronized activity in particular.<br />
Centre for Vision Research<br />
The Blue Mountains eye study<br />
The Blue Mountains Eye Study is a benchmark populationbased<br />
study in ophthalmology. As well as defining the<br />
prevalence, incidence and risk factors for eye diseases, many<br />
novel systemic associations have been explored. The 10-<br />
year mortality and cause of death information from this<br />
Blue Mountains population has been explored in relation<br />
to information derived from grading photographs taken of<br />
the retina at the back of the eye. Retinal vessels may carry<br />
information about the circulation system in the brain and<br />
in other end organs of the body. Our data have shown<br />
that retinal photographs provide information on structural<br />
changes in small vessels of the retina. These signs may<br />
be independent sub clinical markers for vascular disease,<br />
predicting subjects at higher risk of future vascular events,<br />
including the development of stroke, stroke-related death,<br />
cardio-vascular death and high blood pressure in older<br />
people. The Centre has also led to data analyses pooling Blue<br />
Mountains Eye Study and Beaver Dam Eye Study (USA)<br />
data to investigate less frequent retinal vascular lesions such as<br />
retinal emboli and retinal vein occlusion.<br />
Retinal vessel signs in acute stroke patients<br />
This multi-centre clinical cohort study has recruited acute<br />
stroke patients from three centres (stroke units at <strong>Westmead</strong><br />
Hospital, Royal Melbourne Hospital and Singapore General<br />
Hospital) to assess whether retinal vessel signs can help to<br />
determine the prognosis for different clinical stroke subtypes,<br />
in collaboration with the Retinal Vascular Imaging Centre<br />
(RetVIC) in Melbourne and stroke specialists in Singapore.<br />
So far, more than 1300 patients have been recruited<br />
following acute stroke. Retinal photographs were taken and<br />
the assessment of these signs is currently underway.<br />
Cataract surgery and risk of age-related macular Degeneration<br />
Age-related Macular Degeneration (AMD) is the leading<br />
cause of blindness in older people. Previous populationbased<br />
studies have suggested at least a 3-fold higher risk of<br />
progression to late-stage AMD in eyes after cataract surgery.<br />
This project aims to confirm these findings in a much larger<br />
sample of older people having cataract surgery and also to<br />
look at cataract surgery outcomes, including the impact on<br />
quality of life.<br />
Almost 2,000 patients undergoing cataract surgery at<br />
<strong>Westmead</strong> Hospital and from private ophthalmologist rooms<br />
have been recruited, with over 1200 patients being reexamined<br />
6 months post-operatively. We plan to follow these<br />
patients for up to 5 years to assess both short-term (2-3 years)<br />
and long-term risks of AMD after cataract surgery.<br />
The Sydney childhood eye study<br />
This project has assessed the frequency and risk factors<br />
associated with myopia and other common eye conditions<br />
in school children aged 6 or 12 years. The project examined<br />
1740 6-year-old and 2353 12-year-old children from almost<br />
60 primary and secondary schools across Sydney.<br />
Reports from this study have identified that reduced outdoor<br />
activity, rather than increased close work, may predict<br />
myopia (short-sightedness). The study also showed that other<br />
common childhood eye conditions like amblyopia (reduced<br />
vision in one eye) and strabismus (squint) are relatively well<br />
detected at present, but identified new risk factors, particularly<br />
modest levels of lower birth weight or prematurity.<br />
The new phase (Sydney Paediatric Eye Disease Study) is now<br />
examining a large sample of children aged less than 6 years<br />
to determine factors associated with the development of<br />
amblyopia and its detection in very young children.<br />
compared first episode schizophrenia patients to the pattern
48 49 > Research Report // AR 2006<br />
Cardio-respiratory<br />
Ludwig Engel Centre for Respiratory Research<br />
Sleep disordered breathing<br />
The centre has a particular emphasis on sleep disordered<br />
breathing with an international reputation for researching<br />
the mechanisms underlying the obstructive sleep apnoea<br />
syndrome (OSAS). In this disorder, patients experience<br />
repetitive episodes of throat blockage during sleep leading<br />
to complete cessation of breathing for short periods of<br />
time. In the short term, this leads to daytime fatigue, poor<br />
concentration, and an increased risk of motor vehicle<br />
accidents. In the long term it has been linked to the<br />
occurrence of heart disease, high blood pressure and stroke.<br />
LECRR researchers are working to understand the processes<br />
associated with the occurrence of obstructed breathing<br />
during sleep in order to improve the treatments available for<br />
this important disorder.<br />
LECRR researchers have also conducted an important study<br />
examining the interaction between sleep apnoea and daytime<br />
blood pressure. A large cohort of Samoan OSAS patients<br />
has shown significant and progressive reductions in daytime<br />
blood pressure following treatment of their OSAS.<br />
Cystic fibrosis<br />
Cystic fibrosis (CF) is the most common lethal inherited<br />
disease affecting Australians. In CF, altered salt transport<br />
across the lining of the airways leads to drying of the airway<br />
surface which impedes the processes which remove mucus<br />
from the lungs. Mucus retention makes the lungs very<br />
susceptible to bacterial infections. People with CF experience<br />
repeated chest infections requiring constant medical care.<br />
During 2006 the group’s researchers continued to provide<br />
a diagnostic service using the nasal potential difference<br />
technique to assist in the diagnosis of CF in patients<br />
referred from physicians in Sydney, Melbourne, Adelaide<br />
and Brisbane. The centre researchers also studied pancreatic<br />
enzymes which are present in the blood to determine the<br />
pancreatic status of CF patients.<br />
Centre for Heart Research<br />
Development of treatments for atrial tachycardias<br />
There are two current research projects being performed. The<br />
first involves the creation of a chronic ovine model of atrial<br />
flutter using purely percutaneous means. Previous models<br />
have required open heart surgery which is far more invasive<br />
and painful for the animal. With the aid of new 3D electro<br />
anatomical imaging, the group has now been able to reliably<br />
induce atrial flutter in sheep that is similar to that found in<br />
humans.<br />
The next step is to attempt to cure this by performing<br />
microwave ablation of the cavotricuspid isthmus using a<br />
novel percutaneous microwave catheter. An ARC funded<br />
collaboration with the University of Technology began<br />
to investigate alternative energy sources for treatment of<br />
abnormal heart rhythms.<br />
The other project aims to develop a chronic ovine model<br />
of atrial fibrillation by inducing heart failure in sheep using<br />
rapid ventricular pacing using implanted pacemakers. Unlike<br />
previous models, the group hopes to be able to develop<br />
ventricular scarring and electrophysiological parameters and<br />
validated a novel approach of electroanatomical mapping of<br />
ventricular scar using non-contact mapping.<br />
Ventricular tachycardia originating from within deep tissue<br />
of the septum is complex and difficult to ablate due to the<br />
limited scope of current ablation technologies, and due to the<br />
inability of current mapping techniques in identifying sublayer<br />
activation of myocardium. Using non-contact mapping<br />
the group has been able to distinguish between deep tissue<br />
and superficial origins of focal ventricular tachycardia. All<br />
aspects of the abovementioned research will be incorporated<br />
into further studies using dual chamber simultaneous noncontact<br />
mapping aimed to identifying successful target sites for<br />
radiofrequency ablation of complex ventricular tachycardia.<br />
Further research is also being undertaken to evaluate an<br />
in-house developed percutaneous deployable catheter which<br />
is more efficient at heating tissue than conventional radio<br />
frequency ablation catheters, and is capable of detecting tip<br />
contact with myocardium.<br />
During 2006 LECRR researchers completed a major<br />
epidemiologic study that identified heavy snoring as a risk<br />
factor for the presence of carotid artery wall atherosclerosis<br />
(plaque). Since dislodgement of carotid artery wall plaque is a<br />
cause of stroke, this finding suggests that heavy snoring alone<br />
poses a significant health threat. Other studies undertaken in<br />
2006 include a large study examining relationships between<br />
cranio-facial structure and OSAS, measurements of the<br />
surface tension of the upper airway lining liquid in healthy<br />
subjects and OSAS patients, studies examining the impact<br />
of snoring on blood pressure control, and the development<br />
of a computer model aimed at defining the relationships<br />
between peri-pharyngeal tissue pressure and upper airway<br />
patency. In collaboration with the University of Sydney,<br />
Asthma and chronic obstructive pulmonary disease<br />
Asthma now affects the lives of over 2 million Australian<br />
children and adults. Despite decades of research into the<br />
causes and treatment of asthma the prevalence of asthma in<br />
the population continues to rise. A major research interest of<br />
the centre is the influence of mouth versus nose breathing on<br />
the occurrence of asthmatic symptoms. The centre’s research<br />
recognised that asthmatic subjects have altered perception of<br />
nasal obstruction, leading them to switch to mouth breathing<br />
more readily than healthy individuals, and that this switch<br />
may contribute to the development of an asthma episode.<br />
Future research will investigate whether nasal breathing can<br />
help to resolve an episode of asthma.<br />
a model of atrial fibrillation that is electrophysiologically<br />
similar to chronic atrial fibrillation as seen in humans. If<br />
successful, this would enable us to trial ablation techniques to<br />
treat this disorder.<br />
Development of treatments for ventricular tachycardia<br />
The project aims to understand how post-myocardial<br />
infarction substrate precipitates ventricular tachycardia<br />
and to develop novel strategies of mapping and ablation<br />
of ventricular tachycardia using non-invasive, non-contact<br />
electrophysiological mapping.<br />
Clinical evidence suggests that ventricular tachycardia often<br />
precipitates at the border zone of scarred and non-scarred<br />
myocardium. In an ovine model of chronic myocardial<br />
infarction the group assessed the association between
50 51 > Research Report // AR 2006<br />
Staff<br />
Infection and Immunity<br />
Centre for Infectious Diseases<br />
and Microbiology<br />
Director<br />
Prof Tania Sorrell<br />
Laboratory Manager<br />
Mr Gary Martinic<br />
Bacterial Pathogenesis<br />
Research Group Leader<br />
A/Prof Jon Iredell<br />
Senior Research Officer<br />
Dr Sally Partridge<br />
Scientific Officer<br />
Ms Damla Power<br />
Mrs Belinda Roychoudhry<br />
PhD Students<br />
Ms Deborah Blanckenberg<br />
Mr Andrew Ginn<br />
Mr Bjorn Espedido<br />
Ms Jubelle Valenzuela<br />
Mr Zhiyong Zong<br />
Masters Student<br />
Mrs Lee Thomas<br />
Fungal Pathogenesis<br />
Research Group Leader<br />
Dr Julianne Djordjevic<br />
Senior Research Officer<br />
Dr Alfred Widmer<br />
Scientific Officer<br />
Dr Catherine Wu<br />
Research Assistant<br />
Ms Sue Dowd<br />
Ms Namfon (Beth) Pantarat<br />
Mrs Ganendren Ranjini<br />
Ms Christabel Wilson<br />
PhD Students<br />
Dr Methee Chayakulkeeree<br />
Ms Orla Morissey<br />
Dr Geoffrey Playford<br />
Ms Rosemary Siafakas<br />
Miss Kylie Turner<br />
Molecular Mycology<br />
Research Group Leader<br />
A/Prof. Wieland Meyer<br />
Post-doctoral Fellow<br />
Dr Clement Tsui<br />
Research Assistant<br />
Ms Krystyna Maszewska<br />
PhD Students<br />
Dr Azian Harun<br />
Miss Sirada Kaocharoen<br />
Mr Popchai Ngamskulrungraj<br />
Miss Luciana Trilles<br />
Mycology<br />
Senior Scientific Officer<br />
Dr Catriona Halliday<br />
Research Officer<br />
Ms Jessie Lay<br />
Public Health<br />
Staff Specialist<br />
Dr Vitali Sintchenko<br />
Research Epidemiologist<br />
Ms Heather Gidding<br />
Research Officer<br />
Dr Qinning Wang<br />
Education Officer<br />
Ms Judith Holford<br />
Technical Officer<br />
Ms Ping Zhu<br />
Centre for Virus Research<br />
Director<br />
Prof Tony Cunningham<br />
Deputy Director<br />
Dr Barry Slobedman<br />
Admin Assistant<br />
Ms Janine Murray<br />
Lab Manager<br />
Ms Rebecca Howard<br />
Clinical Research Officer<br />
Ms Janette Taylor<br />
Cytomegalovirus Research<br />
Research Group Leader<br />
Dr Barry Slobedman<br />
Research Associate<br />
Dr Josh Stern<br />
Research Assistant<br />
Miss Winnie Garcia<br />
PhD Student<br />
Mr Selmir Avdic<br />
Mr Allen Cheung<br />
Mr Michael Godwin<br />
Ms Joanne Tan<br />
Honours Student<br />
Mr John Cao<br />
Mr Brad Webster<br />
Herpes Immunopathogenesis<br />
Research Group Leader<br />
Professor Tony Cunningham<br />
Research Officer<br />
Dr Min Kim<br />
Dr Monica Miranda-Saksena<br />
Ms Lidija Bosnjak<br />
Research Assistant<br />
Mr Bibing Tijono<br />
PhD Student<br />
Mrs Anupriya Aggarwal<br />
Honours Student<br />
Miss Fay Roberson<br />
Herpes Protein Chemistry<br />
Research Group Leader<br />
Dr Russell Diefenbach<br />
PhD Student<br />
Ms Debbie Ko<br />
Ms Branka Mijatov<br />
Ms April Morton<br />
Honours Student<br />
Mr Jin Lee<br />
HIV Molecular Pathogenesis<br />
Research Officer<br />
Dr Andrew Harman<br />
Dr Najla Nasr<br />
Post-doctoral Fellow<br />
Dr Heather Donaghy<br />
Research Assistant<br />
Mr Joey Lai<br />
Miss Valerie Marsden<br />
Miss Sarah Mercier<br />
PhD Student<br />
Miss Kerrie Dunstan<br />
Dr Susan Maddocks<br />
HIV Protein Function and Interaction<br />
Research Group Leader<br />
Dr Sabine Piller<br />
Research Assistant<br />
Miss Eleanor Hitchen<br />
PhD Student<br />
Miss Judy Edmonds<br />
Ms Vicki Kassouf<br />
Honours Student<br />
Miss Suzanah Philipsz<br />
Miss Sarah Sherwood<br />
HIV Retroviral Genetics<br />
Research Group Leader<br />
Dr Nitin Saksena<br />
Postdoctoral Fellow<br />
Dr Bin Wang<br />
Staff Specialist<br />
Dr Dominic Dwyer<br />
PhD Student<br />
Ms Da’ed Haddad<br />
Mr Shwen Ho<br />
Ms Katherine Lau<br />
Ms Megan Steain<br />
Ms Jingqin Wu<br />
Ms Julie Zhou<br />
Varicella Zoster Research<br />
Research Group Leader<br />
Dr Allison Abendroth<br />
Research Assistant<br />
Miss Elizabeth Sloan<br />
PhD Student<br />
Mr Joshua Bowles<br />
Ms Kavitha Gowrishankar<br />
Ms Jennifer Huch<br />
Honours Student<br />
Mr Rodney Henriquez<br />
Centre for Transplant and<br />
Renal Research<br />
Director - Transplantation<br />
A/Prof Philip O’Connell<br />
Director – Nephrology<br />
Prof David Harris<br />
Director - Renal Medicine<br />
Prof Jeremy Chapman<br />
Visiting Medical Officer<br />
Dr Brian Nankivell<br />
Laboratory Manager<br />
Mr Gary Martinic<br />
Business Manager<br />
Ms Lara Stretton<br />
Research Administrator<br />
Ms Debra Tucker<br />
Islet Transplantation<br />
Senior research fellow<br />
Dr Wayne Hawthorne<br />
Scientific Officers<br />
Mr Denbigh Simond<br />
Mrs Tina Patel<br />
Ms Lindy Williams<br />
Technical Officers<br />
Ms Jennifer O’Hara<br />
Ms Kelly Hucker<br />
Ms Kay Waite<br />
PhD student<br />
Dr Satoshi Akima<br />
Mr Chiomad (Chi) Abili-Morris<br />
Visiting Scholar<br />
Mrs Xuehong Lu<br />
Xeno Transplant Group<br />
Senior Scientist<br />
Dr Shounan Yi<br />
Scientist<br />
Miss Elvira Jimenez-Vera<br />
PhD Student<br />
Mr Matthew Vittalone<br />
Mr Moses Wavamuno<br />
Visiting scholar<br />
Miss Jing Jing Wu<br />
Miss Yiling (Elise) Fu<br />
Renal Medicine<br />
Renal Medicine<br />
Director<br />
Prof David Harris<br />
Scientist<br />
Dr Deepika Mahajan<br />
Dr Yiping Wang<br />
Dr Guoping Zheng<br />
PhD Student<br />
Mr Vincent Lee<br />
Mr Alvin Tan<br />
Dr Ying (Cindy) Wang<br />
Mr Dong Zheng<br />
Research Assistant<br />
Ms Zolaikha Rahimi<br />
Kidney Regeneration<br />
Research Group Leader<br />
Dr Gopala Rangan<br />
PhD Students<br />
Mr Jason Coombes<br />
Miss Lena Succar<br />
<strong>Institute</strong> for Dental Research<br />
Director<br />
Prof Neil Hunter<br />
Deputy Director<br />
Prof Neil Jacques<br />
Honorary Research Associate<br />
A/Prof John Gibbins<br />
Honorary Research Fellow<br />
Dr Bettine Webb<br />
Senior Lecturer<br />
Dr Liz Martin<br />
Senior Research Scientist<br />
Dr Derek Harty<br />
Post-doctoral Fellow<br />
Dr Ping Ye<br />
Research Fellows<br />
Dr Roy Byun<br />
Dr Cherly Chapple<br />
Dr Mangala Nadkarni<br />
Dr Cathy Rathsam<br />
Dr Peter Yun<br />
Research Assistant<br />
Miss Gina Browne<br />
Miss Ruth Eaton<br />
Technical Officer<br />
Mrs Mara Cvejic<br />
Ms Mary Simonian<br />
PhD Student<br />
Ms Kim Chhour<br />
Ms Hongya Xie<br />
Masters Student<br />
Dr Kersten Angner<br />
Dr Nazilla Babapoor<br />
Admin Assistant<br />
Ms Tracey Bowerman<br />
<strong>Institute</strong> for Immunology<br />
and Allergy<br />
Research Director<br />
Prof Graeme Stewart<br />
Lab Manager<br />
Mr Stephen Schibeci<br />
Clinical Research Leader<br />
Dr David Fulcher<br />
Dr Rob Heard<br />
A/Prof Connie Katelaris<br />
Genetics of Multiple Sclerosis<br />
Research Group Leader<br />
Dr David Booth<br />
Hospital Scientist<br />
Dr Fiona McKay<br />
Research Assistant<br />
Mrs Najwa Marmash<br />
Immunogenetics<br />
Scientific Officer<br />
Dr Marc Buhler<br />
Immunology<br />
Registrar<br />
Dr Lucinda Berglund<br />
Molecular Genetics of Asthma and<br />
Allergy<br />
Research Group Leader<br />
Dr Graham Jones<br />
Research Assistant<br />
Ms Emily Clarke<br />
PhD Student<br />
Ms Nusrat Rahman<br />
Molecular Immunology<br />
Post-doctoral Fellow<br />
Dr Salvador Gala<br />
Viral Immunobiology and Apoptosis<br />
Research Group Leader<br />
Dr Lisa Sedger<br />
Research Assistant<br />
Mrs Sarah Osvath<br />
PhD Student<br />
Ms Arna Katew<br />
Masters Student<br />
Ms Nuruliza Roslan<br />
Honours Student<br />
Miss Maha Mahmassani<br />
B cell Immunobiology<br />
Research Group Leader<br />
Dr David Fulcher<br />
Research Assistant<br />
Shreya Malik<br />
Cancer<br />
<strong>Westmead</strong> <strong>Institute</strong> for Cancer Research<br />
Director<br />
Prof Rick Kefford<br />
PA to Rick Kefford<br />
Ms Annette Arkell<br />
Deputy Director<br />
A/Prof Ken Bradstock<br />
Lab Manager<br />
Dr Greg Kaplan<br />
Flow Cytometry<br />
Senior Scientific Officer<br />
Ms Mary Sartor<br />
Technical Assistant<br />
Mrs Alicia Smith-Wildey<br />
Admin Assistant<br />
Ms Carol Godson<br />
Miss Rozanne Kazminski<br />
Breast Cancer<br />
Research Group Leader<br />
A/Prof Christine Clarke<br />
Postdoctoral Fellow<br />
Dr Dinny Graham<br />
Dr Patricia Mote<br />
Research Assistant<br />
Miss Adrienne Hanson<br />
Ms Usha Salagame<br />
Mrs Ornella Tolhurst<br />
Technical Assistant<br />
Ms Jadranka Tomas<br />
PhD Student<br />
Ms Hazel Hill<br />
Breast Cancer Tissue Bank<br />
Project Manager<br />
Mrs Jane Carpenter<br />
Tumour Bank Officer<br />
Ms Virginia James<br />
Database Administrator<br />
Mr James Miller<br />
Mr Eftaker Molla<br />
Cell Cycle Research<br />
Research Group Leader<br />
Dr Helen Rizos<br />
Research Officer<br />
Dr Therese Becker<br />
Dr Lyndee Scurr<br />
Research Assistant<br />
Ms Ana Ayub<br />
Mrs Malama Irvine<br />
PhD Student<br />
Miss Prerna Badhwar<br />
Mr Stuart Gallagher<br />
Mr Sebastian Haferkamp<br />
Ms Heather McKenzie<br />
Cellular Therapies<br />
Research Group Leader<br />
A/Prof David Gottlieb<br />
Senior Scientific Officer<br />
Ms Vicki Antonenas<br />
Research Officer<br />
Dr Anita Gamvrellis<br />
Research Assistant<br />
Mr Leighton Clancy<br />
PhD Student<br />
Mr Kurt Forrester<br />
Ms Jenny Lau<br />
Dr Ken Micklethwaite<br />
Dr Philip Saunders<br />
Familial Cancer<br />
Clinical Director<br />
A/Prof Judy Kirk<br />
Research Group Leader<br />
Dr Jenny Leary<br />
Scientific Officer<br />
Ms Barb Guild<br />
Research Assistant<br />
Ms Monique Dyson-Dalziel<br />
Data Manager<br />
Mrs Nishath Syed<br />
Gene Expression<br />
Research Group Leader<br />
Dr Beric Henderson<br />
Post-doctoral Fellow<br />
Dr Mariana Brocardo<br />
Dr Ying Lei<br />
Dr Manisha Sharma<br />
Dr Myth Tsz Shun Mok<br />
Research Assistant<br />
Miss Kirsty Brodie<br />
PhD Student<br />
Miss Wendy Au<br />
Mrs Varsha Tembe<br />
Honours Student<br />
Mr Michael Johnson<br />
Gynaecological Oncology<br />
Research Group Leader<br />
Dr Anna deFazio<br />
Research Assistant<br />
Ms Yoke-Eng Chiew<br />
Ms Catherine Kennedy<br />
PhD Student<br />
Miss Natalie Gava<br />
Miss Kylie Pryor<br />
Miss Catherine Anne Emmanuel
52 53 > Research Report // AR 2006<br />
Leukaemia Cell Biology<br />
Research Group Leader<br />
Dr Linda Bendall<br />
Research Associate<br />
Dr John Hewson<br />
Research Officer<br />
Ms Aileen dela Pena<br />
Dr Roman Crazzolara<br />
Research Assistant<br />
Ms Rana Baraz<br />
Mr Adam Cisterne<br />
Miss Taoran Wang<br />
PhD Student<br />
Ms Shiva Gaundar<br />
Mr Julius Juarez<br />
Mr Naveed Khan<br />
Honours Student<br />
Miss Mandy Khoo<br />
Miss Danielle Tyrrell<br />
Melanoma and Genetic Epidemiology<br />
Research Group Leader<br />
A/Prof Graham Mann<br />
Research Officer<br />
Dr Gulietta Pupo<br />
Biospecimen Manager<br />
Miss Chantelle Agha-Hamilton<br />
Project Co-ordinator<br />
Ms Helen Schmid<br />
Research Assistant<br />
Ms Elizabeth Holland<br />
Mr James Indsto<br />
Mrs Gina Sherry<br />
Ms CarolineWatts<br />
PhD Student<br />
Mrs Robyn Dalziell<br />
Dr Sally de Zwaan<br />
Ms Nadine Kasparian<br />
Dr Angelo Sklavos<br />
Translational Oncology<br />
Research Group Leader<br />
Dr Rosemary Balleine<br />
Research Assistant<br />
Miss Pamela Provan<br />
PhD Student<br />
Miss Lucy Webster<br />
Dr Mark Wong<br />
Liver and Metabolic<br />
Storr Liver Unit<br />
Acting Directors<br />
Prof Jacob George<br />
Prof Chris Liddle<br />
Laboratory Manager<br />
Ms Linda Frost<br />
Clinical Hepatology<br />
Director<br />
Prof Jacob George<br />
CCRE Project Co-ordinator<br />
Dr Rosemary Carney<br />
Staff Specialist<br />
Dr Rita Lin<br />
Research Fellow<br />
Dr Dev Samarasinghe<br />
PhD Students<br />
Dr Hossein Poustchi<br />
Ms Alexis St George<br />
Clinical Research<br />
Registered Nurse<br />
Mrs Jasmin Canete<br />
Research Nurse<br />
Ms Seng Kee Teo<br />
Dieticians<br />
Miss Lauren McGrath<br />
Technical Officer<br />
Mrs Lee Russell<br />
Ms Keshni Sharma<br />
PhD Student<br />
Ms Amanda Johnston<br />
Molecular Pharmacology<br />
Director<br />
Prof Chris Liddle<br />
Research Officer<br />
Dr Kumar Subramanian<br />
Research Assistant<br />
Ms Sally Coulter<br />
Technical Assistant<br />
Ms Caroline Wilson<br />
PhD Student<br />
Miss Marina Kacevska<br />
NASH studies<br />
Research Officer<br />
Dr Roslyn London<br />
Dr Jianhua Wang<br />
Research Assistant<br />
Mrs Joanne Brymora<br />
Mr James Hurrell<br />
Neuroscience and Vision<br />
Brain Dynamics Centre<br />
Director<br />
A/Prof Lea Williams<br />
Deputy Director, Clinical Research<br />
Dr Anthony Harris<br />
Deputy Director, Basic Research<br />
Dr Chris Rennie<br />
Admin Officer<br />
Ms Estelle de Neumann<br />
Computer Systems Officer<br />
Mr James Moey<br />
Laboratory Manager<br />
Dr Peter Boord<br />
Project Officer<br />
Ms Jan Ambrose<br />
Attention Deficit Hyperactivity Disorder<br />
ADHD Co-ordinator<br />
Mr Daniel Hermens<br />
Post-doc/Fellow<br />
Dr Ilario Lazzaro (honorary)<br />
PhD Student<br />
Mr Nick Cooper<br />
Brain Modelling<br />
Head of Unit<br />
Dr Chris Rennie<br />
Prof Peter Robinson<br />
Post-doc/Fellows<br />
Dr Michael Breakspear (honorary)<br />
Dr Jong-Won Kim<br />
Dr Peter Loxley<br />
Dr Donald Rowe (honorary)<br />
Senior Research Officer<br />
Dr Dmitri Melkonyan<br />
Research Associate<br />
Dr Peter Drysdale<br />
PhD Students<br />
Mr Matthew Barton<br />
Mr Alan Chiang<br />
Mr Jonathon Clearwater<br />
Mr Richard Gray<br />
Mr Hal Henke<br />
Mr Sacha Van Albada<br />
Ms Hui Ying Wu<br />
Cognitive Neuroscience<br />
Head of Unit<br />
A/Prof Lea Williams<br />
Research Associates<br />
Ms Danielle Mathersul<br />
Post-doc/Fellows<br />
Dr Kerri Brown<br />
Dr Justine Gatt<br />
Dr Stacey Kuan<br />
Dr Thomas Whitford<br />
PhD Students<br />
Ms Ainslie Hatch<br />
Mr Kristan Kang<br />
Ms Pamela Marsh<br />
Ms Donna Palmer<br />
Depression<br />
Post-doc/Fellow<br />
Dr Andrew Kemp<br />
PhD Student<br />
Mr Patrick Hopkinson<br />
Honours Student<br />
Ms Jane Tu<br />
Post –traumatic stress disorder<br />
Head of Unit<br />
Prof Richard Bryant<br />
Post-doc/Fellow<br />
Dr Kim Felmingham<br />
Clinical Psychologists<br />
Ms Catherine Cahill<br />
Ms Sally Hopwood<br />
Ms Eva Kandris<br />
Dr Lucy Kenny<br />
Dr Julie Mastrodomenico<br />
Dr Kathryn Taylor<br />
PhD Students<br />
Ms Leah Campbell<br />
Ms Erin Falconer<br />
Ms Fiona McCallum<br />
Schizophrenia<br />
Head of Unit<br />
Dr Anthony Harris<br />
Senior Research Officer<br />
Dr Pritha Das<br />
PhD Students<br />
Dr Gary Flynn<br />
Ms Daniella Toscana<br />
Centre for Vision Research<br />
Director<br />
Prof Paul Mitchell<br />
Deputy Director<br />
Dr Jie Jin Wang<br />
Administrative Manager<br />
Ms Kirsten Jakobsen<br />
Senior Hospital Scientist<br />
Dr Xiao Yang Wang<br />
Nutrional Epidemiologist<br />
Dr Victoria Flood<br />
Orthoptist<br />
Mr Michael Cosstick<br />
Data Entry<br />
Ms Gail Leddin<br />
Ms Anastasia Rochtchina<br />
Senior Statistician<br />
Ms Elena Rochtchina<br />
Statistician<br />
Mr George Burlutsky<br />
Ms Annette Kifley<br />
Photographic Grader,<br />
Data and Computer Manager<br />
Ms Ava Grace Tan<br />
Photographic Grader<br />
Ms Bronwen Taylor<br />
Ms Victoria Cosatto<br />
Ms Mireille Moffitt<br />
Study Coordinator<br />
Ms Melissa Mackay<br />
Ms Tania de Loryn<br />
Administrative Assistant<br />
Ms Cora Li<br />
Research Assistant<br />
Mr Thomas Hong<br />
PhD Students<br />
Dr Ee-Munn Chia<br />
Dr Sudha Cugati<br />
Dr Reena Fotedar<br />
Dr Paul Healey<br />
Dr Jenny Ip<br />
Dr Shweta Kaushik<br />
Dr Anne Lee<br />
Dr Gerald Liew<br />
Dr Dana Robaei<br />
Dr Jennifer Tan<br />
Cardio-Respiratory<br />
Centre for Heart Research<br />
Director<br />
Dr Pramesh Kovoor<br />
Research Leaders<br />
Prof David Ross<br />
Dr Aravinda Thiagalingam<br />
Dr Liza Thomas<br />
Dr Stuart Thomas<br />
Research Assistant<br />
Mrs Anita Boyd<br />
Miss Michelle Mikhail<br />
Miss Valerie See<br />
Mr Gary Wu<br />
Technical Officer<br />
Mr Tony Barry<br />
PhD Student<br />
Dr Toon Wei Lim<br />
Mr Jim Pouliopoulos<br />
Dr Gopal Sivagangabalan<br />
Masters Student<br />
Dr Suzanne Eshoo<br />
Ludwig Engel Centre for<br />
Respiratory Research<br />
Director<br />
A/Prof John Wheatley<br />
Associate Director Research<br />
Dr Terence Amis<br />
Research Leaders<br />
Dr Kristina Kairatis<br />
A/Prof Peter Middleton<br />
Dr Tracey Robinson<br />
Research Fellow<br />
Dr Jamie Lam<br />
Research Officer<br />
Dr Mervat Hallani<br />
Research Assistant<br />
Ms Manisha Verma<br />
Research Study Co-ordinator<br />
Mrs Sharon Lee<br />
PhD Student<br />
Mr Jason Amatoury<br />
Miss Jyotishna Narayan<br />
Masters Student<br />
Miss Rita Perri<br />
Executive<br />
Director<br />
Professor Tony Cunningham<br />
Chief Operating Officer<br />
Mr Mark Dado<br />
Executive Assistant<br />
Mrs Claire Wolczak<br />
Operations and Support<br />
Operations Manager<br />
Mr Glenn Holden<br />
Facilities and Grants Administration<br />
Manager<br />
Mr Mark Smith<br />
Finance Manager<br />
Mr Mark Wissam<br />
Marketing and Communications<br />
Manager<br />
Ms Gayle McNaught (to April 2006)<br />
Laboratory Managers<br />
Ms Linda Frost<br />
Ms Rebecca Howard<br />
Dr Greg Kaplan<br />
Mr Gary Martinic<br />
Mr Stephen Schibeci<br />
HR Manager<br />
Amanda Clout (to May 2006)<br />
Shalini Singh<br />
IT Manager<br />
Mr Ian Magee<br />
Computer Support Officers<br />
Ms Chris Cannon<br />
Mr Blair Lawton<br />
Mr Bruno Marion<br />
Mr Adrian Plummer<br />
Admin Officer<br />
Mrs Brenda Wilson<br />
Safety and Training Officer<br />
Mr Brian Horsfield<br />
Stores Officer<br />
Mr Cecil Nast<br />
Reception<br />
Mrs Gail Ladner<br />
Biomedical Engineer<br />
Dr Rob Wilkins<br />
Research Facilities Co-ordinators<br />
Mrs Christine Browne<br />
Ms Caitlin van Holst Pellekaan<br />
Wash Room Technicians<br />
Ms Carol Devine<br />
Mrs Hongya Liu<br />
Core Technology Facilities<br />
Confocal Microscopy<br />
Imaging Officer<br />
Ms Jacqui Mills<br />
DNA Microarray<br />
Microarray Technician<br />
Ms Amanda Croft<br />
Electron Microscope<br />
E.M. Unit Co-ordinator<br />
Mr Ross Boadle<br />
Flow Cytometry<br />
Flow Cytometry Technician<br />
Ms Sandra Lum<br />
Histology Services<br />
Histology Technician<br />
Ms Aysen Yuksel<br />
Transgenics<br />
Transgenic Animal Co-Ordinator<br />
Ms Sandie Brown<br />
Protein Production Facility<br />
Proteomics Officer<br />
Dr Eve Diefenbach<br />
<strong>Westmead</strong> DNA<br />
Manager<br />
Mr Ilya Henner<br />
Technical Officer<br />
Miss Maryann Pincevic<br />
Masters Student<br />
Mr Mehdi Ramezani-Moghadam
54 55 > Research Report // AR 2006<br />
Publications 2006<br />
Alexander DM, Arns MW, Paul RH, Rowe DL,<br />
Cooper N, Esser AH, Fallahpour K, Stephan<br />
BCM, Heesen E, Breteler R, Williams LM<br />
& Gordon E EEG Markers for Cognitive<br />
Decline in Elderly Subjects with Subjective<br />
Memory Complaints. Journal of Integrative<br />
Neuroscience, 5, 49 - 74.<br />
Alexander DM, Trengove C, Wright JJ, Boord<br />
PR and Gordon E Measurement of phase<br />
gradients in the EEG. Journal of Neuroscience<br />
Methods, 156, 111 - 128.<br />
Amatoury J, Howitt L, Wheatley JR, Avolio<br />
AP, Amis TC. “Snoring-related energy<br />
transmission to the carotid artery in rabbits.”<br />
J Appl Physiol.<br />
Amatoury, J., L. Howitt, et al. “Snoringrelated<br />
energy transmission to the carotid<br />
artery in rabbits.” J Appl Physiol.<br />
Anaissie, E. J., Segal, B. H., Graybill, J. R.<br />
& other authors Clinical research in the lay<br />
press: irresponsible journalism raises a huge<br />
dose of doubt. Clin Infect Dis 43, 1031-1039.<br />
Anstey KJ, Lord SR, Hennessy M, Mitchell<br />
P, Mill K, von Sanden C. The effect of<br />
cataract surgery on neuropsychological<br />
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60<br />
<strong>Westmead</strong> <strong>Millennium</strong> <strong>Institute</strong> at a glance<br />
Research Divisions<br />
Collaborative Research Centres<br />
Trp 211(A)<br />
Infection and Immunity<br />
Centre for Infectious Diseases and Microbiology<br />
Centre for Transplant and Renal Research<br />
Centre for Virus Research<br />
<strong>Institute</strong> for Dental Research<br />
<strong>Institute</strong> for Immunology and Allergy<br />
Cancer<br />
<strong>Westmead</strong> <strong>Institute</strong> for Cancer Research<br />
Liver and Metabolic<br />
Storr Liver Unit<br />
Neuroscience and Vision<br />
Brain Dynamics Centre<br />
Centre for Vision Research<br />
Cardio-respiratory<br />
Ludwig Engel Centre for Respiratory Medicine<br />
Centre for Heart Research<br />
NHMRC Centre of Clinical Research Excellence to Improve<br />
Outcomes in Chronic Liver Disease<br />
NHMRC Centre of Clinical Research Excellence in Renal Medicine<br />
NHMRC Centre of Clinical Research Excellence to Improve<br />
Outcomes in Immunosuppressed Haematology Patients<br />
Australian Centre for HIV and Hepatitis Virology Research<br />
NSW Breast Cancer Tissue Bank<br />
International Melanoma Consortium<br />
Kathleen Cuningham Foundation Consortium for Research into<br />
Familial Breast Cancer<br />
Genes Associated with Multiple Sclerosis in Europeans (GAME)<br />
Swedish and Australian Collaboration for Research into Atopic<br />
Dermatitis<br />
National Pancreas Transplantation Centre<br />
The <strong>Millennium</strong> Foundation<br />
Medical research relies on the support of individuals,<br />
business, community and service groups. The <strong>Millennium</strong><br />
Foundation is the main fundraising body supporting <strong>Westmead</strong><br />
<strong>Millennium</strong> <strong>Institute</strong>.<br />
Glu 118(A)<br />
013<br />
Pro 137(A)<br />
Glu 116(A)<br />
Ile 136(A)<br />
Core Technology Platforms<br />
Confocal Microscopy<br />
DNA Microarray<br />
Electron Microscopy<br />
Flow Cytometry<br />
Histology Services<br />
Transgenics<br />
Protein Production Facilities<br />
<strong>Westmead</strong> DNA<br />
The <strong>Millennium</strong> Foundation is grateful for any support, as<br />
every donation is valuable.<br />
Donations over $2.00 are tax deductible. Donations can be<br />
made by sending a cheque, money order or credit card details<br />
to the following address (please indicate if you have a specific<br />
interest in a particular research area).<br />
The <strong>Millennium</strong> Foundation, PO Box 74, <strong>Westmead</strong> NSW 2145,<br />
or contact us on our toll free number: 1800 639 037.<br />
3.20<br />
C3<br />
C2<br />
019<br />
C14 C12<br />
C7<br />
N8<br />
2.82<br />
C9<br />
3.27<br />
C16<br />
O15<br />
C11 N10<br />
2.79<br />
C16<br />
3.01<br />
2.70<br />
Founding donors include: Australian Cancer Research Foundation, The <strong>Millennium</strong> Foundation, Robert W Storr Estate,<br />
University of Sydney, and Staff Specialists of <strong>Westmead</strong> Hospital.<br />
We wish to thank the staff and the families that assisted<br />
in the development of the WMI Annual Report 2006.<br />
Jessica and Colette Grassi<br />
Nick Jones and Kirsten Hartshome<br />
Diane and Andrew Luccitti<br />
Production Manager – Victoria Hollick<br />
Design – Cross Media Communications Pty Ltd<br />
Ala218(A)<br />
Darcy Road, PO Box 412<br />
<strong>Westmead</strong> NSW Australia<br />
Telephone +61 2 9845 9000<br />
Fax + 61 2 9845 9100<br />
www.wmi.usyd.edu.com.au<br />
Leu 214(A)
(R)-mon-97<br />
E118<br />
G117<br />
A133<br />
P137<br />
R119<br />
W127<br />
Y211