Victor Chang

2009

VICTOR CHANG CARDIAC RESEARCH INSTITUTE ANNUAL REVIEW

“BIOMEDICAL RESEARCH IS A GLOBAL ENTERPRISE INVOLVING A NETWORK OF WORLDWIDE COLLABORATIONS”

ESTIMATED AMOUNT OF AUSTR ALIANS WITH A LONG TERM CARDIOVASCULAR

PEOPLE WAITING FOR HEART

HEART DISEASE DOESN'T

A HEART IS VIABLE OUTSIDE THE

AFTER OUR RECENT

FIRST ORGAN TO BEGIN

PEOPLE WHO DIE OF (CVD) IN

ML’S OF BLOOD PUMPED EACH

MISSION

MARY AIKENHEAD MINISTRIES CHAIR: MR. RICHARD HARPHAM

•••

The relief of pain and suffering and the promotion of well-being, through an understanding of the fundamental mechanisms of cardiovascular biology in health and disease.

Contents

S T. VINCENT’S HEALTH AUSTRALIA LTD CEO: DR. TRACEY BATTEN

ST. VINCENT'S & MATER HEALTH CEO: MR. STEVEN RUBIC

VICTOR CHANG CARDIAC RESEARCH INSTITUTE

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02 Victor Chang (1936-1991) 03 Our History 04 Overview 06 2009 Chairman's Report 08 2009 Executive Director's Report 10 15 Years of Discovery

Board Committees —

12 Board of Directors 14 Our Committees 15 Vale 16 Our Institute

VCCRI ORGANISATIONAL STRUCTURE

BOARD CHAIRMAN MR. STEVEN LOWY, AM

SCIENTIFIC ADVISORY BOARD

COMMITTEES EXECUTIVE MANAGEMENT MR. STEVEN LOWY, AM

UNIVERSITY OF NSW VICE CHANCELLOR: PROFESSOR FRED HILMER, AO

FINANCE MR. JOHN KEAN

Research Divisions

APPEALS MR. JOHN MCGUIGAN

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18 Developmental Biology 22 Molecular Cardiology and Biophysics 28 Molecular Genetics 32 Structural and Computational Biology 36 Cardiac Physiology and Transportation

Awards and Seminars —

41 42 44 48 49

VCCRI Awardees Awards and Achievements Seminar Series Symposium/Princesses Lecture Publications 08/09

Administration —

54 55 56 58 59 60

Finance Report VCCRI Spotlight Fundraising and Functions School Science Awards VCCRI Limited Members VCCRI Supporters

EXECUTIVE DIRECTOR PROFESSOR ROBERT GRAHAM, AO

RESEARCH DIVISIONS

CHIEF OPERATING OFFICER

ADMINISTRATIVE SUPPORT CORE FACILITIES

ESSENTIAL SERVICES

VCCRI ANNUAL REVIEW 2009 01.

VICTOR CHANG (1936-1991) •••

A pioneer of the modern era of heart transplantation, Victor Chang established the National Heart Transplant Unit at St. Vincent’s Hospital in 1984.

Healer of Hearts —

Victor Chang (Yam Him) was born in Shanghai of Australian born Chinese parents. He came to Australia in 1953 to complete his schooling at Christian Brothers College, Lewisham, and then moved to medical training at Sydney University. Graduating in 1962, he became an intern and later a registrar in cardiothoracic surgery at St. Vincent’s Hospital.

After completing additional training in England, and then at the prestigious Mayo Clinic in the US, he returned to St. Vincent’s Hospital in 1972 to join the elite St. Vincent’s cardiothoracic team that already included Harry Windsor and Mark Shanahan.

A pioneer of the modern era of heart transplantation, Victor Chang established the National Heart Transplant Unit at St. Vincent’s Hospital in 1984.

During the 1980’s he became widely known as a man of vision, as a caring surgeon, as a researcher and as an ambassador for Australia and the people of South East Asia. During this time he nurtured a vision to establish an internationally recognised cardiac research centre at St. Vincent’s and to this end, in 1990 he and others launched the “Heart of St. Vincent’s Appeal”.

02. VCCRI ANNUAL REVIEW 2009

OUR HISTORY •••

History

Royal Opening

With his tragic and untimely death in Sydney on July 4, 1991, efforts to realise Victor Chang’s dream accelerated, resulting in generous donations from the Federal Government, the late Mr. Kerry Packer, AC and the Australian public.

Her Royal Highness Crown Princess Mary of Denmark officially opened the Lowy Packer Building on Wednesday September 3, 2008 in front of 250 guests. That night both their Royal Highnesses Crown Prince Frederik and Crown Prince Mary attended a celebratory dinner in the building.

With these funds St. Vincent’s Hospital established the Victor Chang Cardiac Research Institute, which was launched on February 14, 1994 by the then Prime Minister of Australia, the Hon. Paul Keating, with the late Mr. Kerry Packer, AC as its Patron and Professor Robert Graham as its Executive Director.

The $80 million purpose-built facility, together with the existing Garvan Building, houses the St. Vincent's Research Precinct, the largest biomedical hub in NSW comprising the Victor Chang Cardiac Research Institute (VCCRI), the St. Vincent's Centre for Applied Medical Research and the Garvan Institute of Medical Research.

On February 27, 1995, the Institute was incorporated as an independent research facility with the Hon. Neville Wran, AC, QC as its Chairman, and on November 1, 1996 the late Diana, Princess of Wales opened the Institute in its then new premises in the Garvan Building. In 2004, Mrs. Ann Chang became a Patron of the Institute, in 2005 Her Royal Highness Crown Princess Mary of Denmark, an Honorary Life Governor and in 2008 the Hon. Neville Wran, AC, QC, our inaugural Chairman retired and became a Patron.

The Lowy Packer Building was built with funds kindly provided by the NSW State Government and Australian Federal Government, as well as generous donations from The Atlantic Philanthropies, the Lowy and Packer families, the National Australia Bank, ANZ Bank and Citigroup, along with many other generous donors.

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Her Royal Highness unveiled a plaque and a bronze life-sized sculpture of the late esteemed cardiac surgeon Dr. Victor Chang, which sits in front of the building. The opening was also attended by the then Premier of New South Wales, the Hon. Morris Iemma, MP and the building was blessed by His Eminence, George Cardinal Pell.

The new building will allow the VCCRI to expand its research and develop vital ancillary core facilities, such as X-Ray crystallography and will provide increased opportunities for research training of students undertaking BSc (Hons), MSc, MD or PhD degrees as well as training postdoctoral students.

02

01

01 Lowy Packer Building 02 VCCRI Students 03 Mrs. Ann Chang and Her Royal Highness Crown Princess Mary of Denmark

03

VCCRI ANNUAL REVIEW 2009 03.

OVERVIEW •••

8

16

17 13

OUR COLLABORATIONS

14 11

9

10

20

12 16 26

The Worldwide Web of Heart Research —

More than ever before, science progresses as an open-ended network of human activity.

The private curiosity, drive, insight and even genius of individual scientists are still at the core of this activity. However, the ability to communicate freely through email and other electronic means, and through the worldwide web to access virtually all of the published literature as well as websites hosting large data sets, has revolutionised the way science is conducted. Ideas now circulate more freely instead of being buried away in obscure books and journals, and can be seized upon, filtered and extended very rapidly by others, much in the same way as cultural ideas and trends pervade the community. Adding to this, the technology of experimental science has changed dramatically.

The scale of our endeavours, aided by computers, is simply mindboggling. Genes provide the heritable code for proteins and RNA, which are the enzymes and structural elements that make up the cells of our bodies.

04. VCCRI ANNUAL REVIEW 2009

Accidental changes in genes or how they are regulated cause disease, or contribute to the severity of disease, including heart disease.

Virtually overnight, we moved from an ability to analyse single genes at a time, extrapolating wildly about the behaviour of the whole cell, to one in which we can interrogate all of the 40,000 or so genes in the human genome in a single experiment. Robots have also allowed us to do hundreds of thousands of manipulations that a singe researcher could not possibly contemplate.

The data sets we generate are huge, and there is a strong expectation in the community that these be made publicly available for other scientists to analyse. As a result, a new generation of scientists skilled in information technology who help us sift through these large data sets for their hidden secrets, has emerged.

Because of the need for a greater range of expertise and technologies, collaborations between laboratories and the sharing of reagents are now vital parts of our work. Science is conducted as a human network spread across the globe.

The Victor Chang Cardiac Research Institute is committed to making important discoveries in cardiovascular biology and medicine. Its scientists are very much embedded in the worldwide web of heart research.

They collaborate widely with researchers internationally, and these collaborations lead to important discoveries, as can be seen by the high impact of our publications.

This impact is as much related to how those discoveries pervade back through the worldwide information network and are used by others, as the discoveries themselves.

These are exciting times, and the brief profiles and stories provided in this VCCRI Annual Report speak not only of the individuals and their achievements, but also of the weblike organism of science and how it impacts our daily lives.

22

More than ever before, science progresses as an open-ended network of human activity.

International Collaborators —

8. Canada

13. Wales

– Howard Hughes Institute – Samuel Lunenfeld Research Institute

– Cardiff University

9. USA

18

15

19

25 24

23

6

5 7

4 3

1 2 21

Local Collaborators —

1. Sydney

4. Melbourne

– Centenary Institute – Garvan Institute – St. Vincent’s Hospital – Children’s Hospital & Medical Research Institute – Bosch Institute – Donate Life, Liverpool Hospital – Macquarie University – Millenium Institute, Westmead – Sydney Melanoma Unit – University of Sydney – Prince of Wales Medical Research Institute – Children's Hospital Westmead – University of New South Wales – EngeneIC Ltd – BMI, Sydney

– St. Vincent’s Institute – Walter & Eliza Hall Institute – Monash University – Peter MacCallum Cancer Centre – Baker IDI – Mesoblast Ltd – University of Melbourne – Royal Melbourne Hospital – Alfred Hospital

2. Wollongong – University of Wollongong 3. Canberra – Australian National University – John Curtin School of Medicine

5. Brisbane – Mater Medical Research Institute – IMB, University of Queensland – Queensland Institute for Medical Research – Griffith University 6. Perth – WA Institute of Medical Research – University of Western Australia – Curtin University 7. Adelaide – Hanson Institute – University of Adelaide – IVMS, Adelaide – University of South Australia

– Harvard Medical School, Boston – Harvard Stem Cell Institute, Boston – Cardiovascular Research Institute, San Francisco – University of San Francisco – Cincinnati Children’s Hospital Medical Centre – University of Virginia – University of Minnesota – University of Wisconsin – Mayo Clinic, Rochester – Vanderbilt University, Tennessee – University of Phoenix, Arizona – Case Western Reserve University, Cleveland – Northwestern University, Chicago – University of Chicago, Chicago – Emory University School of Medicine, Atlanta – Children’s Hospital Oakland Research Institute, California – Stanford University, California – UC San Diego, California – Burnham Institute for Medical Research, La Jolla – UMDNJ-New Jersey Medical School, Newark – Rochester University, NY – Cold Spring Harbour Laboratories, NY – University of Illinois UrbanaChampaign – UTMB, Galveston, Texas – University of Texas – Louisiana State University Health Sciences Centre – Chori, USA – CSHL, USA – University of Birmingham, Alabama 10. Netherlands – University of Amsterdam – Academic Medical Centre, Amsterdam – VIB, Netherlands 11. France – Pasteur Institute, Paris – University of Nice, Sophia-Antipolis 12. Germany – Institute of Molecular Biology, Hanover – Karlsruhe Institute of Technology, Karlsruhe – University of Cologne, Koeln – University of Heidelberg – EMBL – Max Planck Institute – Medical University, Berlin

14. Denmark – Royal Danish Academy of Sciences & Letters 15. Japan – Osaka University – RIKEN, Saitama 16. Sweden – Karolinksa Institute, Stockholm 17. UK – University of Oxford, England – Royal Devon & Exeter Hospital, Exeter – University of Liverpool – Addenbrooke’s Hospital, Cambridge – University of Cambridge – University of Oxford – Imperial College of London – Royal Brompton Hospital, London – University of Newcastle Upon Tyne – Sanger Centre, Great Britain – Royal College of Surgeons, Ireland 18. Korea – Yonsei University College of Medicine, Seoul 19. China – Zensun Ltd, Shanghai 20. Switzerland – University of Geneva 21. New Zealand – Starship Hospital, Auckland – University of Auckland – University of Otago, Dunedin 22. Poland – Warsaw University 23. Singapore – Nanyang University 24. India – Centre for Cellular & Molecular Biology, Hyderabad 25. Hong Kong – University of Hong Kong 26. Italy – EMBL, Montorotondo

VCCRI ANNUAL REVIEW 2009 05.

2009 CHAIRMAN’S REPORT •••

During our 15th year, the Institute was able to reflect on how far it has come.

It has established an international reputation in understanding the heart and the mechanisms that make it work.

Each member of our faculty is recognised worldwide for their work and it is because of them that the Institute has been able to be recognised as one of the world’s leading research institutes.

Steven Lowy Chairman — The Victor Chang Cardiac Research Institute remains a powerful symbol of how one person can make an extraordinary impact on the lives of many.

When he was alive, heart transplant surgeon Dr Victor Chang spoke of his vision for a research centre dedicated to eradicating heart disease.

He recognised that heart disease was the worst health epidemic we face.

Each day 70 Australians die of heart disease. Heart and circulatory diseases kill one Australian every 11 minutes.

More children die of heart disease than all other childhood diseases combined.

After Dr Victor Chang’s tragic death in 1991 a concerted effort by dedicated individuals, including Mr Kerry Packer AC, together with donations from the Commonwealth Government and the public, helped begin to turn Victor’s vision into a reality.

The Victor Chang Cardiac Research Institute was launched on February 15, 1994, with relatively modest resources and operating from the old St Vincent’s Hospital medical students’ quarters.

Temporary facilities were later opened by the late Diana, Princess of Wales, in the Garvan Building and, finally, in 2008 the Lowy Packer Building, a state-of-theart facility dedicated entirely to research, was opened by HRH Crown Princess Mary of Denmark.

06. VCCRI ANNUAL REVIEW 2009

In fact, I’m very pleased to report that the 5-yearly review of the Institute conducted by our Scientific Advisory Board has been completed very recently and has borne out this assessment of the standing of the Institute. As you might know, the Advisory Board is made up of six of the world’s most eminent scientists.

I would like to quote just a few preliminary words: “Under the leadership of Professor Graham the Institute has developed to be one of the best-known and most highly-respected medical research institutes in Australia and has an international reputation for its cardiac research.

“The Victor Chang Institute has survived, indeed thrived, through the global financial crisis and has managed a complex building and relocation program, recently moving into the Lowy Packer Building which provides world-class facilities.”

In summary, it found that: “The Victor Chang Institute has developed admirably and is at the most exciting point in its 15-year journey.

There is a realisation among the leadership, strongly endorsed by the Scientific Advisory Board, that this is the right time to take a deep breath and plan strategically for the next phase of the Institute’s development.”

I don’t think we could hope for a more powerful endorsement of the work we are all undertaking here, and it gives Bob and his team great encouragement for the future.

Each of the past 15 years has been marked by at least one major discovery in a wide-ranging area of heart disease biology. These discoveries range from studies showing the benefits of lowering cholesterol to studies that explain how the severity of a disease can differ even between identical twins. Our researchers have discovered that diseases can by caused by a defect in the activity of a gene rather than in its structure – part of a new field called epigenetics.

We have had breakthroughs in understanding the cause of heart defects in babies and finding that mouse hearts can regenerate. We have developed a new treatment that more than doubles the time a heart can remain healthy after being removed from a donor and before transplantation into a heart failure recipient. This is an enormously important advance, especially in Australia where large distances limit the availability of hearts to a region within four hours travelling time. Indeed, this advance has worldwide ramifications where the same limitations apply and often means that a patient with heart failure dies before they can get a suitably matched donor heart.

In a recent landmark study our researchers identified a gene which can lead to permanent kidney damage when there are not enough nutrients provided to a baby in the womb – another major discovery given that kidney disease often leads to high blood pressure and heart failure.

All of these breakthroughs, and many more, are detailed in the published work of the Institute which is one of the most important measures of our success.

Since last year, our researchers have published 128 research papers in highly regarded journals around the world, as well as 8 book chapters. This is just one indicator of the incredible output generated by our team.

Fundraising and functions Without VCCRI friends and supporters our institute would not exist. Despite the difficult economic conditions of the past two years donors continued to give generously thanks to the efforts of the Board and Appeals Committee.

Our fundraising events have been more successful than ever. This year the Pall Mall Manufacturing Company, and the Schwartz Foundation in partnership with the Mercure, Sydney, launched new fundraising programs on behalf of the VCCRI. In August 2009, more than 760 people attended the annual Heart to Heart Ball in support of heart research and heard a landmark speech from James Packer about the enormous challenge of finding new and better ways to fund medical research.

A wide range of other fundraising and promotional activities were held during the year, from the Miedecke Motorsport promotion at the Targa Tasmania race, to the Club Marconi charity ball, Steve Quinn’s cycling marathon from Melbourne to Sydney as well as our traditional golf days.

Awards and Honours I am delighted to report that our executive director, Professor Robert Graham, was awarded an Order of Australia, an AO, in the 2009 year’s Queen’s Birthday Honours list, and I might say that few awards have been so richly deserved.

The 2009 Life Governor Award was presented to Mrs Roslyn Packer, AO. All of us here are familiar with the enormous contribution Ros has made over the entire life of the Institute, personally and financially, and she is deservedly regarded as one of the principal driving forces and reasons for our success.

Tony Campologno OAM from Club Marconi, Chum Darvall of Deutsche Bank, Martha Kennedy from LK Jewellery and Cameron Irving were all appointed as Ambassadors.

Our inaugural Victor Chang Young Ambassador Award was presented to Mark Vincent for his continuing support of the Institute. As many of you would know Mark is the grandson of the late Bruno Riccio, is a staunch supporter of the Institute and won the 2009 Australia’s Got Talent competition.

Finances Our financial position today remains sustainable. Given the increased costs associated with our first full year in the new building we had budgeted for a deficit in 2009 of some $1.96 million. I’m pleased however to say we completed the year with a small profit of $92,000, ahead of budget by approximately $2.1 million.

In 2009 our researchers attracted a record $10.6 million in grant income from the NHMRC, Australian Research Council and other peer-reviewed funding bodies.

As expected in the prevailing economic climate, grants from private funding bodies fell but the amount of NHMRC grants awarded to the VCCRI increased by 20% over the previous year.

Total income for the Institute was up from $16.1 million to $17.2 million, this is a very good result, but we continue to face some very real funding challenges going forward.

Board and Appeals Committee In these times of global financial uncertainty, the VCCRI is guided by a talented leadership team that ensures our continued research success and I acknowledge their important contributions. Two board members, Mrs Roslyn Packer AO and Professor Ian Dawes, retired after many years of invaluable service. I thank them sincerely for their outstanding efforts.

I would like to take this opportunity to introduce and welcome three new members to the board, Dr Gary Weiss, Ms Jill Margo, AM and Mr Angelos Frangopoulos.

I also thank the Sisters of Charity through the Mary Aikenhead Ministries for their continued support and guidance.

Conclusion Strong supporters are at the heart of our institute. Without their generosity, your generosity, support and encouragement we would not have achieved these outstanding results and on behalf of the team at the Victor Chang Cardiac Research Institute, I extend our heartfelt thanks.

We look forward to sharing the next 15 years with you to bridge the gap between hope and cure. I believe that with your help, we can go a long way towards making the Victor Chang’s vision – the eradication of heart disease – a reality.

Our fundraising challenge means it will be important for the Institute to go on promoting its work to the public and explaining its importance.

The board remains committed to this objective and will think creatively in the years ahead about how to broaden the funding base and build sustainable income streams for the future.

Steven Lowy AM, BComm (Hons)

VCCRI ANNUAL REVIEW 2009 07.

2009 EXECUTIVE DIRECTOR’S REPORT •••

Since our last report, our researchers have published 128 research papers in highly regarded journals as well as eight book chapters, and in 2009 our researchers attracted a record $10.6 million in grant income from the NHMRC, Australian Research Council and other funding bodies - an increase of almost 20% over the past two years.

Professor Robert M. Graham Executive Director —

Overview Since its establishment in 1994, the Victor Chang Cardiac Research Institute (VCCRI) has been committed to unlocking the mysteries of heart disease. Despite the disruption of moving into the new Lowy Packer building at the end of 2008, we have been able to maintain our momentum, with continued strong progress and many discoveries in 2009. Of course this new facility is much needed and gives us the opportunity to now move ahead at an increased and by expanding our research team.

In this our 15th year of operations, I am pleased to report that an independent survey by the Australia National University ranked the VCCRI 6th out of Australia’s top 37 medical research institutes. The report also showed that we have established a strong international reputation with our research having almost double the impact of that of biomedical research carried out worldwide and

by Australian universities and other research organisations.

08. VCCRI ANNUAL REVIEW 2009

Awards and honours Further evidence of the Institute’s scholarship is the many awards and fellowships garnered by our faculty and trainees. Some of the highlights from the past two years include of course the prestigious Australia Fellowship awarded to Professor Richard Harvey.

In addition, Monique Ohanian who, whilst at high school, won the VCCRI Science Award and then went on to win the University of Western Sydney Dean’s medal for her honours project conducted jointly with the VCCRI. Monique has now commenced her PhD with us. James Chong was awarded the inaugural NSW Fulbright Australia-America Commission Fellowship, which supports students to complete their PhD in Australia or the United States. Alasdair Watson has been awarded a research fellowship from the Royal Australasian College of Surgeons.

Professor Peter MacDonald was nominated as an Australian of the Year and has also been appointed the president-elect of the Transplantation Society of Australia and New Zealand.

A full list of our awards and honours recipients can be found later in this report.

Symposia and lectures The VCCRI believes in creating an environment that encourages collaboration and communication among researchers, clinician scientists and students. In addition to our regular seminars, we host a yearly international Princesses’ Lecture. In 2008 and 2009, two world renowned researchers, Professor Richard Henderson from the MRC Laboratory of Molecular Biology in Cambridge and Professor Andreas Zeiher from the University of Frankfurt were our Princesses’ lecturers and spoke at two further international symposia that the Institute organised – these symposia also featuring many other nationally and internationally acclaimed scientists and clinicians.

In 2009, the Honourable Jodi McKay, NSW Minister for Science and Medical Research, who has been a strong supporter of our sector, kindly opened the last of these symposia.

Other happenings For the past year I have held the presidency of the Association of Australian Medical Research Institutes, the peak lobby group for independent institutes including the VCCRI. Modern medicine is founded on scientific discoveries. I am working to ensure that scientists have a strong voice in improving our health care system to ensure that research into heart disease, cancer, and other major diseases is funded as an important component of improving Australia’s health care and hospital system into the future.

On a sad note, this year we farewelled our finance manager, Monica O’Loughlin, who tragically died suddenly of heart disease while visiting her mother. She is much missed by all at the institute, and sadly her death at such a young age again highlights the fact that heart disease claims four times more women’s lives than breast cancer or indeed any other cause.

Education

Thanks

In 2009, PhD degrees for work carried out at the institute, in conjunction with the University of NSW Faculty of Medicine, were awarded to Alfred Hing and Jacque-Lynne Johnson. Carol Mark was awarded First Class Honours in bioinformatics.

It would not be possible to conduct our important research without the generous support of our Friends – the many people who give so generously to support our work. This year, for example, we unveiled our new confocal microscope, which was made possible by a generous bequest from the estate of the late Herbert Sydney Smith.

This vital piece of equipment allows our researchers to see the tiny particles inside a living cell, but also to ‘slice’ it very finely so all the components of the cells can be visualised individually.

Community activities The VCCRI now has 100 schools participating in its School Science Awards program and will expand into the Illawarra and South East Region in the near future. The program was developed to foster and encourage an interest in science among secondary school students, with the view to promoting careers in science and biomedical research. This year’s winners came from schools in the Penrith, Blacktown, Bankstown and Campbelltown areas.

The VCCRI continues to hold weekly tours of the institute for the public, to give them an insight into the research we are conducting. The tours have proved to be very popular with Probus, Rotary, Lions and View Clubs. Our researchers were also invited to speak about the institute’s work and heart disease to various community groups.

We again participated in the Science in the City Expo, and Science Exposed, which are aimed at school students.

My most sincere thanks also to our Board, headed so ably by Mr. Steven Lowy, AM, our Appeals Committee, chaired by Mr. John McGuigan, our Finance Committee, headed by Mr. John Kean, the Sisters of Charity, and all of our scientific and administrative staff.

Professor Robert M. Graham AO, FAA, MBBS (Hons), MD, FRACP, FACP, FAHA

An independent survey has shown the VCCRI is 6th out of Australia's Top 37 Medical Research Institutes.

The Hon Neville Wran AC, QC

— Retirement of our inaugral Chairman On June 30, 2008 our inaugural Chairman, the Hon Neville Wran, AC, QC retired from the Victor Chang Board after 14 years at its helm.

His tenure saw the Institute grow from having very few staff, renting a floor in the Garvan Building, to having its own purpose built $80 million facility with a staff of 130 world-class scientists.

Mr Wran was an incredibly generous and inclusive Chairman. He encouraged other directors and sought their views.

He was a master at chairing meetings – he was a stickler for punctuality and ensured meetings never ran over the allotted time.

There are two things a good Chairman must do, he would say.

The first is never run out of money, the second make sure you have a great Chief Executive.

His consumate political skills and his tact meant the interests of the Victor Chang were always at the front and centre, but not at the expense of our reputation, or our long-term relationship with other important institutions.

Mr Wran graciously accepted our invitation to be a Patron of the Institute upon his retirement and as an acknowledgment of his enormous contribution, the boardroom in our new facility is named The Hon Neville K Wran, AC, QC in his honour.

The Institute is what it is today thanks to the Chairmanship of Mr Wran. We thank him for his mentoring, guidance and wisdom in making it a world-class research institute.

VCCRI ANNUAL REVIEW 2009 09.

15 YEARS OF DISCOVERY ••• 1996 2000 1998 1994

2001 1995 1997 1999

2009 marked the 15th Birthday of The Victor Chang Cardiac Research Institute. Our researchers are passionate, dedicated and committed to finding a cure for heart disease.

1994

1996

1999

2001

2003

The VCCRI officially launched by the Prime Minister the Hon Paul Keating, MP with Mr. Kerry Packer, AC as Patron.

Major review of the family of proteins on the surface of cells that allow adrenaline, released at times of stress, to regulate heart function.

An entirely unexplained but important phenomenon – in identical twins disease severity can vary markedly. ie one twin may have very severe disease, the other is only mildly affected or normal. Given that such twins have identical genes, the difference is not in the genes themselves but differences in how their genes function.

Since the human gene has been sequenced we now know the order of millions of DNA bases. What cannot fully be predicted from this sequence is where all the genes lie compared to all the extra DNA material. For the first time the precise location of thousands of genes that are active in the developing embryo which is critical for reading our genome map has now been discovered.

Muscle is composed of two types of fibre – fast twitch provides strength and slow twitch is required for endurance. Previously unidentified signals have been discovered that control the development of slow twitch muscles in zebrafish.

The findings should be directly applicable to our understanding of human muscle development and physiology, and muscle diseases.

Reported for the first time that an enzyme involved in forming protein polymers is also able to function as a critical molecule linking the activation of cells, such as those in the heart, with enhanced functioning of these cells in response to stress.

1995 Major finding demonstrates how the metabolism of an expensive immunosuppressant drug used in transplant patients can be slowed by the use of another cheaper drug used to prevent infections in these patients.

10. VCCRI ANNUAL REVIEW 2009

1997 Clumping of red blood cells results in changes that can be observed non-invasively with anechocardiogram and used to diagnose patients with an increased risk for blood clots and strokes.

1998 Landmark study demonstrating the far reaching benefits of lowering cholesterol regardless of how high it is before treatment.

2000 hen both copies of the gene W Nkx2.5 are not functioning, the heart fails to develop, but if only one of the genes is defective, this results in a higher rate of hole in the heart, the commonest form of heart disease present at birth.

2002 A detailed review of inherited causes of heart muscle disease that result in excessive thickening or dilation of the heart disorders that often lead to severe heart failure requiring a heart transplant was undertaken.

2004

2006

2009 2007

2005 2003 2002

2008

2004

2006

2007

2008

2009

Major advance in the understanding of adult stem cell biology and in the application of adult stem cells to treat cardiac disease.

Groundbreaking evidence showing how dietary choices in pregnancy affect children for at least two generations.

In an international first, our researchers reported that the diet of pregnant mothers can affect, not only in the children, but in their grandchildren as well.

2. Interactions between inherited gene changes and stretch or dilation of the low pressure upper chambers of the heart, the atria, may be important in the onset of atrial fibrillation, which is the most common heart rhythm abnormality in our community and is a major risk factor for heart failure and stroke.

esearchers find that the R embryonic mouse heart has an astounding capacity to regenerate, a phenomenon previously observed only in non-mammalian species.

2. The finding that problems with the placenta may affect kidney development.

This could account for the development of a particular unexplained kidney disorder (renal medullary displasia) and abnormalities in kidney function in children who experience growth delay whilst in the womb.

Although it has been long known that structural gene – defects (or mutations) can be inherited and cause disease, it was a surprise to find that so too can defects in gene activity (epimutations).

2005 A breakthrough discovery in how a newly uncovered natural mechanism works to control how much protein is produced from a gene.

2007 1. Breakthrough discovery in understanding heart problems in babies by addressing origin of heart defects and discovering that certain types of congenital heart problems occur at a much earlier stage in the development of a baby than ever expected.

3. Abnormalities in a cardiac gene TBX20 (a member of the T-box family of genes that regulate how other sets of genes are turned on and off in the embryo) which are responsible for heart malformations in children identified.

2009 1. A world-first technique has been developed that will almost double the time a donor heart can spend in transit, from the current four to five hour limit, up to 14 hours.

Researchers say the technique will give greater scope to accept a variety of donors, including those from interstate and overseas.

4. Patients with severe heart disease may soon have access to a simple injection to help manage their symptoms and reduce their need for large amount of pain relief.

VCCRI ANNUAL REVIEW 2009 11.

BOARD OF DIRECTORS •••

The successful operations of The Victor Chang Cardiac Research Institute are heavily reliant upon the dedication, commitment and vision provided by the Board of Directors and subsidiary committees.

Mr. Steven Lowy

Ms. Jill Margo

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Mr Lowy joined the Victor Chang Board as an inaugural member in 1995 and became Chairman in 2008.

Ms Margo joined the Victor Chang Board in 2008. She is a a medical journalist on The Australian Financial Review. She has won numerous international and national media awards, including two Walkleys.

Since 2000, she has been a member of working parties charged with developing clinical and consumer guidelines for the management of prostate cancer.

In 2006 Jill was awarded an Order of Australia for services to journalism and cancer. She holds a BA (Honours) in English literature, is a best selling author and biographer.

Mr. Lowy holds a Bachelor of Commerce (Hons) degree from University of NSW. Prior to joining Westfield in 1987, he worked in investment banking in the US. Mr. Lowy is President of the Board of Trustees of the Art Gallery of New South Wales; a director of the Lowy Institute for International Policy; a member of the Prime Minister’s Business-Government Advisory Group on National Security; and Chairman of the Board of Management for the Associate Degree of Policing Practice (ADPP).

Professor Robert M. Graham AO, FAA, MBBS (Hons), MD, FRACP, FACP, FAHA

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Professor Graham has been the Executive Director and a Board member since the Institute's inception in 1995 and is a member of its Executive Management, Appeals and Finance Committees.

He is the Des Renford Professor of Medicine, and Professor of Biotechnology and Biomolecular Science, University of NSW, and Professor (adjunct) of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio.

He is Fellow, Australian Academy of Science, and a member of the American Society of Clinical Investigation, the American Heart Association, and the National Heart Foundation of Australia (NSW Division).

Mrs. Ros Packer AO

— Mrs Packer has been a member of the Victor Chang Board since 1998. She is a member of the Board of Trustees of St. Vincent’s Clinic Foundation. She is also a member of the Board of Directors of the Sydney Festival, member of the Council of the National Gallery of Australia, and Patron of the ladies Committee, St. Vincent’s Private Hospital.

Mrs Packer retired from the Board at the end of 2009.

12. VCCRI ANNUAL REVIEW 2009

BSc, DPhil (Oxon)

— Professor Dawes joined the Victor Chang Board as an inaugural member in 1995. He is Scientia Professor of Genetics in the School of Biotechnology and Biomolecular Sciences. He is also Director of the Ramaciotti Centre for Gene Function analysis and an ARC Professorial Fellow as well as a university medallist and Rhodes Scholar.

Professor Dawes retired from the Board in 2009.

AM, BA (Hons)

AM, BComm (Hons)

Mr. Lowy was appointed Managing Director of Westfield Holdings in 1997 and currently serves as group Managing Director of the Westfield Group.

Professor Ian Dawes

Dr. Gary H. Weiss LLB (Hons), LLM

— Dr Weiss joined the Victor Chang Board in 2009. He is Chairman of Coats plc and an Executive Director of Guinness Peat Group plc, Ariadne Australia Limited, Tag Pacific Limited, the Westfield Group and Premier Investments Limited.

Sr. Anthea Groves

OAM, RSC, RN LHA Dip. of Nursing Administration

— Sr Anthea Groves has been a member of the Victor Chang Board since 2003 and is a member of the congregation of the Sisters of Charity and is Patient Liaison Officer at St. Vincent’s Hospital Sydney.

Sr. Anthea is a Director of the Sisters of Charity Foundation.

Mr. John McGuigan

Professor. Leslie D Field

—

—

Mr McGuigan joined the Victor Chang Board in 2004. He is a co-founder of Hunter Bay Partners, a private investment company with investments in the Energy and Food sectors. He has both an accounting and legal background, leading to senior positions at Price Waterhouse and then Baker & McKenzie.

Professor Field joined the Board in 2009. He was appointed to his current position as Deputy Vice-Chancellor (Research) at the University of NSW in 2005.

BSc, PhD

LLB

He has served on the boards of a number of public and private companies, and maintains an active involvement in charitable and civic organisations. In addition to serving as a Director of the VCCRI, he is Chairman of its Appeals Committee.

Mr. Angelos Frangopoulos BA(Comm), MAICD, JP

— Mr Frangopoulos joined the Victor Chang Board in 2009. He is the CEO of Australian News Channel Pty Ltd having joined the company in July 1996, 5 months after the channel’s inception.

Before joining Australian News Channel, he held positions at British Sky Broadcasting, the Nine Network and Prime Television Canberra.

His main areas of research are organometallic chemistry, catalysis and NMR spectroscopy. He is the author of more than 170 scientific papers and 4 text books. He was recipient of the Organic Chemistry Medical of the Royal Australian Chemical Institute in 1994 and was elected as a Fellow of the Australia Academy of Science in 1996.

Mr Frangopoulos is a council member of Charles Sturt University and sits on the board of the NSW Australia Day Council.

Mr. Chum Darvall BA, FFin, FAICD

— Mr Darvall joined the Victor Chang Board in 2008. He was appointed Chief Executive Officer of Deutsche Bank Australia and New Zealand in 2002. He joined the bank in 1994 as Director of Treasury, managing the money market, swaps and foreign exchange units and group funding. In early 1998, he became Head of Global Markets responsible for all financial market-related activities. Chum was also part of the management group responsible for the integration of the New Zealand operation of Bankers Trust with Deutsche Bank in 1999 Mr Darvall is a member for the Business Council of Australia and sits on a number of Boards.

Mr. David Craig

Mrs. Barbara Ell

—

Mrs Ell has been a Victor Chang Board member since 2001. Born in Auckland, New Zealand and educated at St. Mary’s College prior to her nursing training at Auckland Hospital, Barbara then continued her nursing career at Merriwa District Hospital. After marrying, Barbara moved to Sydney, where she raised her three children, Justine, Sara and Robert. In addition to serving on the VCCRI Appeals Committee, Barbara is widely recognised for her leadership in philanthropy and charity work.

—

BEC, FCA, CTFP

Mr Craig joined the Victor Chang Board in 2007. He commenced as Chief Financial Officer of the Commonwealth Bank in September 2006 and has over 30 years of experience in financial management, strategy, mergers and acquisitions.

Prior to joining the Bank, Mr Craig was Chief Financial Officer for Australand where he was responsible for leading the finance, treasury, IT and investor relations functions.

Mr. John Kean FCA, FAICD

— Mr Kean has been a member of the Victor Chang Board since 2003. He is Executive Chairman of Pinpoint Pty Limited. He was a founding Partner of WHK Greenwoods, Chartered Accountants.

He also acts as an Independent Business Advisor and holds Directorships in various businesses involved in marketing, finance, retail, primary production, technology and international trade. In addition to serving as a Director of the VCCRI, he chairs the Finance Committee and has been a member of the Appeals Committee since its inception.

Past Board Members —

– The Hon Neville Wran, AC, QC – Mr. Kerry James, AM – Mrs. Ann Chang – Dr. Tina Clifton – Mr. Paul Kelly – Mr. John Laws, CBE – Mr. Malcolm Irving, AM – Sr. Paulina Pilkington, AM, RSC – Mr. Cameron O’Reilly – The Late Sr. Claire Nolan, RSC – Ms. Anne Keating – Mr. Mark Johnson, AO – Mr. Sam Chisholm

VCCRI ANNUAL REVIEW 2009 13.

OUR COMMITTEES •••

Appeals Committee

Finance Committee

Scientific Advisory Board

The Appeals Committee consists of a group of volunteers and institute staff who are responsible for the Institute’s fundraising events to raise the vital funds needed by the Institute to conduct its groundbreaking research.

The Finance Committee is responsible for the oversight of finances for the Board of Directors.

The Committee oversees the audit of the VCCRI’s accounts, investment management, management remuneration, and also sets finance policy for management to follow.

The Scientific Advisory Board comprises of some of the world’s most eminent scientists who, every five years, evaluate the Institute’s faculty and research programs.

—

Members – Mrs. Ann Chang – Mrs. Barbara Matthews – Professor Robert M. Graham – Mr. John McGuigan – Mrs. Linda Duncombe – Mr. John Kean – Sr. Paulina Pilkington – Mr. Michael Renford – Mr. John Shim – Mrs. Antoinette Ogilvie – Mr. Russell Feilen – Ms. Bernie Connolly – Mr. Peter Homan – Ms. Jan Savage – Mrs. Stephanie Hughes – Mr. Rob Tunchon – Mr. Alan Crouch – Ms. Anne-Marie Allgrove – Mr. Robert Ryan – Mrs. Louise Di Francesco – Mr. Ross Kosarchsky – Mr. Das Menon – Mr. Kerry James

—

Members

Members – Professor Doug Hilton, Director Walter and Eliza Hall Institute, Australia, (Chairman)

– Mr. John Kean – Mr. David Craig – Mr. Chum Darvall – Professor Robert M. Graham – Ms. Jan Savage – Mrs. Carla Northam – Mr. Bhavin Raval – Ms. Beverley Hillsdon (retired at the end of 2009)

– Professor Witold Filipowicz, Professor of Biochemistry, Fredrich Miescher Institute for Biomedical Research (FMI), Switzerland

Mrs. Monica O’Loughlin was a member of the Finance Committee until her death in May, 2009.

– Emeritus Professor John Chalmers, Senior Director and Head, Professorial Unit, The George Institute for International Health and University of Sydney, Australia

Intellectual Property and Commercialisation Committee —

The Intellectual Property and Commercialisation Committee (IP&CC) is responsible for the oversight and management of the intellectual property and commercialisation activities of the Institute. The Committee meets formally twice a year, and on a “needs to” basis at other times.

Members – Professor Robert M. Graham – Ms. Mhairi Donohoe – Ms. Anne-Marie Allgrove – Dr. Trevor Davies – Professor Joan Dawes – Ms. Britt Granath – Dr. Melissa McBurnie – Mrs. Carla Northam

14. VCCRI ANNUAL REVIEW 2009

—

– Dr Lily Jan, Jack and DeLoris Lange, Professor of Physiology and Biophysics, University of California, USA

– Professor Janet Rossant, Chief of Research, The Hospital for Sick Children, Canada – Professor Stephen Vatner, Chairman, Department of Cell Biology and Molecular Medicine, New Jersey Medical School, USA

Our hardworking Committees are the Heart and Soul of the Victor Chang Research Institute.

VALE •••

Monica Frances O’Loughlin February 2, 1958 – May 5, 2009

John Patrick Joseph Baker

—

—

The Victor Chang Cardiac Research Institute (VCCRI) lost one of its most treasured employees on May 5, 2009. Our Finance Manager Mrs. Monica O’Loughlin, wife and mother of 5 died suddenly from a heart attack whilst visiting her mother in Taree.

When John Baker entered a room he certainly made his presence felt. If it wasn’t his colourful attire, matching shirts, socks and braces that got everyone’s attention, it was his grand entrance.

He had the knack of turning a stressful meeting into a fun event making everyone laugh with his witty comments and, at times, risqué jokes.

He was an integral part of the Victor Chang Ball committee and even at the tender age of 80 still did his bit to ensure the event was a great success.

Monica joined the VCCRI over eight years ago, initially on a part-time basis, but then soon became a full-time employee looking after the Institute’s finances which was a massive task especially during the construction period of our new building.

Coping with full-time work and the demands of a large family weren’t enough for Monica, in her spare time she managed to get a diploma in psychology and had started an honours degree at the time of her death.

Monica was always quick to volunteer to help at any fundraising events and embraced all the ‘special’ holidays with great enthusiasm.

Monica was much loved by the Institute and her death has had a great impact on us all.

Her family remain in our thoughts and prayers.

February 23, 1929 – August 15, 2009

The perfect guest, John was a gentleman through and through. He garnered friends from around the world and kept in touch with each and every one of them. He never forgot birthdays or special occasions and sent the most fitting cards. He sent postcards from wherever he was visiting. The only problem being his writing – it was appalling – he’d be home before you could decipher the few words he had written on the card!

John Patrick Joseph Baker died on August 15 at St. Vincent’s Hospital. We loved him and we miss him. But he has left us with a legacy of many happy memories.

VCCRI ANNUAL REVIEW 2009 15.

OUR INSTITUTE •••

With funds donated, St. Vincent’s Hospital established the Victor Chang Cardiac Research Institute, which was launched on February 14, 1994.

DEVELOPMENTAL BIOLOGY

07

MOLECULAR CARDIOLOGY AND BIOPHYSICS

06

MOLECULAR GENETICS STRUCTURAL AND COMPUTATIONAL BIOLOGY

05

ADMINISTRATION AND FINANCE

04

RECEPTION, STORES, LOADING DOCK AND CRYOGENICS

03

BIOCORE FACILITY AND AQUARIUM

01

A/Professor David Muller Lab Head

A/Professor Sally Dunwoodie Lab Head

A/Professor Jamie Vandenberg Lab Head

A/Professor Diane Fatkin Lab Head

Professor Boris Martinac Lab Head

Professor Terry Campbell Lab Head

Professor Robert M. Graham Division Head

MOLECULAR CARDIOLOGY AND BIOPHYSICS

Professor Peter Macdonald Lab Head

Professor Richard Harvey Division Head

Dr Catherine Suter Lab Head

A/Professor Thomas Preiss Acting Division Head

MOLECULAR GENETICS

Dr. Merridee Wouters Group Leader

Dr. Daniela Stock Acting Division Head

STRUCTURAL AND COMPUTATIONAL BIOLOGY

Professor Michael O’Rourke Lab Head

Professor Anne Keogh Lab Head

Professor Michael Feneley Division Head

CARDIAC PHYSIOLOGY AND TRANSPLANTATION

DEVELOPMENTAL BIOLOGY

17. VCCRI ANNUAL REVIEW 2009

•••

RESEARCH DIVISIONS

•••

DEVELOPMENTAL BIOLOGY 01 Harvey Lab Researchers 02 Researchers, Stanley Artap, Danielle De Jong and Helena Milonowska

01

Center for Cellular and Molecular Biology, Hyderabad, India.

J. Dhawan

(EMBL, Montorotondo, Italy; textbook co-editor and role of Igf1 in adult stem cells).

Nadia Rosenthal

(University of Hong Kong; role of collagen in Bmp signaling in heart development).

Kathy Cheah

(Medical University, Berlin, Germany; role of TBX20 mutations in CHD).

Maximilian Posch

(Pasteur Institute, Paris, France; heart development).

Margaret Buckingham

(Academic Medical Centre, Amsterdam; heart development).

Antoon Moorman

(University of Amsterdam, Netherlands; heart development).

Vincent Christoffels

(Royal College of Surgeons, Ireland; Neuregulin-1 knockout mice as a model of schizophrenia).

John Waddington

(Cardiovascular Research Institute, San Francisco, USA; heart development).

— Brian Black

Overseas Collaborations

19. VCCRI ANNUAL REVIEW 2009

The Harvey laboratory is focused on unravelling the molecular events that guide heart formation in the embryo, and how this information relates to congenital heart diseases in children.

In recent work, using the laboratory mouse as a model, we have shown how congenital malformation of the outflow tract of the type often seen in children, relate back to defects in the expansion of cardiomyocyte stem cells at the very earliest stages of heart formation. The laboratory has defined a “genetic module� that is absolutely critical for how these stem cells are regulated. The regulatory gene, Nkx2-5, is known to be required for heart formation and for proper differentiation of heart muscle cells.

In normal development, the Nkx2-5 gene along with other important heart regulatory genes, is activated by secreted factors that are called cardiac inducers. The laboratory discovered that one of the earliest functions of Nkx2-5 was to inhibit a cardiac inducer called Bmp2.

This is because Bmp2, in addition to inducing

The aims of the Developmental Biology Division are to understand how the vertebrate embryo grows and acquires form, pattern and function, to map the genetic and epigenetic pathways that guide these important processes, and to investigate how such processes are defective in congenital and adult-onset disease.

—

Deputy Director, Division Head

Professor Richard Harvey

02

A relatively new initiative in the laboratory is aimed at mapping the stem cells that exist in the adult heart and exploring how they might be used to regenerate the heart after injury such as heart attack. Again the laboratory is using the mouse as a model, since it allows us to bring very powerful genetic tools to the problem. The laboratory has defined a population of immature cells that have some of the cardinal properties of stem cells: they can expand, self-renew (propagate themselves serially without change) and form differentiated progeny for multiple cell lineages.

These cells are similar to others that exist in many organs, although cardiac stem cells have specific adaptations that suit their cardiac roles.

The laboratory is now working to see what these cells do in the normal and diseased heart, and in particular whether they can be stimulated to contribute more effectively to heart repair.

The Harvey laboratory is focused on unravelling the molecular events that guide heart formation in the embryo.

the formation of muscle progenitor cells, represses their expansion that is necessary to build up numbers for the growing heart. Nkx2-5 therefore plays a vital role: after the initial stages of induction have occurred, Bmp2 is repressed and cardiac stem cells are allowed to expand so that they can build the components of the heart including the right ventricle and outflow vessels.

When Nkx2-5 is mutated, as in some human families, Bmp2 remains high, cardiomyocyte stem cells do not expand, and not enough cardiomyoctyes are formed to build a normally structured organ. This regulatory module is called a negative feedback loop and the laboratory has been able to visualise how such a loop is critical in fine-tuning the growth of the heart at its earliest stages. This finding opens up many new avenues to finding additional genes that cause congenital malformations.

•••

Mouse embryos that lack the Cited2 gene develop severe and complex heart defects like those that develop in humans. A series of genetic experiments have lead to the discovery that the Cited2 gene is not required in the heart

Heart defects are the most common form of birth defects; they occur in about 1% of live births and are a major cause of stillbirths.

Heart formation can be affected during embryonic development if key genes expressed in the heart are mutated, if the embryonic vasculature is malformed, or if the placenta is not formed properly. The laboratory studies the Cited genes and the Notch signalling pathway as key players in heart, vascular and placenta development.

A/Professor Sally Dunwoodie’s laboratory aims to discover which genes and signalling pathways are relevant to mammalian embryonic development, and how they influence the formation and function of the heart.

—

Laboratory Head

A/Professor Sally Dunwoodie

DEVELOPMENTAL BIOLOGY

The laboratory has also discovered the genetic cause of a birth defect that affects the spine, called spondylocostal dysostosis (SCD).

Individuals with SCD have a truncated vertebral column, which causes complications with breathing and some heart difficulties. Mutations in four genes cause SCD, DLL3, MESP2, LFNG and HES7. These genes are components of the Notch signalling pathway, a pathway that is also key to development of the heart and vasculature.

for its formation but rather at much earlier stages of embryo formation in setting up the left-right body axis. Consequently Cited2 null embryos develop two right sides to the heart (right atrial isomerism) a heart defect also present in humans.

01

eart defects are the most H common form of birth defects; they occur in about 1% of live births.

21. VCCRI ANNUAL REVIEW 2009

04

02

03

01 Dunwoodie Lab Researchers 02 Researcher Helena Milonowska 03 Researcher Stanley Artap with the Confocal Microscope 04 Confocal Microscope

Case Western Reserve University, Cleveland, USA.

Yu Chung Yang

Royal Devon & Exeter Hospital, Exeter, UK.

Peter Turnpenny

Harvard Stem Cell Institute, Boston, USA.

Jeffrey Macklis

Karolinska Institute, Stockholm, Sweden.

Urban Lendahl

University of Phoenix, Arizona, USA.

Kenro Kusumi

Osaka University, Osaka, Japan.

Hiroshi Hamada

Institute for Molecular Biology, Hanover, Germany.

Achim Gossler

Vanderbilt University, Tennessee, USA.

Mark de Caestecker

Cardiff University, Wales.

Alan Clarke

Harvard Medical School, Boston, USA.

— Stephen Blacklow

Overseas Collaborations

•••

MOLECULAR CARDIOLOGY AND BIOPHYSICS 01

01 Graham Lab Researchers 02 A slice of heart tissue 03 Researcher Sara Holman at work

02

Cold Spring Harbor Laboratories, NY, USA.

Bruce Stillman

Zensun, Shanghai, China.

Mingdong Zhou/Xifu Liu

Yonsei University College of Medicine, Seoul, Korea.

Ki-Chul Hwang

UC San Diego, California, USA.

Robert Terkeltaub

UMDNJ-New Jersey Medical School, Newark, NJ, USA.

Stephen Vatner

University of Liverpool, UK.

Richard J Pease

Stanford University, California, USA.

M. Bishr Omary

Rochester University, NY, USA.

Gail V W Johnson

RIKEN, Saitama, Japan.

Shoichi Kojima

Children’s Hospital Oakland Research Institute, California, USA.

David Martin

Cardiology Dept. Emory University, Atlanta, USA.

Ahsan Husain

Dept of Celland Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, USA.

— Laszlo Lorand

Overseas Collaborations

23. VCCRI ANNUAL REVIEW 2009

Adrenergic receptors are proteins on the surface of cells and receive hormonal signals.

Upon activation of these receptors by hormones such as adrenaline, signals are generated within the cell, which can lead to events such as contraction of heart muscle cells. We have shown in animal models that by increasing the amount of a particular kinds of adrenergic receptor (α1a) on heart muscle cells leads to protection against heart failure after a heart attack (myocardial infact) or in the presence of high pressure. However, excessive amounts of the α1a -receptor can result in undesirable scar tissue formation within the heart.

In particular, the laboratory is interested in α1a -adrenergic receptors and a related novel G-protein, termed Gh (or tissue transglutaminase). Both may play an important role in the development of abnormal thickening of the heart muscle – a condition known as cardiac hypertrophy – and in the development of heart-rhythm disturbances (called arrhythmias).

Professor Graham’s laboratory is focused on understanding the structure and function of G-protein-coupled receptors. These receptors, already the targets of over 50% of all known drugs, are present on the surface of every major tissue and organ of the body, where they play an important role in regulating their function in response to a variety of different stresses.

—

Division Head

Professor Bob Graham

Finally, we are undertaking clinical and basic studies of stem cells to evaluate their potential in the treatment of cardiac disorders such as ischaemia and heart failure.

Another focus of the laboratory is to understand the causes of cardiac hypertrophy (abnormal thickening of heart muscle) – a major risk factor for premature death in our community.

The laboratory is interested in the signaling pathways and the role that growth factors may play in the disease.

Gh is found throughout the body and is a multifunctional protein with important biological effects in both heart health and disease.

The laboratory is evaluating the physiological role of Gh as well as the mechanisms by which the protein is activated and inactivated. We have demonstrated that Gh is involved in the cellular responses to stress hormones and would healing. In collaboration with Dr. Soichi Kojima in Japan and Dr. Mark Zern in the US we have shown that Gh plays an important role in the liver damage and liver cell death due to alcohol.

03

An exciting new initiative in our laboratory is the development of animal models to derive more biologically-relevant information about mutant protein function.

•••

Dilated cardiomyopathy is a myocardial disorder characterised by enlargement of the heart’s chambers and reduced contraction. In 50% cases, DCM is caused by conditions that impair the function or survival of heart cells, such as viral infection, coronary artery disease or damage from drugs or alcohol. In the remaining 50% cases, an identifiable cause is unable to be found and DCM is termed idiopathic. At least one in three patients with “idiopathic” DCM have a positive family history, suggesting that inherited gene changes may be involved. Studies in

Heart failure is a major cause of illness and death.

It is increasingly being recognised that inherited gene defects that affect the heart’s contraction and rhythm can predispose to the development of heart failure. What these genes are, and the ways in which changes in these genes alter heart function, are poorly understood. To better understand the role of gene defects in heart disease, the Fatkin laboratory team is studying families with dilated cardiomyopathy (DCM) and atrial fibrillation (AF), as well as using in vitro cell models and in vivo animal models to elucidate disease mechanisms.

—

Laboratory Head

A/Professor Diane Fatkin

01

MOLECULAR CARDIOLOGY AND BIOPHYSICS

Atrial fibrillation is characterised by disordered electrical activity in the atria and is the most common heart rhythm disorder and a major risk factor for stroke, as well as heart failure.

Like DCM, there are a number of cardiac and systemic disorders that can be associated with AF development. AF has traditionally been regarded as a non-genetic disorder but there is now increasing evidence that genetic factors may

This genotype information can be used to find asymptomatic family members who carry a mutant gene and who are at risk of developing DCM in the future. Early intervention in these individuals may enable DCM to be prevented.

To better understand how nuclear defects can cause cardiac contractile dysfunction, and to evaluate different forms of treatment, we have been studying a mouse model in which the LMNA gene has been knocked out. These mice develop DCM and are a valuable resource for studying the human disease. Nuclei from mice that lack normal lamin A/C have abnormal size and shape, as well as weakened connections with cytoskeletal proteins that may critically affect cardiomyocyte contraction. We have found that DCM is less likely to develop in young mice if they undergo periods of regular moderate exercise training or oral administration of β-blocker drugs. These results hold promise for new approaches to patient therapy and warrant further evaluation in clinical trials.

families have been instrumental in unravelling the molecular defects underpinning this condition.

Nearly 40 chromosomal loci and disease genes have now been associated with familial and sporadic forms of DCM. However, mutations in these genes account for a minority of cases and the genetic basis for DCM in most families is still unknown. Mutations in the LMNA gene, that encodes the nuclear lamina proteins, lamins A and C, are the most frequent cause of familial DCM identified to date. We have performed mutation screening of the LMNA gene in a large cohort of families with DCM and have found a number of novel mutations.

University of Oxford, Oxford, UK.

H. Watkins

Addenbrooke’s Hospital, Cambridge, England, UK.

C. Shanahan

Harvard Medical School, Boston, USA.

J&C Seidman

Emory University School of Medicine, Atlanta, Georgia, USA.

M. Hedge

University of Geneva, Switzerland.

G. Gabbiani

Burnham Institute for Medical Research, La Jolla, California, USA.

— R. Bodmer

Overseas Collaborations

Since ion channels have a critical role in regulating the heart’s electrical activity, we have performed mutation screening of ion channel genes in our cohort of families with AF. A number of mutations have been found and have been shown to alter electrical properties in cell models. An exciting new initiative in our laboratory is the development of animal models to derive more biologically-relevant information about mutant protein function and we are exploring the use of genetically-engineered zebrafish for this purpose. Zebrafish hearts are transparent in embryonic life and cardiac function can be directly observed. We hope to develop techniques to study cardiac structure and function in adult zebrafish, which should greatly facilitate our ability to find out more about the causes of AF. Ultimately, we hope our studies will lead to new ways of diagnosing and treating patients with DCM and cardiac arrhythmias.

have an important role. To find out more about what these genetic factors are, we are studying families and twins with AF.

25. VCCRI ANNUAL REVIEW 2009

02

03

01 02 03 04

Fatkin Lab Researchers Researcher Stephanie Hackworthy Vandenberg Lab Researchers Martinac Lab Researchers

The research highlight of the last year was the elucidation of the molecular basis of how drugs bind to different configurations of the hERG potassium channel. This work has significant implications for understanding why many drugs in common clinical practice can have the unwanted side-effect of increasing the risk of arrhythmias. Following on from this work we are developing assays to improve the detection of this potentially lethal side-effect early in the drug development process.

4. Genotype-phenotype relationships in Familial Atrial Fibrillation

3. Structure-function studies of HERG K+ channels

2. Genotype-phenotype relationships in the congenital Long QT syndrome

1. Molecular basis of drug binding to hERG K+ channels

Electrical impulses in the heart are controlled by ion-channels, molecular structures that facilitate the passage of ions into and out of cells.

We have four major projects looking at different aspects of how ion channels work and how disturbances in ion channel function affects the heart:

The coordinated spread of electrical impulses down the heart is required for it to pump blood efficiently. If this process becomes disordered the heart pumps inefficiently or may even stop, resulting in sudden death. The aim of the work in the Mark Cowley Lidwill Research Program in Cardiac Electrophysiology is to investigate situations where these electrical impulses become disordered and to understand the causes of such conditions.

Mark Cowley Lidwill Research Program in Cardiac Electrophysiology

—

Laboratory Heads

A/Professor Jamie Vandenberg and Professor Terry Campbell

Mayo Clinic, Rochester MN.

M. Ackerman

Starship Hospital, Auckland, NZ.

J. Skinner

Auckland Bioengineering Institute, University of Auckland, NZ.

B. Smaill

Auckland Bioengineering Institute, University of Auckland, NZ.

— P.J. Hunter

Overseas Collaborations

The Mark Cowley Lidwill Research Program in Cardiac Electrophysiology has seen a significant expansion in the last 12 months with four new post-doctoral scientists starting in the laboratory. This has enabled us to expand our work in the areas of structural biology of ion channels, computer modeling of how ion channels work. We have also established a combined electrophysiology and fluorescence spectroscopy work station which will enable us to simultaneously monitor the flow of electrical current and how the different parts of the channel are moving as it opens and shuts during a cardiac action potential.

In the last year we have also made significant progress in understanding why different mutations in the hERG potassium channel gene carry a different level of risk of sudden death.

This may lead to the development of better risk stratification strategies for patients with inherited long QT syndromes. We have also solved the structure of a cytoplasmic domain of the hERG potassium channel, using NMR spectroscopy. This work will have important implications for understanding how the channel is regulated during health as well as in disease.

•••

The molecular basis of sensing odorants, hormones and neurotransmitters is well understood. In comparison, little is known about how living cells detect mechanical forces acting upon them. What is known however is that at the basis of sensory inputs in all living organisms, including mechanosensory transduction, are integral membrane proteins such as ion channels that involved in a large variety of physiological functions and currently constitute about 60% of pharmaceutical drug targets. Structural studies of these proteins using traditional methods such as X-ray crystallography or NMR is quite challenging, and even when successful, provides only a snap-shot view of the proteins. Moreover, in many of these methods, the proteins have to be removed from their natural lipid environment and it can be difficult to trap the protein in specific functional states. Therefore, spectroscopic methods such as site-directed spin labelling electron paramagnetic resonance (SDSL EPR) and site-directed fluorophore labelling Förster resonance energy transfer (SDFL FRET) spectroscopy are important for revealing conformational dynamics and structural mechanisms of protein function as they function in natural lipid environments.

—

Laboratory Head

Professor Boris Martinac

MOLECULAR CARDIOLOGY AND BIOPHYSICS

Since joining VCCRI in January 2009 the laboratory has become functional during the first half of the year. Basic molecular biological and protein biochemistry techniques required for the projects in the laboratory have been quickly established. Two patch-clamp setups are currently available for standard single channel recordings from MS channels. The third setup is being built within the Confocal Microscopy Facility for “Patch Fluorimetry”,

As the primary molecular transducers of mechanical force in living cells mechanosensitive (MS) ion channels have been implicated in various mechanosensory physiological processes. Testing the key hypothesis that mechanical force is delivered through the lipid bilayer to MS ion channels in membranes of prokaryotic and eukaryotic cells is central to the research in Mehanosensory Biophysics Laboratory. By studying structure and function of mechanosensitive channels of bacteria and eukaryotic cells the research in the laboratory is aiming to elucidate the general physical principles underlying the biophysics and physiology of mechanosensory transduction using a multidisciplinary approach including molecular biology, protein biochemistry, patch clamp recording and spectroscopic techniques.

Professor Martinac’s group currently includes Paul Rohde, BSc MMedSc (Laboratory Manager), Evgeny Petrov, PhD (Postdoctoral Fellow) and Andrew Battle, PhD (Postdoctoral Fellow). At present, the laboratory is hiring a Research Assistant to aid in the growing demands for preparations of purified MS channel proteins for electrophysiological and structural studies. It is also expected that two new postdoctoral research fellows will join the laboratory early in 2010.

which should enable recording activities from single MS channels simultaneously with SDFL FRET spectroscopy of the labelled channels.

This setup is built together with colleagues from the research group of A/Professor Jamie Vandenberg and will be used by both groups.

Since joining VCCRI the research program in the Mechanosensory Biophysics Laboratory has also expanded into studies of eukaryotic MS channels suspected to play a role in heart arrhythmias.

04

27. VCCRI ANNUAL REVIEW 2009

Basic molecular biological and protein biochemistry techniques required for the projects in the laboratory have been quickly established.

University of San Francisco, San Francisco, CA, USA.

D. Minor

University of Heidelberg, Heidelberg, Germany.

O. Friedrich

University of Cologne, Koeln, Germany.

R. Krämer

Karlsruhe Institute of Technology, Karlsruhe, Germany.

S. Grage

University of Nice, Sophia-Antipolis, France.

E. Honoré

University of Wisconsin, Madison, WI, USA.

C. Kung

Stanford University, Stanford, CA, USA.

K.C. Huang

UTMB, Galveston, TX, USA.

O.P. Hamill

University of Illinois Urbana-Champaign, IL, USA.

K. Schulten

University of Chicago, Chicago, IL, USA.

— E. Perozo

Overseas Collaborations

•••

MOLECULAR GENETICS

Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 153, Heidelberg, Germany.

Martina U. Muckenthaler

Children’s Hospital Oakland Research Institute, Oakland, California, United States of America.

David I. K. Martin

Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow St, Dundee, United Kingdom.

Mark Larance

European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, Germany.

Matthias W. Hentze

Department of Medicine, University of California, San Francisco, California, USA.

Andrei Goga

Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93, Warsaw, Poland.

— Edward Darzynkiewicz

Overseas Collaborations

Genes do not only encode proteins but also a multitude of regulatory RNA.

29. VCCRI ANNUAL REVIEW 2009

A/Professor Preiss and his laboratory study translation and how it is controlled to contribute knowledge that will underpin the development of new disease treatments. Diseases with a recognised involvement of de-regulated protein production include major killers such as heart muscle disease, various forms of cancer, and several heritable diseases. The laboratory works on several related themes.

To ‘express’ the information contained in genes they are first copied from DNA into messenger RNA (mRNA). During translation cellular machines called ribosomes use the mRNA as their template to make the proteins.

To attract the ribosome to them, mRNAs are decorated with a Cap on one end and a string of adenines, termed Poly-A tail, on the other.

Many accessory factors bind to the cap and tail to help with ribosome recruitment.

Humans have roughly 30 thousand genes in each of their trillion cells. The genes are a blue-print of how we are built, and their complex workings are controlled and regulated to allow for proper body development and maintenance, as well as to prevent or fight disease. Genes reside in DNA and carry the code to make proteins. These proteins, in turn, are the workers in our cells and they are made in a process called translation.

—

Acting Division Head

A/Professor Thomas Preiss

The Poly-A tail attracts ribosomes and translation factors to the mRNA and has a big impact on how much protein is made from them. Regulating its length is known to be involved in embryonic development and during learning and memory in the brain, for instance.

The laboratory is studying the commonalities and differences between mRNA tail lengths in cells from sources as diverse as yeast

Genes do not only encode proteins but also a multitude of regulatory RNA. Another focus of the laboratory is the class of regulators called microRNAs. Cells use these ‘tiny brakes’ to slow gene expression. microRNAs are essential for stem cell differentiation and heart development, and are major players in cancer. The laboratory investigates how microRNAs control translation and they have discovered that microRNAs block the function of the mRNA Cap and cause a severe shortening of Poly-A tail. This work explains how a major class of gene regulators functions.

Members of the eIF4G protein family are akin to adaptors that world travellers use to connect to local power sources. Ribosomes use eIF4G to ‘plug’ into the various components needed for translation. The laboratory investigates how eIF4G and related proteins carry out their ‘translational adapter’ function. This work has led them to the study of previously undiscovered chemical marks on RNA.

Finally, together with colleague Dr Cath Suter in the Molecular Genetics Division Preiss has established a new technology at the institute that allows us to look at genes and their function in a level of detail that would have been unimaginable just a few years ago.

The technology is called ‘Next Generation Sequencing’ and is opening up new avenues of research for several laboratories at the institute.

cultures or the mammalian heart. Their data provide a fascinating insight into the substantial coordination between different layers of gene control that exists in cells to ensure coherent protein production. Given that Poly-A tails play a major role in how microRNAs function, this work also holds promise in deciphering how gene expression goes awry in cancers, Alzheimer’s disease, as well as heart development and disease.

01

02

Dr Suter and her co-workers are dedicated to understanding the contribution of epigenetic gene regulation to non-genetic variation and disease.

•••

MOLECULAR GENETICS

04

01 Preiss Lab Researchers 02 Paul Young with a SOLiD Sequencer 03 Paul Young with the computer that runs the SOLiD Sequencer 04 Suter Lab Researchers

03

31. VCCRI ANNUAL REVIEW 2009

By studying genetically identical mice the laboratory has demonstrated that alteration of a mother’s diet can affect the epigenetic state of hundreds genes in her offspring – some of these changes impact on the health of the mice. One important question that arises is whether such environmentally-induced epigenetic changes can be passed from one generation to the next.

Epigenetic changes that occur to the DNA determine which of our genes are “switched on” and which are “switched off”, and all this happens without any change to the DNA code itself. This process is vital for the life of all multicellular organisms but despite the importance of epigenetic gene regulation it remains a system that is poorly understood.

Dr Suter and her co-workers are dedicated to understanding the contribution of epigenetic gene regulation to non-genetic variation and disease.

—

Laboratory Head

Dr Catherine Suter

It is well known that a suboptimal nutrition during pregnancy can have long lasting consequences for the health of the offspring: for example, very low birth weight babies have a higher risk of cardiovascular disease as adults. The group continues to concentrate on dissecting the relationships between maternal nutrition, adult health, and epigenetics, and have also begun to examine how the epigenetic “memory” of environmental exposure can be passed on to offspring.

This year the lab found that an epigenetic change induced by a changed diet can be passed on through many generations, and even be maintained for several generations once the diet has returned to normal. These experiments have important ramifications given the changes we have seen in human diets over the last few generations.

Cold Springs Harbour Laboratory, USA.

Rob Martienssen

Max Planck Institute, Munich, Germany.

Gunter Meister

Children’s Hospital Oakland Research Institute, Oakland, California, USA.

— David I K Martin

Overseas Collaborations

The Stock laboratory is particularly interested in the structure and function of membrane proteins, which constitute about 30% of all proteins in a genome.

•••

STRUCTURAL AND COMPUTATIONAL BIOLOGY

01

01 02 03 04

02

X-ray Crystallography Machine Alistair Stewart Stock Lab Researchers Wouters Lab Researchers

33. VCCRI ANNUAL REVIEW 2009

More than 50% of all drugs on the market interact with membrane proteins and further development of drugs requires structure determination of these proteins at high resolution. Despite considerable efforts, only 1.5% of all protein structures determined to date are membrane proteins. The reason is that they are exceedingly difficult to express, purify and crystallise due to their hydrophobic nature that allows them to penetrate membranes.

Membrane proteins, such as receptors, ion channels and transporters are located in the oily environments of the cell wall and allow cells to communicate with the outside world.

Another major group of membrane proteins are responsible for biological energy conversion such as respiration and photosynthesis.

Dr Stock’s laboratory uses X-ray crystallography to determine the structure of proteins and protein complexes at high resolution. The visualisation of the structure of any protein is essential to understand the protein’s function in health and disease, for diagnosis of disease and for development of treatments using rational drug design.

—

Acting Division Head

Dr Daniela Stock

In addition, the laboratory collaborates with other groups within the Victor Chang Cardiac Research Institute to determine structures of cardiologically important membrane proteins, such as ion channels (Vandenberg laboratory) and G protein coupled receptors (Graham laboratory).

The Stock laboratory aims to improve current technologies for membrane protein structure determination by simplifying and automating the cloning and expression procedure and by using synthetic antibody technology to facilitate crystallisation. With the move to the new building the laboratory has a state of the art X-ray facility, including crystallisation robot, X-ray generator and computer graphics.

The current focus of the laboratory is on the structure determination of protein complexes that contain molecular rotary motors such as vacuolar ATPases and the flagellar motor. Both complexes are involved in proton translocation through membranes and the laboratory is investigating the overall architecture of the proton paths, the molecular mechanisms of proton translocation and the generation of rotation. By comparing two very different systems some of the general principles of biological rotary motors may be discovered.

Osaka University, Japan.

Keiichi Namba

Nanyang University, Singapore.

Gerhard Grueber

University of Texas at El Paso, USA.

Ricardo Bernal

Imperial College London, UK.

So Iwata

University of Cambridge, UK.

— Carol Robinson

Overseas Collaborations

03

•••

University of Newcastle-Upon-Tyne Disulfides.

Professor Elizabeth Veal

VIB Netherlands Disulfides.

— Dr Joris Messens

Overseas Collaborations

04

STRUCTURAL AND COMPUTATIONAL BIOLOGY

In collaboration with A/Professor Diane Fatkin, the group is developing computer programs that will predict genes that could cause inherited diseases. This project combines genetic information collected from families of people who suffer from inherited diseases with vast amounts of data on the function of all human genes and known relationships to disease.

This data is collected from clinical and scientific studies performed throughout the world that is stored in large databases. Predicted disease genes are then loaded back onto our own webserver so they can be accessed by other researchers around the world.

The structural bioinformatics group use and develop computer programs that source and collate vast amounts of information on proteins in an attempt to understand their function. The group seeks to understand the function of proteins that may be involved in heart muscle disease as well as related questions and problems.

Proteins are the building blocks of the body.

Many are essentially small machines that do all the work in the body including building tissues and organs and passing messages between cells. Others form the architecture of cells.

These include low-complexity proteins that form rope-like structures such as collagen.

Understanding how proteins perform their function is a challenge for structural biologists and using computers to help interpret large amounts of complex biological and medical information is a valuable tool in this quest.

—

Group Leader

Dr Merridee Wouters The group is also examining the role of disulfide cross-links in proteins. Proteins are initially manufactured in the body as linear structures but collapse into globular structures, like balls of wool, in the final stages of production. Disulfide cross-links are a particular type of chemical cross-link that weld the globular structure together and prevent it from unravelling.

Until recently, all disulfides were thought to be fixed structural welds. Scientists working in plants were the first to discover that some of these joins can in fact be broken and reformed in structures in response to changes in environmental conditions, such as oxidative stress. The Structural Bioinformatics group at the VCCRI is at the forefront of efforts to devise computational methods to predict these “switchable” disulfides in proteins.

This work is likely to be important for diseases involving oxidative stress including heart disease, diabetes, neurodegenerative disease and ageing.

35. VCCRI ANNUAL REVIEW 2009

Proteins are the building blocks of the body. Many are essentially small machines that do all the work in the body including building tissues and organs and passing messages between cells.

•••

01

CARDIAC PHYSIOLOGY AND TRANSPLANTATION

Of particular interest to the division are genetically-engineered animal models of human heart diseases. By isolating heart cells from these models and then investigating their contractile function, a detailed understanding can be obtained into the mechanisms whereby specific genes and the proteins they encode can alter heart contractile function. These approaches should provide new insight into the initial changes in heart muscle function that ultimately lead to heart disease and failure.

The research division, headed by Professor Feneley, has developed sophisticated approaches to directly measure heart muscle contractility. Moreover, this laboratory is broadbased, performing studies extending from the isolated heart muscle cell (or cardiac myocyte) to integrated physiological experiments in mice and rats, to cardiac transplantation any myocardial preservation in pigs, under the direction of Professor Peter Macdonald, to clinical research in patients with dilated cardiomyopathies and other causes of heart failure.

The Cardiac Physiology Division investigates the contractile properties of the heart and how these properties can change under the different conditions. Contractility of the heart is a major determinant of its ability to pump blood around the body. Because the heart is a muscle, it can adapt to different conditions that directly affects its contractility and efficiency.

However, evaluating heart contractility is difficult because changes in blood pressure and flow due to alterations in blood vessels can markedly alter the pumping efficiency of the heart, in a manner that is independent of its intrinsic ability co contract.

—

Division Head

Professor Michael Feneley

Laboratory Head

Center for Heart Failure Research, University of Birmingham, Alabama, USA

— Ahsan Husain

Overseas Collaborations

A/Professor David Muller is investigating new treatments to prevent, treat and reverse coronary artery disease, the main cause of heart attacks, particularly in patients who have received a heart transplant.

—

A/Professor David Muller

02

37. VCCRI ANNUAL REVIEW 2009

Royal Brompton Hospital, London UK Pulmonary hypertension in diffuse lung disease.

Professor Athol Wells & Dr Stephen Wort

Zensun Sci & Tech Co. Ltd, Shanghai, China Experimental and clinical studies with rhNRG-1.

— Dr Mingdong Zhou & Dr Xifu Liu

Overseas Collaborations

The biological processes that occur in heart transplantation exposes the donor heart to a number of insults that leads to reduced quality and function of the donor organ, and also increases the risk of organ rejection after transplantation. The laboratory has been focusing on treatment to reverse and in many cases, prevent these injuries from occurring in order to improve quality of donor hearts.

At present, heart transplantation is the only potentially definitive treatment for people with end-stage heart muscle disease and failure. The major focus of Professor Macdonald’s laboratory is to develop new methods for managing organ donors and preserving donor hearts in order to improve short-term and long-term outcomes of heart recipients. These treatments will potentially lead to more heart transplants being performed utilising the currently available donors – a significant problem in human transplantation, where the need for heart transplantation greatly exceeds the number of donor hearts available.

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Laboratory Head

Professor Peter Macdonald

In the past two years, they have shown that hormonal treatments in organ donors prior to transplantation can improve the quality of the heart, leading to better functioning hearts in the recipient and also enabling the use of donor hearts that were previously unsuitable for transplantation. In addition, the laboratory has devised and successfully tested an organ preservation regime in the porcine model that further improves the functioning of the transplanted donor heart.

New treatments are initially investigated using an isolated working rat heart model, which enables rapid and inexpensive evaluation of these treatments. Any promising treatments identified are then tested on a porcine orthotopic heart transplantation model. This model is critically important as results obtained are directly applicable to human clinical practice and provides clinically relevant evidence to initiate human clinical trials.

03

01 Feneley Lab Researchers 02 David Muller 03 Pipettes 04 Macdonald Lab Researchers

04

As we age, our heart has to work harder to pump blood intermittently into stiffened arteries, creating greater pulsations and placing much more strain on the arterial vessels throughout the body. These pulsations cause damage to the arteries, especially the tiny arterial vessels of the brain and kidneys. Over time, small arterial damage causes tiny strokes, resulting in dementia and kidney failure. By reducing pulsatile pressure, especially through reducing wave reflection, damage to the small blood vessels can be decreased or delayed. This is accomplished through regular exercise, diet and modern blood pressure lowering medicines.

The laboratory is interested in large blood vessel stiffening, which is an inevitable consequence of the aging process, and caused by the breakdown of elastic fibres in blood vessels that result from their repetitive pulsations. Healthy young blood vessels are flexible; but by the age of thirty they are already showing signs of fatigue and fracture or “wear and tear”, which causes them to dilate and stiffen.

The Vascular-Ventricular Interactions Program is focused on understanding how the physical structure of blood vessels and the dynamics of pulsatile blood flow are altered during human aging and with heart disease.

—

Laboratory Head

Professor Michael O’Rourke

•••

CARDIAC PHYSIOLOGY AND TRANSPLANTATION

New approaches have also been developed to analyse Doppler flow waveforms as well as pressure waveforms, and to use all for estimation of cardiovascular risk. To date we have shown that it is possible to predict risk, and gauge response to treatment more precisely from the pulse waveform than from conventional brachial cuff sphygmomanometry.

Another area of interest for the group has been the effect of arterial stiffening on pulse wave transmission and reflection, and on how such disturbances adversely affect both left ventricular load and function. Our group has shown that ill effects are far greater than estimated in the past from conventional recordings of arterial pressure with the brachial cuff sphygmomanometer (the method used by doctors to test blood pressure for over a century). To this end, a major achievement has been the development of a new method to measure more accurately the effects of arterial damage from the peripheral pulse.

This technology has now been commercialised and is being applied to ongoing research in more than 2000 sites around the world.

01 O’Rourke Lab Researchers 02 Professor O’Rourke and patient 03 Professor Anne Keogh

01

02

In place now is a comprehensive management system for treating pulmonary hypertension from any cause.

39. VCCRI ANNUAL REVIEW 2009

Professor Keogh’s research focuses on pulmonary arterial hypertension, heart transplantation, immunosuppression and heart failure.

03

Pulmonary arterial hypertension is a relatively rare but serious disease of the cardiovascular system in which the blood pressure in the lungs is highly elevated leading to breathlessness, dizziness and chest pain.

The right ventricle becomes unable to pump against this pressure and fails, leading to low cardiac output, liver congestion, fluid retention and shortness of breath.

Professor Keogh’s research focuses on pulmonary arterial hypertension, heart transplantation, immunosuppression and heart failure. The program aims to determine the best tailored therapy for individual patients with Class I-IV heart failure, including drug therapy, synchronised pacing and ventricular assist devices.

—

Laboratory Head

Professor Anne Keogh

The group is also working on post transplant immunosuppressive trials. These include sirolimus drug trials for cyclosporine toxicity of the kidneys and disease of the blood vessels due to transplant surgery, and everolimus drug trials post heart transplant.

In place now is a comprehensive management system for treating pulmonary hypertension from any cause, ranging from drug therapy to surgery, with virtual “cure” possible in many cases.

The group is working with a broad range of drugs for pulmonary hypertension in clinical trials. Available agents include drugs for patients who fail to respond to Bosentan or who are not eligible. These include sitaxsentan, ambrisentan, sildenafil, and inhaled iloprost and treprostinil with very exciting new drugs coming in 2010, cicletanine, riociguat and a new Pg12 agonist.

40. VCCRI ANNUAL REVIEW 2009

Professor Robert M. Graham Executive Director, VCCRI

“If we can successfully preserve the donor heart for a longer period, we will reduce deterioration and therefore allow the heart to function more quickly and effectively after surgery. This is a major issue given the vast size of countries such asv Australia and the time it can take to transport a heart from a donor to a recipient.”

“The longer a donor heart lives outside the recipient, the more it will deteriorate, increasing the risk of injury or even death during transplantation, due to restricted blood flow.”

A world-first technique has been developed by Australian scientists at the Victor Chang Cardiac Research Institute (VCCRI) and St. Vincent’s Hospital (SVH) that will extend the life of donor hearts being transported for transplant surgery.

•••

CARDIAC PHYSIOLOGY AND TRANSPLANTATION

BEFORE

4HRS

14HRS NOW

Medical scientists have successfully trialled a new combination of drugs extending the time a donor heart can spend in transit, from the current 4 to 5 hour limit, up to 14 hours.

VCCRI AWARDEES •••

03

The Heart and Soul of the VCCRI —

Our voluntary Committee Members, Patrons, Life Governors, Ambassadors, Life Members, Donors and Supporters are the heart and soul of the VCCRI. Their dedication, commitment and encouragement of our research is unconditional. We thank them for their generosity, enormous time and the expertise they provide so willingly and freely.

04

Patrons

Life Governors

Ambassadors

– Mrs. Ann Chang – The Hon Neville Wran, AC, QC

– Abigroup – ANZ Bank – Mr. Sam Chisholm – Citigroup – Mr. John David – Mrs. Barbara Ell – Lady Mary Fairfax, AC,OBE – The late Lady Finley – The Freedman Foundation – The Freshest Group – Mr. Frank Lowy, AC – Mr. Steven Lowy, AM – Mr. James Packer – National Australia Bank – Mr. Robert Oatley – Strathfield Group Limited – Mr. Ziggy Switkowski – Telstra Corporation – Mrs. Jennie Thomas, AM – Mr. Lance Rosenberg – Mr. Mark Johnson, AO – The late Mr. Ken Lee – Mr. & Mrs. David & Diana Ritchie – The Atlantic Philanthropies – Ingham Enterprises – Mrs. Roslyn Packer, AO

– Baker & McKenzie – The Crane Group – Crestbrook Mountain Springs – The late Mr. Alan David – The late Amana Finley – Mr. John Laws, CBE – Mr. Ken Laing, AM – Schute Bell Badgery Lumby – Steve Costi Seafoods – Mr. & Mrs. Scott & Rhonda Gibbons – Mr. & Mrs. Russell & Julieanne Cooper – Mr. & Mrs. John & Margaret Ingram – Mr. & Mrs. Ralph & Lorraine Keyes – Guinness Peat Group – Club Marconi – LK Jewellery – Mr. Cameron Irving – Deutsche Bank

—

Past Patron —

– The Late Mr. Kerry Packer, AC

Honorary Life Governor —

– Her Royal Highness Crown Princess Mary of Denmark

01

—

—

Honorary Life Members —

– Ms. Fiona Coote, AM – Mr. Kerry James, AM

Young Ambassador Award —

– Mr. Mark Vincent 02

01 02 03 04

Ralph & Lorraine Keyes with Bob Graham and Steven Lowy Ingham Enterprises, John Ingham with Bob Graham & Steven Lowy LK Jewellery's Martha Kennedy with Bob Graham & Steven Lowy Mark Vincent receiving his Young Ambassador Award

VCCRI ANNUAL REVIEW 2009 41.

AWARDS AND ACHIEVEMENTS 2008 •••

Achievements

Degrees Awarded

—

—

Dr Catherine Suter

Jacque-Lynne Johnson

Marco Nousch

Received funding from the Cure Cancer Australia Foundation as well as being awarded the 2008 Macquarie Group Foundation Fellowship.

Received an NGED conference participation award to attend the 2008 Santa Cruz Developmental Biology Meeting June 26-29 at UC Santa Cruz.

Awarded his PhD at the University of New South Wales, School of Biotechnology and Biomolecular Sciences.

Dr Merridee Wouters

Monique Ohanian

Milena Furtado

Awarded International Travel Grant at the Joint 52nd Annual Meeting of Biophysical Society and 16th IUPAB International Biophysics Congress at Long Beach California, February 2-6 2008.

Received the Lorna Byrne Public Speaking Trophy for Best Honours thesis presentation, School of Natural Sciences, University of Western Sydney.

Awarded PhD, University of New South Wales (Faculty of Medicine).

Leah Cannon

Awarded PhD, University of New South Wales (School of Women’s and Children’s Health, Faculty of Medicine).

Professor R M Graham Commenced a 2-year term as President, Australian Association of Medical Research Institutes in November 2008.

A/Professor Sally Dunwoodie Won the inaugural Australian & New Zealand Society for Cell & Developmental Biology (ANZSCDB) Young Investigator Award.

Laura Ng Received the D.I. McCloskey Prize for Physiology/Pharmacology Honours.

Dr Arie Jacoby Received a Network in Genes and Environment in Development (NGED) Conference Participation Award to attend the 8th International Meeting on Zebrafish Development and Genetics in the USA in June 2008 and was selected to speak in a “plenary session”.

Wendy Saad Awarded the John Yu Scholarship by the Royal Alexandria Hospital (Children’s Hospital at Westmead) to complete her Honours degree in B.Medical Science through Sydney University.

42. VCCRI ANNUAL REVIEW 2009

Awarded the Cardiac Society Australia & New Zealand (CSANZ) Travelling Fellowship to attend the American Heart Association Scientific Sessions in New Orleans in November 2008.

Professor Richard Harvey Elected as an Associate Member of the European Molecular Biology Organisation (EMBO) and in 2008 was awarded an Australian Fellowship, National Health and Medical Research Council.

Dr Rob Bryson-Richardson Received a travel award from the NGED, which allowed him to be an invited instructor at the European Molecular Biology Organisation (EMBO) practical course on 3D Developmental Imaging in Lisbon, Portugal.

Paul Korner Seminar Series 2008 Adam Hill was the winner of the 2008 Paul Korner Seminar Series with Traude Beilharz runner up and the Staff Choice Award being presented to both Leah Cannon and Lawrence Lee.

Edwin Kirk

Ishtiaq Ahmed Awarded his PhD at the University of Durham (Faculty of Biological and Biomedical Sciences).

AWARDS AND ACHIEVEMENTS 2009 •••

Achievements

Degrees Awarded

—

—

Professor Robert Graham

Adam Hill

Alfred Hing

Awarded an AO in the Queen’s Birthday Honours for service to medicine, particularly through stewardship of the Victor Chang Cardiac Research Institute and research in the field of molecular cardiology.

Elected NSW State Representative for the Australian Society for Biophysics.

Won the inaugural NSW Fulbright Australia-America Commission Fellowship for 2010.

Awarded his PhD at the University of New South Wales (Faculty of Medicine, St. Vincent’s Clinical School). Alfred’s project “Optimising the quality of donor organs for transplantation: Studies of hormone resuscitation of the brain-dead multi-organ donor and the development of a long-term preservation strategy to optimise function of the transplanted heart in a porcine model” demonstrated that the use of hormone resuscitation of the organ donor improved the quality and function of the donor heart.

Paul Korner Seminar Series 2009

Jacque-Lynne Johnson

Awarded the “Best PhD Student Talk” for his presentation “Molecular Architecture of the T.thermophilus A-ATPase Stator Complex”.

Lawrence Lee was the winner of the 2009 Paul Korner Seminar Series with Sharon Chih and James Chong the runners up. The Staff Choice Awards were presented to both Chris Blair and Liz Yeo.

Christiana Leimena

Cheryl Li

Received The Miltenyi Biotech Student Poster Prize at the 19th St. Vincent’s & Mater Health Sydney Research Symposium.

Awarded best oral presentation from a student at the Annual Epigenetics Conference in Melbourne.

Awarded her PhD at the University of NSW (Faculty of Medicine).

Jacque-Lynne’s project: “The role of the zebrafish scube gene family in Hedgehog signaling and slow muscle development” investigated how this family of three genes interacted with the Hedgehog pathway to specify slow muscle cell fate in the developing zebrafish embryo. Jacque-Lynne showed that all three scube genes were required for slow muscle development and functioned redundantly in slow muscle specification acting upstream of the obligate receptor patched. JacqueLynne was awarded an International Postgraduate Award from the University of New South Wales to undertake her PhD at the Victor Chang Cardiac Research Institute.

Lawrence Lee Awarded the “Best Postdoc Talk” for his presentation “The structure of the torque-generating ring of the bacterial flagellar motor and the molecular basis for the rotational switching at the 2009 East Coast Protein Meeting”.

Alastair Stewart

Cheryl Li Received the Genesearch Award for Excellence in Oral Presentation at the 19th St. Vincent’s & Mater Health Sydney Research Symposium.

Professor Richard Harvey Won the Australian and New Zealand Society of Cell and Developmental Biology President’s Medal and Oration (presented at Combio 2009).

James Chong

Carol Mak BE Bioinformatics Honours Class.

VCCRI ANNUAL REVIEW 2009 43.

PAUL KORNER SEMINAR SERIES 2008 ••• The Paul Korner Seminar Series are presented weekly, giving the young scientists within the Institute the opportunity to present some of the groundbreaking work they are carrying out within the individual research programs.

This Seminar Series was established in 1998 to recognise the outstanding contributions of Professor Paul Korner to cardiovascular research.

Stefan Mann

David Humphreys

“ Electrical transgenesis: a dynamic approach”

“ Contribution of poly(A) tail deadenylation in miRNA mediated repression”.

Liz Yeo “ Evaluation of mechanisms of contractile dysfunction and hypertrophy development in Lamin A/C-deficient mice”

Leah Cannon Claus Hallwirth

Michelle Woolford

“ Investigating the closed-loop model of mRNA translation in eukaryotes”

“ Investigating the function of Gfpt2 in heart development”

Arie Jacoby

Romaric Bouveret

“ Damage and recovery of skeletal muscle: why softy is hardy”

“ Genome-wide identification of target genes of key cardiac transcription factors”

Traude Beilharz

Lawrence Lee

“ Finding the targets of miRNA mediated repression”

Unsolved Mysteries of the Rotary ATPase Enzymes “Marvelous Rotary Engine(s) of the Cell”

Ling Gao “ Polypharmaceutical Strategies against Ischemia-Reperfusion Injury in Donor Heart Preservation”

Nick Cole “ Morphogenesis and evolution of vertebrate appendicular muscle formation”

Duncan Sparrow

Cheryl Li

“ SNP, SNP, Array for Affymetrix!

Getting HESterical about SCD”

“ Epigenetic programming in a perturbed intrauterine environment.”

Kylie Lopes-Floro “ Cited2 is required for left-right asymmetry, but where on earth does it act? Weighing up the evidence”

James Chong “ Where did I come from?

– A Cardiac Stem/Progenitor Cell Perspective”

Tom Hall

Joachim Berger

“ Dystrophic models and post-embryonic muscle growth in zebrafish”

“ sapje, a model for Duchenne Muscular Dystrophy”

44. VCCRI ANNUAL REVIEW 2009

“ Characterisation of a Regulatable Mouse Model of Left Ventricular Hypertrophy”

Jair Kwan “ Strategies to improve donor heart preservation during cardiac transplantation”

Sam Fan “ A structure based method for identifying redox-regulated cysteine residues in yeast”

Chris Blair “ Assessment of a multipotent marrow stormal cell therapy for cardiac repair in a murine model of acute myocardial infarction”

Ting Wai Yiu “ Transglutaminase 2: a dynamic modulator of fibroblast adhesion pathways and skin wound healing in mice”

Alex Shaw “ MicroRNA repression of p53 contributes to survival of embryonic stem cells and neuroblastomas”

Mark Perrin “ State Dependent Drug Binding to hERG”

Robert Bryson-Richardson “ Muscle Specification and Early Onset Myopathies in the Zebrafish”

Merridee Wouters “ Disulfides as Redox Switches in protein Structures”

Vashe Chandrakathan “ Characterization of A Novel Cardiac Cell-Type With Stem and Progenitor Cell Properties”

Adam Hill “ Risk stratification in LQTS2: Laboratory insights into a clinical problem.”

Jennifer Cropley “ Epimutation in health and disease”

Christiana Leimena “ Familial Atrial Fibrillation and Role of BKCa Channel in normal Cardiomyocyte Function and Heart Disease.”

David Wang “ The use of phi value analysis to investigate the inactivation mechanism of the human ethera-go-go-related gene (HERG) potassium channel”

PAUL KORNER SEMINAR SERIES 2009 ••• Jason Liu

Duncan Sparrow

Alasdair Watson

Stanley Artap

“ Gentrepid: A candidate gene prediction system and webserver”

“ Placental insufficiency and embryonic kidney formation”

“ Exploring the nonhaematopoietic effects of erythropoietin in cardiac transplantation”

“ Cited2 is necessary for determining the left-right body axis and to the development of the placenta in the mouse”

Liz Yeo

Vesna Nikolova

“ Evaluation of mechanisms of contractile dysfunction in mouse model of dilated cardiomyopathy, Lamin A/C-deficient mice”

“ When Nesprins Snap - Getting to the Core of Heart Disease”

Orit Wolstein “ Tbx20 Is Essential For Cardiac Proliferation And Differentiation Independently of Tbx2”

Kylie Lopes-Floro “ Branching out into hypoxia: The role of Hif1a during placental development”

Traude Beilharaz “ Working in Circles: The determination of mRNA configuration in active translation”

Marion Mohl “ Involvement of a novel alpha1Aadrenergic receptor signaling pathway in cardiac contractility”

Jeff Squires “ Investigating RNA methylation with bisulfite sequencing”

Michelle Holland “ Profiling the transcriptome during cardiac differentiation and other projects”

Gavin Chapman

Mark Perrin “ The kinetics of hERG drug binding and their effect on high throughput screening assays”

Munira Xaymardan “ Characterization of Sca-1+/ PECAM-1-/PDGFRa+ Cardiac Stem Cells”

Chris Blair

“ piRNAs and the aberrant silencing of genes”

“ Mesenchymal stem cell transplantation for functional recovery following acute myocardial infarction”

Sam Fan

Merridee Wouters

Simon Keam

“Heart development in plants”

“ Expression and localisation of Notch pathway proteins during somitogenesis”

Ling Gao

Scott Kesteven

“ Structure-based identification of redox-regulated thiols”

“ Data Mining: a tool for knowledge discovery”

“ Cardioprotective effects of sodium hydrogen exchange inhibition by Zoniporide: association with pro-survival signaling pathway activation”

“ Developmental Changes in Ventricular Diastolic Function”

Ting Wai Yiu

Andy Mg

Andrew Jabbour

“ Transglutaminase 2: a role in skin wound healing”

“ Getting to the heart of hERG K+ channel gating”

James Chong

Adam Hill

“ An Epicardial Origin for Sca1+/ CD31-/PDGFRa+ Cardiac Stem Cells”

“ Unlocking the gate to potassium channel inactivation”

Romaric Bouveret

Lawrence Lee “ The Victor Chang’s first protein crystal structure The molecular basis for rotation and switching of the bacterial flagellar rotary motor”

David Humphreys “ Two small RNA stories: (i) Contribution of poly(A) tail in miRNA function and (ii) Early experiences in preparing small RNA libraries for Solid deep sequencing.”

Peter Riek “ Do canonical p-helical structures exist in proteins?”

“ Targeting Myocardial Apoptosis and Ischaemia Reperfusion Injury. Recombinant Human Neuregulin-1 in Heart Failure and Transplantation”

Alex Shaw

Sharon Chih

“ miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in neuroblastoma”

“ Granulocyte-colony stimulating factor to stimulate neovascularisation in chronic angina”

Leah Cannon

Christiana Leimena

“ Investigation of the pathogenesis of LVH due to the R403Q MHC mutation”

“ Role of BKCa Channel - in the normal cardiomyocyte and in heart disease”

David Szekely “ An improved curvilinear gradient method for model parameterisation: application to a novel hERG model”

Vashe Chandrakathan “ A cardiac cell-type with stem and progenitor cell properties in the developing and adult murine heart”

Cheryl Li “ Epigenetic programming in a perturbed intrauterine environment”

VCCRI ANNUAL REVIEW 2009 45.

BARBARA ELL SEMINAR SERIES 2008 •••

This Seminar Series was named after Mrs Barbara Ell an avid supporter of the Institute and a hard working member of both the Board and Appeals Committee.

Each month the Institute invites a renowned Australian Scientist to present a lecture as a part of the Barbara Ell Seminar Series.

Professor Bryan Williams

Professor Greg Gibson

Professor Doug Hilton

Director, Monash Institute of Medical Research, Victoria

School of Biological Sciences, University of Queensland

“ RNAi and Innate Immunity“

“ Genomic dissection of complex disease in flies and humans“

Head Molecular Medicine, Walter & Eliza Institute of Medical Research Victoria

Dr. Julie McMullen Cardiac Hypertrophy Lab, Baker IDI, Victoria “ Protective role of the IGF1PI3K(p110alpha) pathway in the heart“

Professor Charles Mackay Director, Immunology and Inflammation Research, Garvan Institute of Medical Research “ Chemoattractant receptors and their role in leukocyte migration, inflammation, HIV infection, and cancer“

“ Genetic Dissection of Blood Cells Formation“.

Professor David Tremethick Group & Genome Biology, The John Curtin School of Medical Research, Australian National University, ACT “ Understanding the link between chromatin structure and function during early development“

Dr. Rohan Teasdale

Dr. Eddy Kizana Faculty of Medicine, University of Sydney & Staff Cardiologist, Dept. of Cardiology, Westmead Hospital “ Transfer of Regulatory RNA Molecules via Gap Junctions in Heart Cells“.

Institute of Molecular Sciences, University of Queensland “ The Dynamic Endosome: A journey through space and time“

Understanding the link between chromatin structure and function during early development.

Professor David Tremethic

46. VCCRI ANNUAL REVIEW 2009

BARBARA ELL SEMINAR SERIES 2009 ••• Dr. Kevin Pfleger Head of the Laboratory for Molecular Endocrinology Western Australian Institute “ Monitoring G Protein-Coupled Receptor Complexes using BRET“

Dr. Himanshu Brahmbhatt & Dr. Jennifer MacDiarmid Co-founders and Managing Directors EnGeneIC Pty Ltd “ Bacterially-derived nanocells for targeted delivery of drugs or siRNAs to tumors in-vivo“

Dr. Marnie Blewitt

Professor Michael Good Director, The Queensland Institute of Medical Research “ Vaccines for the developing world – status of rheumatic fever“

Glenn King Group leader – IMB Chemical & Structural Biology

WEHI , Bioinformatics Division

“ Venomics as a drug discovery platform“

“ Studies on the molecular mechanisms behind epigenetic control - stories about Smchd1 and polycomb group proteins“

Dr. Jackie Wilce

Dr. Carola Vinuesa Viertel Senior Medical Research Fellow / Group Leader Division of Immunology and Genetics , John Curtin School of Medical Research Australian National University “ Dissecting the cellular and molecular layers that control antibody quality and prevent autoimmunity“

Dr. Melanie Bahlo WEHI, Bioinformatics Division “ Using high throughput technologies for disease gene identification“

Faculty of Medicine, Nursing and Health Sciences, Monash University Victoria

Dissecting the cellular and molecular layers that control antibody quality and prevent autoimmunity.

Dr. Carola Vinuesa

“ mRNA recognition by proteins involved in translation regulation“

Dr. Ryszard Maleszka Molecular Genetics and Evolution Group, Research School of Biological Sciences “ How the interplay between genes and environment generates organismal and behavioural complexity: insights from the honey bee epigenomics“

Professor Jennifer Gamble Professor of Vascular Biology Medicine, Central Clinical School Centenary Institute of Cancer Medicine & Cell Biology “ Regulation of Vascular Phenotypes“

VCCRI ANNUAL REVIEW 2009 47.

PRINCESSES’ LECTURE SERIES AND INTERNATIONAL SYMPOSIUMS •••

The Princesses’ Lecture Series is an annual VCCRI event inaugurated in 1998. The lecture series is named in honour of the late Diana, Princess of Wales and Her Royal Highness Crown Princess Mary of Denmark, both strong supporters of the Institute and its research.

01

The VCCRI’s 10th International Symposium Molecular Pharmacology of G ProteinCoupled Receptors, was held in November 2008 and featured a number of leading international and national investigators.

02

Speakers – Dr. Stephane Angers,(Canada) – Professor Michel Bouvier, (Canada) – Professor Nigel Bunnett, (USA) – Professor Arthur Christopoulos, (Australia) – A /Professor Arthur Conigrave, (Australia) – Dr. Shaun Coughlin, (USA) – Debbie Hay, (NZ) – Professor Graeme Henderson, (UK) – Dr. Brian Kobilka, (USA) – Professor Tsutomu Kouyama (Japan) – Dr. Laurence Miller, (USA) – Mr. Klaus Mohr, (Germany) – Dr. Rama Ranganthan, (USA) – Gebhard Franz Xaver Schertler – A /Professor Gunnar Schulte, (Sweden) – Roger Summers, (Australia) – A /Professor Roger Sunahara, (USA) – Celine Valant, (Australia) – Dr. Mark von Zastrow, (USA) – Professor Richard Henderson, MRC Laboratory of Molecular Biology, Cambridge, UK delivered the Princesses’ Lecture speaking on the topic of ‘Structural changes underlying function in 7-helix membrane proteins including GPCRs’.

48. VCCRI ANNUAL REVIEW 2009

01 Diana, Princess of Wales 02 Her Royal Highness Crown Princess Mary of Denmark

The VCCRI’s 11th International Symposium Cardiology at the Frontier – Development, Stem Cells and Heart Failure was held in October 2009 featuring a number of leading international, national and VCCRI speakers.

We would like to sincerely thank the following companies for supporting our symposiums.

International speakers

Companies

– Professor Stefanie Dimmeler (Germany) – Professor Antoon Moorman (Netherlands) – Professor Shoumo Bhattacharya (UK) – Professor Brian Black (USA) – A /Professor Vincent Christoffels (Netherlands) – Dr. Rob Doughty (NZ) – Dr. Nicola Hiemann (Germany) – Professor Ahsan Husain (USA) – Dr. Robert Kelly (France) – A/Professor Anne Moon (USA) – Professor Nadia Rosenthal (Italy/UK/Australia) – Richard G Smith (USA) – Professor Andreas Zeiher (Germany), delivered the Princesses’ Lecture speaking on ‘Regeneration therapies for the failing heart’.

Merck, Pfizer, addex, TGR BioSciences, Amgen, GlaxoSmithKline, Biolab, Beckman Coulter, Perkin Elmer, AstraZeneca, Mar Research; Wyeth, BristolMyers Squibb, GE Healthcare, Roche, Discoverx, Prism, Pathtech, KI Scientific, Bioline, British Pharmacological Society, John Morris Scientific, Rigaku, Meeco, Eppendorf, Bayer HealthCare, MACs, Genesearch, ScheringPlough, Quantum Scientific, Millipore, Australian Stem Cell Centre, NGED, Sapphire Bioscience, SDR Clinical Technology, RISS, Janssen-Cilag, International Society of Developmental Biologists, ARMI, Solvay Pharmaceuticals, Scisense, NSW Government Industry & Investment, Heart Repair, Novartis, SynCardia, Alphapharm, Heart Ware, Servier and Actelion.

PUBLICATIONS 2008 •••

01. Amirahmadi F, Turnbull L, Du XJ, Graham RM, Woodcock EA. Heightened alpha1Aadrenergic receptor activity suppresses ischaemia/ reperfusion-induced Ins(1,4,5) P3 generation in the mouse heart: a comparison with ischaemic preconditioning. Clin Sci (Lond) 2008; 114:157-64.

07. Chen Y, Doughman YQ, GuS, Jarrell A, Aota S, Cvekl A, Watanabe M, Dunwoodie SL, Johnson RS, van Heyningen V, Kleinjan DA, Beebe DC, Yang YC. Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis. Development 2008, 135:2939-48

02. Bansal PS, Torres AM, Crossett B, Wong KK, Koh JM, Geraghty D, Vandenberg JI, Kuchel PW. Substrate specificity of platypus venom L-to-D-peptide isomerase. J Biol Chem 2008; 283:8969-75.

08. Clarke CE, Veale EL, Wyse K, Vandenberg JI, Mathie A. The M1P1 loop of TASK3 K2P channels apposes the selectivity filter and influences channel function. J Biol Chem.

2008; 283:16985-92

03. Banfor PN, Preusser LC, Campbell TJ, Marsh KC, Polakowski JS, Reinhart GA, Cox BF, Fryer RM. Comparative effects of levosimendan, OR1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in dogs. Am J Physiol Heart Circ Physiol 2008; 294:H238-48.

09. Coman D, Bacic S, Boys A, Sparrow DB, Dunwoodie SL, Savarirayan R, Amor DJ. Spondylocostal Dysostosis in a pregnancy complicated by Confined Placental Mosaicism for Tetrasomy 9p. American Journal of Medical Genetics: Part A, 2008; 146A, 1972-1976.

04. Blewitt ME, Gendrel AV, Pang Z, Sparrow DB, Whitelaw N, Craig JM, Apedaile A, Hilton DJ, Dunwoodie SL, Brockdorff N, Kay GF, Whitelaw E. SmcHD1, containing a structural-maintenanceof-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet. 2008; 40:663-9.

05. Bryson-Richardson RJ, Currie PD. The genetics of vertebrate myogenesis. Nat Rev Genet.

2008; (8):632-46.

06. Butt AJ, Sergio CM, Inman CK, Anderson LR, McNeil CM, Russell AJ, Nousch M, Preiss T, Biankin AV, Sutherland RL, Musgrove EA. The estrogen and c-Myc target gene HSPC111 is over-expressed in breast cancer and associated with poor patient outcome.

Breast Cancer Res. 2008; 10:R28.

10. Cropley JE, Martin DIK, Suter CM. Germline epimutation in humans. Pharmacogenomics.

2008 Dec;9(12):1861-8.

11. Esteban O, Bernal RA, Donohoe M, Videler H, Sharon M, Robinson CV, Stock D. Stoichiometry and Localization of the Stator Subunits E and Gin Thermus thermophilus H+ATPase/Synthase. J Biol Chem 2008; 283:2595-603.

12. Furtado MB, Solloway MJ, Franklin V, Costa MW, Biben B, Wolstein O, Preis JI, Sparrow DB, Saga Y, Dunwoodie SL, Robertson EJ, Tam PPL, Harvey RP. (2008). BMP/SMAD1 signalling sets a threshold for the left/ right pathway in lateral plate mesoderm and limits availability of SMAD4. Genes Dev 2008; 22:3037-49.

13. George RA, Smith TD, Callaghan S, Hardman L, Pierides C, Horaitis O, Wouters MA, Cotton RG. Response to Stenson et al on the review of general mutation databases. J Med Genet. 2008; 45:319-20.

14. George RA, Smith TD, Callaghan S, Hardman L, Pierides C, Horaitis O, Wouters MA, Cotton RG. General mutation databases: analysis and review. J Med Genet.

2008; 45:65-70.

15. Hashimoto J, O’Rourke MF. Arterial stiffness: does it predict risk over blood pressure?

Current Cardiovascular Risk Reports 2008; 2:133-140.

16. Hashimoto J, Nichols WW, O’Rourke MF, Imai Y. Association Between Wasted Pressure Effort and Left Ventricular Hypertrophy in Hypertension: Influence of Arterial Wave Reflection. Am J Hypertens 2008;21:329-33.

17. Hashimoto J, Westerhof BE, Westerhof N, O’Rourke MF. Different role of wave reflection magnitude and timing on left ventricular mass reduction during antihypertensive treatment. Hypertension 2008; 26:1017-1024.

18. Keogh A, Jabbour A, Hayward C, Macdonald P. Clinical deterioration after sildenafil cessation in patients with pulmonary hypertension.

Vascular Health and Risk Management 2008; 4:1111-13.

20. Kovacic JC, Macdonald PS, Feneley MP, Muller DWM, Freund J, Dodds A, Milliken S, Tao H, Itescu S, Moore J, Ma D, Graham RM. Safety and efficacy of consecutive cycles of granulocyte-colony stimulating factor, and an intracoronary CD133+ cell infusion in patients with chronic refractory ischemic heart disease: the Gain I trial. Am Heart J 2008;156:954-63.

21. Li M, Naqvi N, Yahiro E, Liu K, Powell PC, Bradley WE, Martin DI, Graham RM, Dell’italia LJ, Husain A. c-kit Is Required for Cardiomyocyte Terminal Differentiation. Circ Res 2008 102:677-85.

22. Loomes KM, Stevens SA, O’Brien ML, Gonzalez DM, Ryan MJ, Segalov M, Dormans NJ, Mimoto MS, Gibson JD, Sewell W, Schaffer AA, Nah HD, Rappaport EF, Pratt SC, Dunwoodie SL, Kusumi K. Dll3 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects. Dev Dyn. 2008; 237:1754.

23. Martin DIK, Cropley JE, Suter CM. Environmental influence on epigenetic inheritance at the Avy allele. Nutr Rev 2008; 66 Suppl 1:S12-4.

19. Kovacic JC, Moore J, Herbert A, Ma D, Boehm M, Graham RM. Endothelial progenitor cells, angioblasts, and angiogenesis-old terms reconsidered from a current perspective. Trends Cardiovasc Med 2008; 18:45-51.

* Names in bold represent our Researchers at VCCRI.

VCCRI ANNUAL REVIEW 2009 49.

PUBLICATIONS 2008 CONTINUED •••

24. Newton PJ, Davidson PM, Macdonald P, Ollerton R, Krum H. Nebulized Furosemide for the Management of Dyspnea: Does the Evidence Support Its Use? J Pain Symptom Manage.

2008; 36:424-41.

25. Nichols WW, Denardo SJ, Wilkinson IB, McEniery CM, Cockcroft J, O’Rourke MF. Effects of arterial stiffness, pulse wave velocity, and wave reflection on the central aortic pressure waveform. J Clin Hypertens (Greenwich) 2008;10:295-303.

26. O’Rourke MF, Adji A. Basis for use of central blood pressure measurement in office clinical practice. J Am Soc Hypertens 2008;2:28-38.

27. O’Rourke MF, Avolio AP. Arterial transfer functions: background, applications and reservations. J Hypertens 2008; 26:8-10.

28. O’Rourke MF, Hirata K. Analysis of Carotid and Ophthalmic Flow Velocity Waveforms. Hypertension 2008; 51:e18.

29. O’Rourke MF, Safar ME. Methods for transfer function assessment. J Hypertens 2008; 26:377-78.

30. O’Tuathaigh CM, O’Connor AM, O’Sullivan GJ, Lai D, Harvey R, Croke DT, Waddington JL. Disruption to social dyadic interactions but not emotional/anxietyrelated behaviour in mice with heterozygous ‘knockout’ of the schizophrenia risk gene neuregulin-1. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2008; 32:462-6.

31. Palmer BM, Wang Y, Teekakirikul P, Hinson JT, Fatkin D, Strouse S, Vanburen P, Seidman CE, Seidman JG, Maughan DW. Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex. Am J Physiol Heart Circ Physiol 2008; 294:H1939-47.

32. Pang CN, Krycer JR, Lek A, Wilkins MR. Are protein complexes made of cores, modules and attachments?

Proteomics. 2008 Feb;8(3):425-34.

33. Pang CN, Wilkins MR. Online resources for the molecular contextualization of disease. Methods Mol Med. 2008;141:287-308.

34. Pang CN, Lin K, Wouters MA, Heringa J, George RA. Identifying foldable regions in protein sequence from the hydrophobic signal. Nucleic Acids Res 2008;36:578-88.

35. Perrin, MJ, Kuchel, PW, Campbell, TJ, Vandenberg, JI. Drug binding to the inactivated state is necessary but not sufficient for high affinity binding to Human Ether-a` -go-go-Related Gene Channels. Mol Pharmacol 2008;74:1443-52.

36. Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP. Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction.

Prog Biophys Mol Biol.

2008;98:137-48.

* Names in bold represent our Researchers at VCCRI.

50. VCCRI ANNUAL REVIEW 2009

37. Riek RP, Finch AA, Begg GE, Graham RM. Wide turn diversity in protein transmembrane helices implications for G-protein coupled receptor and other polytopic membrane protein structure and function. Mol Pharmacol 2008 73:1092-104.

38. Strange G, Keogh A, Williams T, Wlodarcyzk J, McNeil K, Gabbay E. Bosentan therapy in patients with pulmonary arterial hypertension: the relationship between improvements in 6 minute walk distance and quality of life. Respirology 2008;13:5:674-82.

39. Sparrow DB, Guillén-Navarro E, Fatkin D, Dunwoodie SL. (2008). Mutation of HAIRY-AND-ENHANCEROF-SPLIT-7 in Humans Causes Spondylocostal Dysostosis. Hum Mol Genet 2008;17:3761-66.

40. Sparrow DB, Boyle SC, Sams RS, Mazuruk B, Zhang L, Moeckel GW, Dunwoodie SL, de Caestecker MP. Placental insufficiency causes renal medullary dysplasia in Cited1 mutant mice. J Am Soc Nephrol accepted 21/10/08 41. Teber ET, Liu JY, Ballouz S, Fatkin D, Wouters MA. Comparison of automated candidate gene prediction systems using genes implicated in type 2 diabetes by genomewide association studies. BMC Bioinformatics 2008;10(Suppl 1): S69 (IF=3.493)

42. Weber T, O’Rourke MF, Ammer M, Kvas E, Punzengruber C. Arterial stiffness and arterial wave reflections are associated with systolic and diastolic function in patients with normal ejection fraction. Am J Hypertens 2008;21:1194-202.

43. Woodcock EA, Du XJ, Reichelt ME, Graham RM. Cardiac {alpha}1-adrenergic drive in pathological remodelling. Cardiovasc Res 2008;77:452-62.44.

Xu B, Qu X, Gu S, Doughman YQ, Watanabe M, Dunwoodie SL, Yang YC. Cited2 is required for fetal lung maturation. Dev Biol. 2008; 317:95-105.

44. Yadava RS, Frenzel-McCardell CD, Yu Q, Srinivasan V, Tucker AL, Puymirat J, Thornton CA, Prall OW, Harvey RP, Mahadevan MS. RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression.

Nat Genet 2008;40:61-8.

Book Research 01. Larson WJ (Harvey RP contributing Ed) Human Embryology (Forth Edition), Churchill Livingstone Inc., New York. [In Press, expected release date April 11th 2008].

Book & Meeting Reviews 02. Kovacic JC, Harvey RP, Dimmeler S. Cardiovascular Regenerative Medicine: digging in for the long-haul.

Meeting Report, Cardiovascular Regenerative Medicine Symposium, NIH-NHLBI, Bethesda, USA, October 1-2-2007. Cell Stem Cell 2008; 1:628-633.

Commentaries & Editorials 03. Trounsen A, Harvey RP. “A critical time for stem cell research in Australia” Cell Stem Cell 2008; 2:118-22.

04. O’Rourke MF, Avolio AP. Arterial transfer function: background, applications, reservations. J Hypertens 2008; 26:4-5 [invited commentary].

05. O’Rourke MF, Safar ME. “Arterial pulse wave velocity but not augmentation index is associated with coronary artery disease extent and severity by Hope et al”. J Hypertens 2008; 26:377-3783 [Letter to the editor].

06. O’Rourke MF. How stiffening of the aorta and elastic arteries leads to compromised coronary flow. (editorial) Heart 2008;94:690-1.

07. O’Rourke MF. How a stiff aorta leads to worse coronary flow. [editorial] Heart 2008 (in press).

08. O’Rourke MF, O’Rourke J, Fansworth A. Aortic dimensions and stiffness in normal man. J Am Coll Cardiol Imag 2008;1:749-51. (editorial) 09. O’Rourke MF. Brain Microbleeds, Amyloid Plaques, Intellectual Deterioration, and Arterial Stiffness. Hypertension 2008 51:e20.

10. O’Rourke MF, Safar ME. Book on Central Arterial Pressure.

Laurent S, Cockcroft J (eds) 11. O’Rourke MF. Letter to the editor “Brain microbleeds, amyloid plaques, intellectual deterioration and arterial stiffness”. Hypertension 2008; 51:e20.

12. O’Rourke MF, Hirata K. “Analysis of carotid and ophthalmic flow velocity waveforms”. Hypertension 2008; 51:e18. [Letter to the editor] 13. O’Rourke MF, Safar ME. “Arterial pulse wave velocity but not augmentation index is associated with coronary artery disease extent and severity

by Hope et al”. J Hypertens 2008;26:377-3783 [Letter to the editor] 14. O’Rourke MF, Safar ME. Methods for transfer function assessment. J Hypertens.

2008; 26:377-8; 378-9. [author reply] 15. O’Rourke MF. How stiffening of the aorta and elastic arteries leads to compromised coronary flow. [editorial] Heart 2008; 94:690-1.

16. O’Rourke MF, O’Rourke J, Fansworth A. Aortic dimensions and stiffness in normal man. J Am Coll Cardiol Imag 2008;1:749-51. (editorial)

Invited Reviews

Book Chapters

01. Fatkin D, Otway R, Richmond Z. Genetics of dilated cardiomyopathy. Heart Failure Clinics (in press-accepted 1/7/08).

17. Turnpenny, PD, Kusumi, K, Dunwoodie SL. DLL3, MESP2, LFNG and spondylocostal dysostosis; MIM 277300. In Inborn Errors of Development: The Molecular Basis of Clinical Disorders and Morphogenesis.

2nd edition. Oxford University Press, Oxford, UK 2007 (In press).

02. Cropley JE, Martin DIK, Suter CM. Germline epimutation in humans.

Pharmacogenomics 2008; 9(12): 1861-1868 [Invited Review].

03. Cropley JE, Suter CM. An epigenetic basis for fetal programming. Highlights 2008;16(1): 22-26 [Invited Review].

04. Martin DIK, Cropley JE, Suter CM. Environmental influence on epigenetic inheritance at the Avy allele.

Nutrition Reviews 2008;66: S12-S14 [Invited Review].

05. Nichols WW, O’Rourke MF. The life and times of Donald A McDonald. Artery Research 2008;2:1-8. (review) 06. O ’Rourke MF, Hashimoto J. Arterial stiffness: a modifiable cardiovascular risk factor? J Cardiopulmonary Rehabilitation and Prevention 2008;8:225-237.

18. Humphreys DT, Westman BJ, Martin DIK, Preiss T. Inhibition of translation initiation a by a miRNA. In: Appasani K, ed. MicroRNAs: From Basic Science to Disease Biology.

Cambridge, UK: Cambridge University Press, 2008; 85-101.

19. Muckenthaler M, Preiss T. Mechanismen der Translationskontrolle in Eukaryonten [Mechanisms of translational control in eukaryotes]. Chapter for the book series “Molekulare Medizin [Molecular Medicine]”, volume 1: ”Grundlagen der Molekularen Medizin [Foundations of molecular medicine]”, Editors: Ruckpaul K and Ganten D, 3rd completely revised edition, Springer-Verlag, Berlin, Heidelberg, New York, London, Paris, Tokyo 2008; p139-158.

20. Chapman G, Dunwoodie SL. Role of Delta-like-3 in mammalian somitogenesis and vertebral column formation. pp 95-112. In Somitogenesis (Advances in Experimental Medicine and Biology, Vol.638, eds. M Maroto and NV Whittock) Landes Bioscience and Springer Science+Business Media (2008). IF = na (na) 21. O’Rourke MF, Safar ME. Foreword. In: Laurent S, Cockcroft J (eds). Central aortic blood pressure.

Paris: Les Laboratoires Servier, 2008.

VCCRI ANNUAL REVIEW 2009 51.

PUBLICATIONS 2009 •••

01. Beilharz TH, Preiss T. Transcriptome-wide measurement of mRNA polyadenylation state. Methods 2009; 48:294-300.

02. Beilharz TH, Humphreys DT, Clancy JL, Thermann R, Martin DIK, Hentze MW, Preiss T. MicroRNA-mediated messenger RNA deadenylation contributes to translational repression in mammalian cells. PLoS One. 2009; 4:e6783.

03. Carballo S, Robinson P, Otway R, Fatkin D, Jongbloed J, de Jonge N, Blair E, van Tintelen JP, Redwood C, Watkins H. Identification and functional characterisation of a novel disease gene in autosomal dominant dilated cardiomyopathy. Circ Res 2009; 105:375-82.

04. Chikhani S, Fernandez F, Poetter K, Toohey B, Harvey R, Griffiths LR.zInvestigation between the S377G GATA-4 Polymorphism and Migraine. The Open Neurology Journal 2009;2:35-38 05. Peterkin T. Gibson A. Patient R. Common genetic control of haemangioblast and cardiac development in zebrafish. Development.

2009; 136:1465-1474.

06. Chen Y, Carlson EC, Chen ZY, Hamik A, Jain MK, Dunwoodie SL, Yang YC. Conditional Deletion of Cited2 Results in Defective Corneal Epithelial Morphogenesis and Maintenance. Dev Biol. 2009; 334:243-52.

07. Chandar S, Yeo LS, Leimena C, Tan JC, Xiao XH, NikolovaKrstevski V, Yasuoka Y, Gardiner-Garden M, Wu J, Kesteven S, Karlsdotter L, Natarajan S, Carlton A, Rainer S, Feneley MP, Fatkin D. Effects of Mechanical Stress and Carvedilol in Lamin A/C-Deficient Dilated Cardiomyopathy. Circ Res. 2009 08. Combes AN, Spiller CM, Harley VR, Sinclair AH, Dunwoodie SL, Wilhelm D, Koopman P. Gonadal defects in Cited2 -mutant mice indicate a role for SF1 in both testis and ovary differentiation.

Int J Dev Biol. 2009.

09. Corte TJ, Wort SJ, Gatzoulis MA, Macdonald P, Hansell DM, Wells AU. 10. D unwoodie SL. Reprint of mutation of the fucose-specific beta1,3 cetylglucosaminyltransferase LFNG results in abnormal formation of the spine.

Biochim Biophys Acta. 2009; 1792:862-73.

11. Dunwoodie SL. The role of hypoxia in development of the Mammalian embryo. Dev Cell.

2009 17:755-73.

12. Du H, Davidson PM, Everett B, Salamonson Y, Zecchin R, Rolley JX, Newton PJ, Macdonald PS. Assessment of a Selfadministered Adapted 6-Minute Walk Test. J Cardiopulm Rehabil Prev. 2009.

13. Esposito G, Grutter G, Drago F, Costa MW, De Santis A, Bosco G, Marino B, Bellacchio E, Lepri F, Harvey RP, Sarkozy A, Dallapiccola B. Molecular analysis of PRKAG2, LAMP2, and NKX2-5 genes in a cohort of 125 patients with accessory atrioventricular connection.

Am J Med Genet A. 2009; 149A:1574-7.

14. Fan SW, George RA, Haworth NL, Feng LL, Liu JY, Wouters MA. Conformational changes in redox pairs of protein structures.

Protein Sci 2009; 18:1745-1765.

15. Foo D, Walker BD, Kuchar DL, Thorburn CW, Tay A, Hayward CS, Macdonald P, Keogh A, Kotlyar E, Spratt P, Jansz P. Left ventricular mechanical assist devices and cardiac device interactions: an observational case series. Pacing Clin Electrophysiol. 2009; 32:879-87.

16. Ferdous A, Caprioli A, Iacovino M, Martin CM, Morris J, Richardson JA, Latif S, Hammer RE, Harvey RP, Olson EN, Kyba M, Garry DJ. Nkx2-5 transactivates the Ets-related protein 71 gene and specifies an endothelial/endocardial fate in the developing embryo. Proc Natl Acad Sci U S A. 2009; 106:814-9.

* Names in bold represent our Researchers at VCCRI.

52. VCCRI ANNUAL REVIEW 2009

17. Hing AJ, Watson A, Hicks M, Gao L, Faddy SC, McMahon AC, Kesteven SH, Wilson MK, Jansz P, Feneley MP, Macdonald PS. Combining cariporide with glyceryl trinitrate optimises cardiac preservation during porcine heart transplantation. American Journal of Transplantation 2009; 9: 1-9.

18. Jacoby AS, Busch-Nentwich E, Bryson-Richardson RJ, Hall TE, Berger J, Berger S, Sonntag C, Sachs C, Geisler R, Stemple DL, Currie PD. The zebrafish dystrophic mutant softy maintains muscle fibre viability despite basement membrane rupture and muscle detachment. Development 2009 136:3367-3376.

19. Ju P, Pages G, Riek RP, Chen PC, Torres AM, Bansal PS, Kuyucak S, Kuchel PW, Vandenberg JI. The pore domain outer helix contributes to both activation and inactivation of the hERG K+ channel. J Biol Chem. 2009; 284: 1000-8.

20. Kurz M, Iturbe-Ormaetxe I, Jarrott R, Shouldice SR, Wouters MA, Frei P, Glockshuber R, Oneill S, Heras B, Martin J. Structural and functional characterization of the oxidoreductase α-DsbA1 from wolbachia pipientis. Antioxid Redox Signal. 2009.

21. Macindoe I, Glockner L, Vukasin P, Stennard FA, Costa MW, Harvey RP, Mackay JP, Sunde M. Conformational stability and DNA binding specificity of the cardiac T-box transcription factor tbx20. J Mol Biol 2009; 12; 389:606-18.

22. Macdiarmid JA, AmaroMugridge NB, Madrid-Weiss J, Petti C, Sedliarou I, Wetzel S, Kochar K, Brahmbhatt V, Phillips L, Stillman B, Graham RM, Brahmbhatt H. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nature Biotech 2009; 27;643-651.

23. Maple-Brown LJ, Cunningham J, Barry RE, Leylsey L, O’Rourke MF, Celermajer DS, O’Dea K. Impact of dyslipidaemia on arterial structure and function in urban Indigenous Australians.

Atherosclerosis. 2009; 202:248-54.

24. Matsui Y, Eguchi K, O’Rourke MF, Ishikawa J, Miyashita H, Shimada K, Kario K. Differential effects between a calcium channel blocker and a diuretic when used in combination with angiotensin II receptor blocker on central aortic pressure in hypertensive patients.

Hypertension. 2009; 54:716-23.

25. Naqvi N, Li M, Yahiro E, Graham RM, Husain A. Insights into the characteristics of mammalian cardiomyocyte terminal differentiation shown through the study of mice with a dysfunctional c-Kit. Pediatr Cardiol. 2009; 30:651-8.

26. Ng LJ, Cropley JE, Pickett HA, Reddel RR Suter CM. Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription.

(2009) Nucleic Acids Res 2009; 37:1152-9.

27. O tton J, Hayward CS, Keogh AM, Glanville AR, Macdonald PS. Everolimus associated pneumonitis in 3 heart transplant recipients. J Heart Lung Transplantation 2009; 28:104-106.

28. O’Rourke MF. Time domain analysis of the arterial pulse in clinical medicine. Med Biol Eng Comput. 2009; 47:119-29.

29. O’Rourke MF, Adji A. Central Pressure and Pulse Wave Amplification in the Up Limb.

Hypertension.

30. Pages G, Torres AM, Ju P, Bansal PS, Alewood PF, Kuchel PW, Vandenberg JI. Structure of the pore-helix of the hERG K+ channel. Eur Biophys J. 2009; 39:111-20.

31. Romantsov T, Battle AR, Hendel JL, Martinac B, Wood JM. Protein localization in Escherichia coli cells: comparison of cytoplasmic membrane proteins ProP, LacY, ProW, AqpZ, MscS, and MscL. J Bacteriol 2009.

32. Sewell W, Sparrow DB, Smith AJ, Gonzalez DM, Rappaport EF, Dunwoodie SL, Kusumi K. Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis. Dev Biol 2009; 329:400-9.

40. Zdanowicz A, Thermann R, Kowalska J, Jemielity J, Duncan K, Preiss T, Darzynkiewicz E, Hentze MW. Drosophila miR2 primarily targets the m7GpppN cap structure for translational repression. Mol Cell. 2009; 35:881-8.

33. Suter CM, Martin DI. Paramutation: the tip of an epigenetic iceberg? Trends Genet. 2009.

41. Zhao J, Hill AP, Varghese A, Cooper AA, Swan H, LaitinenForsblom PJ, Rees MI, Skinner JR, Campbell TJ, Vandenberg JI. Not all hERG pore domain mutations have a severe phenotype: G584S has an inactivation gating defect with mild phenotype compared to G572S which has a dominant negative trafficking defect and a severe phenotype. J Cardiovasc Electrophysiol 2009; 8:923-30.

34. Tatsukawa H, Fukaya Y, Frampton G, Martinez-Fuentes A, Suzuki K, Kuo TF, Nagatsuma K, Shimokado K, Okuno M, Wu J, Iismaa S, Matsuura T, Tsukamoto H, Zern MA, Graham RM, Kojima S. Role of Transglutaminase 2 in liver injury via cross-linking and silencing of transcription factor Sp. Gastroenterology 2009; 136:1783-95.

35. Teber ET, Liu JY, Ballouz S, Fatkin D, Wouters MA. Comparison of automated candidate gene prediction systems using genes implicated in type 2 diabetes by genome-wide association studies. BMC Bioinformatics 2009; 10 Suppl 1:S69.

36. Tomiyama K, O’Tuathaigh CM, O’Sullivan GJ, Kinsella A, Lai D, Harvey RP, Tighe O, Croke DT, Koshikawa N, Waddington JL. Phenotype of spontaneous orofacial dyskinesia in neuregulin-1 ‘knockout’ mice.

Prog Neuro-Psych Biol Psych 2009; 33:330-3.

37. Traven A, Beilharz TH, Lo TL, Lueder F, Preiss T, Heierhorst J. The Ccr4-Pop2-NOT mRNA Deadenylase contributes to septin organization in saccharomyces cerevisiae.

Genetics 2009; 182:955-66.

38. Wouters MA, Fan SW, Haworth NL. Disulfides as redox switches: from molecular mechanisms to functional significances. Antioxid Redox Signal. 2009.

39. Xaymardan M, Cimini M, Fazel S, Weisel RD, Lu WY, Martin U, Harvey RP, Li RK. c-Kit function is necessary for in vitro myogenic differentiation of bone marrow hematopoietic cells. Stem Cells.

2009; 27:1911-20.

42. Dunwoodie SL. The role of hypoxia in development of the Mammalian

Commentaries & Editorials 01. Grossfeld P, Ye M, Harvey R. Hypoplastic left heart syndrome: new genetic insights. J Am Coll Cardiol. 2009 24;53:1072-4 02. Harvey RP, Meilhac SM, Buckingham ME. Landmarks and lineages in the developing heart.

Cic Res. 2009; 104:1235-7 03. Nichols WW, O’Rourke MF. Aortic pulse wave velocity, reflection site distance, and augmentation index.

Hypertension. 2009;53:e9; author reply.

04. O’Rourke MF, Safar ME. Cardiovascular risk in young adults. J Hypertens. 2009; 27:1504-5; author reply 1505.

05. O’Rourke MF, Weber T. Stroke risk and antihypertensive drug therapy. J Hypertens. 2009; 27:1505-6; author reply 1506-7.

06. O’Rourke MF, Takazawa K. Flawed Measurement of Brachial Tonometry for Calculating Aortic Pressure? Hypertension. 2009; 54:e131; author reply e132.

07. Vandenberg JI, Kuchel PW. Proteins, membranes and cells: the structure-function nexus-ASB 2008. Eur Biophys J. 2009;39:1.

Reviews 08.

DunwoodieSL.Mutationof the fucose-specific beta1,3 cetylglucosaminyltransferase LFNG results in abnormal formation of the spine.

Biochim Biophys Acta. 2009; 1792:100-11.

09. Dunwoodie SL. The role of Notch in patterning the human vertebral column. Curr Opin Genet Dev. 2009; 19:329-37.

10. Giampietro PF, Dunwoodie SL, Kusumi K, Pourquié O, Tassy O, Offiah AC, Cornier AS, Alman BA, Blank RD, Raggio CL, Glurich I, Turnpenny PD. Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans. Ann N Y Acad Sci. 2009; 1151:38-67.

11. Iismaa SE, Mearns B, Lorand L, Graham RM. Transglutaminases and Disease: Lessons from Genetically-Engineered Mouse Models and Inherited Disorders.

Invited review. Physiol Rev 2009; 89:991-1023.

17. Safar ME, O’Rourke MF. The brachial-ankle pulse wave velocity. J Hypertens. 2009; 1960-1961.

18. Sparrow DB, Boyle SC, Sams RS, Mazuruk B, Zhang L, Moeckel GW, Dunwoodie SL, de Caestecker MP. Placental insufficiency associated with loss of Cited1 causes renal medullary dysplasia. J A Soc Nephrol 2009; 4:777-86.

Letters to the Editor 01. Kovacic JC, Macdonald P, Feneley MP, Graham RM. Granulocyte-colony stimulating factor in ischemic heart disease: throwing stones from glass houses. Am Heart J. 2009; 27:157:e39; author reply e41.

02. Macdonald PS. Heart transplantation of cardiac amloidosis. Internal Med J 2009; 27:157:e39 03. Vandenberg JI, Kuchel PW. Proteins, membranes and cells: the structure-function nexusASB 2008. European Journal of Biophysics 2009; 39:1.

12. Newton PJ, Betihavas V, Macdonald P. The role of b-type natriuretic peptide in heart failure management. Aust Crit Care.

2009; 22:117-23.

13. O’Rourke MF, Hayward CS. The pulse of cardiology: quo vadis? J Am Coll Cardiol. 2009; 54:714-7.

14. O’Rourke MF. How stiffening of the aorta and elastic arteries leads to compromised coronary flow. Heart. 2008; 94:690-1.

15. O’Rourke MF, Hashimoto J. Arterial stiffness: a modifiable cardiovascular risk factor? J Cardiopulm Rehabil Prev. 2008 Jul-Aug; 28:225-37.

16. Weber T, Ammer M, Rammer M, Adji A, O’Rourke MF, Wassertheurer S, Rosenkranz S, Eber B. Noninvasive determination of carotid-femoral pulse wave velocity depends critically on assessment of travel distance: a comparison with invasive measurement. J Hypertens. 2009; 27:1624-30.

VCCRI ANNUAL REVIEW 2009 53.

FINANCE REPORT •••

Victor Chang Cardiac Research Institute Limited ABN 61 068 363 235

Income Grants Fund Raising Other

2009

2008

$

$

10,592,617

10,518,509

4,358,749

2,668,125

2,268,181

2,941,595

17,219,547

16,128,229

425,289

617,126

–

–

Salaries and related expenses

9,788,699

9,015,326

Research Consumables

1,946,559

2,430,288

–

286,338

60,511

173,566

3,049,821

2,745,513

14,845,590

14,651,031

15,270,879

15,268,157

Surplus / (Deficit) Before Depreciation

1,948,668

860,072

Depreciation

1,331,146

1,109,826

617,522

(249,754)

Total Income Expenses Fundraising Events Expenses Operating and Overhead Expenses

Building Fees Repairs and Maintenance Other Total Operating and Overhead Expenses

Total Expenses

Net Operating Surplus / (Deficit)

54. VCCRI ANNUAL REVIEW 2009

VCCRI SPOTLIGHT •••

Des Renford Gala Day —

On the eve of the new millennium, Australia lost an icon and the Institute lost a dear friend – Des Renford, MBE, OHC. Des lived life to the fullest despite knowing that at any time his fight with heart disease might claim his life. He was an avid supporter of the Institute and had a reputation for not wasting time whilst he was recuperating in hospital. Having had three open heart surgeries and a transient stroke he spent his hospital days visiting fellow patients and selling Victor Chang merchandise.

To celebrate his life an all day tribute commencing with a swim-a-thon in a 25 metre, one lane purpose built pool, erected on the old casino site which at that time had been taken over by Doltone House. Many of Des’ friends came along to swim in his honour - Murray Rose, John Devitt, Barry Rodgers, Guy Leech, to name just a few. As night fell, 600 guests attended a black tie fundraiser to help raise money to establish the Des Renford Chair of Heart Research at the VCCRI. $250,000 was raised that night which was put towards the $1.5 million needed to establish the Chair.

With $750,000 still to raise, Michael Renford, Des’ youngest son, decided he would step into his father’s shoes and take his place on the VC Appeal Committee.

The memory of Des Renford will live on in our hearts and through the Des Renford Chair of Medicine.

Des had spent many an hour at the Maroubra Aquatic Centre, which was renamed the Des Renford Aquatic Centre in his honour, so an annual Gala Day at the pool for the last ten years has helped raise the additional funds needed to fund the Chair with the help of Des and Michael’s friends and Randwick Council.

Michael, not content with just the Gala Day, has been the inspiration for many other fundraisers to keep the Chair viable. He not only swam across the English Channel but has done the Manhattan Island and Catalina Island swims as well as many other local challenges.

We are very grateful to Michael, his lovely wife Vanessa and his friends especially Errol and Gerry Goldberg, Tony Johnston, Baden Green, Des’ Coffee Club friends, Randwick Council and the staff at the Des Renford Aquatic Centre for their continued support and friendship.

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The memory of Des Renford will live on in our hearts and through the Des Renford Chair of Medicine.

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Des Renford Face painting Group entertainment Children learning to swim

VCCRI ANNUAL REVIEW 2009 55.

FUNDRAISING AND FUNCTIONS •••

On behalf of everyone at the VCCRI, thank you to all of our donors for your continued support. This is your institute and its success over the past fifteen years is due to your faith in our research.

We hope you are proud of our achievements and we look forward to you working with us as we try to unlock the mystery of heart disease.

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01 Paceline riders at the end of their Melbourne to Sydney ride with VCCRI staff & family members 02 Golfers at the 2008 VC Golf Day at Concord 03 2009 Westfield Belconnen Golf Day 04 Executive Director Bob Graham with Lisa Curry-Kenny and Sonia Kruger at the 2008 Ball 05 Steve Quinn presenting cheque at the 2008 Ball 06 2008 Hawkesbury Race Day

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56. VCCRI ANNUAL REVIEW 2009

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07 Crabfest 08 Crabfest; the celebrity Chefs 09 2008 Steer Auction Royal Easter Show 10 Artist George Ward puts the finishing touches to his painting 11 Cooper Brothers Durack Stable Opening 12 John Aloisi with Steven Lowy and Sr Elizabeth Dodds, RSC 13 Heart to Heart Ball 14 James and Erica Packer with Steven Lowy at the 2009 Heart to Heart Ball 15 Jim Redman with Confocal Microscope 16 James Morrision performing at the Heart to Heart Ball 17 Scots College Pipes & Drums & Rhythm on Tap, 2009 Heart to Heart Ball 10

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VCCRI ANNUAL REVIEW 2009 57.

SCHOOL SCIENCE AWARDS •••

Designed to recognise excellence in school science and inspire students to make careers in scientific research.

Monique Ohanian, the Victor Chang 2004 inaugural School Science Award winner, remembers her excitement at winning the Award at Loyola Senior High School, Mount Druitt.

As a part of her prize Monique spent a day at the Institute to see first-hand the research being done. She later did a week of work experience at the Institute, then a month in 2005 followed by 2 months in 2006 on a Scholarship and in 2007 worked parttime whilst completing her degree – a Bachelor of Medical Science. Monique now works full time at the Institute and recently not only completed her Honours degree with the Institute but graduated with First Class Honours and received the University Medal from the University of Western Sydney (Hawkesbury Campus).

The Victor Chang School Science Award program is directly in line with one of the Institute’s major missions, namely the provision of world-class training in biomedical research and related sciences. The Institute’s other major mission being to produce cutting-edge research, and to facilitate the rapid translation of research advances to patient care.

Since the awards were first presented in 2004 we now have well over 100 schools participating from Campbelltown, Bankstown, Blacktown and Penrith areas. In 2010 we anticipate them being introduced to schools in Wollongong and surrounding areas.

The Victor Chang School Science Awards are presented to Year 11 students who are selected by their school as having excelled in their science studies during the year.

Awardees are presented with a framed Certificate-of-Achievement at presentation ceremonies and are given the opportunity to visit the Institute for some hands on experience.

The Institute is extending its reach into the community for the good of science, and it is hoped that one day this will benefit the lives and health of all Australians.

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58. VCCRI ANNUAL REVIEW 2009

01 Monique Ohanian 02 Blacktown presentation 03 Professor Graham congratulating a student at Bankstown 04 Penrith presentation

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VCCRI LIMITED MEMBERS •••

The Mary Aikenhead Ministries Trustees

The Trustees —

—

Mary Aikenhead Ministries was established by the Congregation of Religious Sisters Charity of Australia to succeed to, and to carry on and expand, the various ministries conducted by the Sisters of Charity of Australia.

Mary Aikenhead Ministries was granted canonical status as a public juridic person of pontifical right by the Congregation for Institutes of Consecrated Life and Societies of Apostolic Life on April 25, 2008 and officially established on July 1, 2009.

Under Mary Aikenhead Ministries the many ministries that have been established and developed by the Sisters of Charity, will be governed by a group of Trustees, consisting initially of members of the Congregation and lay colleagues.

Richard Harpham, Chairman lives in Sydney. He has over 36 years experience in the financial services and banking industry within Australia and overseas. The bulk of his career has been in commercial banking with Citibank, Westpac and St. George. He attended St. Ignatius College, Riverview and is a graduate of the University of Queensland. Richard has been involved with the Sisters of Charity for well over 10 years serving on a number of boards and committees relating to health, education and the Congregation’s financial administration.

Rowena McNally was born in Papua New Guinea and attended primary school there.

She completed her education in Sydney and at All Hallows in Brisbane, where she now resides. Her qualifications in law entitle her to practice in the Federal Court and the High Court of Australia. She is an accredited mediator, arbitrator andconstruction industry adjudicator. She is a director of St. Vincent’s & Holy Spirit Health.

Sister Elizabeth Dodds, RSC has twelve years experience as a Trustee of the Sisters of Charity of Australia serving as a Congregational Councillor and in the immediate past as Congregational Leader. She is a graduate of the University of Sydney and the Australian Catholic University. Her ministry experience includes education, governance and administration, serving on both education and health boards within the Sisters of Charity and other Religious Institutes and as a member of the Stewardship Board of Catholic Health Australia.

David Robinson resides in Sydney. He was educated by the Sisters of Charity and the Christian Brothers and is a graduate of the University of Sydney. David is a Chartered Accountant and a Company Director. He has been involved with the Sisters of Charity since 1989, serving on education boards and other committees and is currently Chairman of the Congregation’s Advisory Finance Committee.

Mary Aikenhead Ministries will invite Sisters of Charity of Australia to contribute their presence, experience, involvement, wisdom and spirituality for as long as Sisters are willing and able.

Sister Linda Ferrington, RSC was born in Sydney and educated by the Sisters of Charity and has been engaged in the ministry of education in various ways for the last thirty years.

Linda was a Trustee of Sisters of Charity Australia for six years while a member of the Congregational Council and has been involved in Governance since 1992. She has served on Education and Health Boards with the Congregation and the wider Church. Linda is Director of the Institute for Mission which is responsible for Adult Faith Formation in the Diocese of Parramatta.

VCCRI ANNUAL REVIEW 2009 59.

VCCRI SUPPORTERS •••

You too can help us conquer the ravages of heart disease by supporting the VCCRI.

Please call the Fund Development Office on 1300 842 867.

Printing donated by Offset Alpine Printing Paper donated by Spicers Paper Photography donated by Ian Barnes Photography

The Victor Chang Cardiac Research Institute 405 Liverpool Street Darlinghurst, NSW 2010 T +61 2 9295 8600 www.victorchang.edu.au

60. VCCRI ANNUAL REVIEW 2009

Designed and produced by www.stopedit.com.au

DISTANCE PER DAY THAT THE BLOOD TRAVELS AROUND THE

AUSTRALIA’S NUMBER ONE

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HEART ATTACKS WITHOUT

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LIFE EXPECTANCY OF

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