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1994 Annual Report

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The

urdoch Institute for /? esearch into

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'll The Murdoch Institute is devoted to advancing knowl edge about genetic diseases and other types of birth defects so that prevention may become possible in the future. The basic research of the Institute finds practical expressions through its clinical arm, the Victorian Clinical Genetics Service, which provides a network of services throughout Victoria available to persons of all ages. The close integration of research and clinical service has provided a rich source of research ideas and prompt implementation of new knowledge.

During its short history of nine years the Murdoch Institute has made important scientific discoveries, achieved recognition as one of Australia's top medical research centres, the premier training centre of clini cal geneticists, and established a network of clinical services which is serving as a model to other countries and states. The generous founding gifts of the Murdoch family, the late Sir Jack Brockhoff and other supporters set the Institute on a sound footing. Many of these generous friends still continue their support, but the Institute desperately needs further supporters to complete the final stage of its establishment - alter ation of space purchased at the Royal Children's Hospital to expand its laboratories and clinical facili ties to the size required. }

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The

Birth defects kill or maim 1 in 50 babies.

Scientific Director: Professor Bob Williamson

The strain on families is enormous. The cost to the Australian community exceeds $2,000,000,000 a year. Research into the genetic causes of birth defects is starting to reduce these figures.

Deputy Scientific Director: Dr. R.G.H. Cotton

The Murdoch Institute needs your support every year to maintain the momentum of research into these genetic conditions. The Institute needs special support to complete its process of establishment by developing laboratories and other essential facilities, at a cost of over $5 mil lion.

Would you please give generously now. tions are tax deductible.

All dona

If you cannot give now, consider helping The Murdoch Institute through a bequest. The following is a suggested form for a bequest to the Murdoch Institute. I bequeath to The Murdoch Institute for Research into Birth Defects the sum of $ ... (or part or all of residue of estate) to be applied for the purposes of the Institute. Eor further information contact the Business Manager, The Murdoch Institute for Research into Birth Defects Royal Children's Hospital Flemington Road, Parkville, Victoria 3052 AUSTRALIA

Telephone: (03) 9345 5045 Fax: (03) 9348 1391

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urdoch Institute

BOARD OF DIRECTORS Mr. L.G. Cox, Chairman Professor J. Angus Dr. C.L. Barnes Mrs. J. Calvert-Jones Dr. R.C.H. Cotton Mr. I. Davies Mr. J.A. Fitzgerald Mr. P. Criffin Mr. J.S. Cuest Mr. W.H. Hodgson, Deputy Chairman Mrs. A. McFarling Mr. A.S. Murdoch Professor C.B. Ryan Professor C.W. Tregear Professor R. Williamson FINANCE COMMITTEE Mr. L.C. Cox Mr. D.T. Craig Mr. P.J. Criffin Mr. C.E. Heeley Mr. D.E. Meikeljohn Mr. F.D. Ryan VICTORIAN CLINICAL GENETICS SERVICES Mr. C.P. Abbott Mr. L.G. Cox, Chairman Dr. C.L. Barnes Dr. J. De Campo Mr. J.S. Guest Mr. W.H. Hodgson Mr. C.E. Heeley Professor R. Williamson

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urdoch Institute onors to the

Founders - Donors of $1 million or more. The Murdoch Family: Dame Elisabeth Murdoch Mr. Rupert Murdoch Mrs. Helen Handbury Mrs. Anne Kantor Mrs. Janet Calvert-Jones The late Sir Jack Brockhoff The Brockhoff Foundation The Scobie and Claire Mackinnon Trust Benefactors - Donors of $250,000 or more The Danks Trust The Miller Foundation The Helen M. Schutt Trust Trustees - Donors of $25,000 or more Arthur Andersen Foundation Coles Myer Limited Professor D.M. Danks H. & L. Hecht Trust J.B. Were & Son Charitable Foundkion Mrs. Joan Roxburgh Mrs. M.L. Griffin National Australia Bank Limited Qantas Repco Corporation Limited (Ariadne) The Broken Hill Pty Ltd The Danks Trust The Friends of the Murdoch Institute The Ian Potter Foundation The late Mr. Clive Roxburgh The late Mrs. L.B. Quayle The Morris Family Trust The News Corporation Limited The Percy Baxter Charitable Trust The Sidney Myer Fund

Corporate sponsor group - Corporations under taking substantial future support

urdoch Institute 1994 onations to the

$ The Jack Brockhoff Foundation 375,000.00 The Danks Trust 250,000.00 The Scobie & Claire MacKinnon Trust 100,000.00 Professor David Danks 52,630.94 The Miller Foundation Ltd 50,000.00 National Australia Bank 35,000.00 The Friends of the Murdoch Institute 26,500.00 Mrs. Joan Roxburgh 25,000.00 Mrs. H. Handbury 20,000.00 Potter Warburg Ltd 10,017.28 H. & L. Hecht Trust 10,000.00 Morris Family Trust 10,000.00 Windermere Foundation 10,000.00 J.B. Were & Son Charitable Fund 5,000.00 Bonorge Pty. Ltd. 2,504.91 J.K. & J.E. Little 2,000.00 Roxburgh Foundation (Uncle Bobs Club) 1,971.75 Tambo Country Deli & Cheeses 1,700.00 Dr. R. Cotton 1,539.00 Mr. & Mrs. G. R. Stephenson 1,500.00 Mrs. N.B. Ganter 1,000.00 Mrs. B. Burzak-Stefanowski (Petra Foundation) 1,000.00 Dr. J.M. Gooch 1,000.00 Mr. Geoffrey E. Heeley 1,000.00 William Anglis Victorian Charitable Trust 1,000.00 McMullen Nominees Pty. Ltd. 900.00 Mr. F.D. Ryan 600.00 Mr. & Mrs. S.F. Gooley 600.00 Little Peoples Association of Australia 500.00 Metal Manufacturers Ltd 500.00 Coltmans Solicitors 500.00 Mr. Kenneth J. Redman 300.00 Mawbray College 248.00 Mr. & Mrs. K. Troon (Emma Ritchie Trust Fund) 200.00 Mrs. G.L. Cuming 200.00 Mr. & Mrs. M.J. Martin 150.00 100.00 Mr. & Mrs. 1. Ochiltree Dr. John M. McNamara 100.00 100.00 Mrs. M. Stewart

Mr. Tony Larkin Robyna Calisthenic College Mr. W. McLaren James A. McLellan Pty. Ltd. Mr. M.D. Pertile Mrs. G.A. Grimwade Dame Patricia Mackinnon Mr. & Mrs. L.R. Mills Dr. L.l. Taft Mr. H.G. Hollole Mr. & Mrs. A.C. Walsh

100.00

92.00 50.00 50.00 50.00 50.00 50.00 50.00 25.00 25.00 25.00

The Institute thanks all those listed for their generous support

The Broken Hill Pty Ltd National Australia Bank Limited

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chairman's Report

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Professor David-M. Banks

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Scientific Meeting

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Director's Report

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Professor Robert Williamson

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Report on the VCGS

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Research in Progress

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A New Method to Detect Faults in Genes

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Staff

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^^hairman's /? eport

mined as David Danks to maintain and build on the existing close relationship between the Institute and the Victorian Clinical Genetics Service.

In 1991 as Professor David Danks led the Institute in its preparation for the NFH&MRC Quinquennial Review of our Block Grant, he realised that his normal date of retirement in 1996 would coincide with the date of the next review. In true David Danks style he saw the need for his successor to be in place well ahead of that review and hence the process of seeking a new Director began. During 1994 a Selection Committee, representing the Institute and the University of Melbourne, considered and interviewed a number of applicants from within Australia and overseas, and appointed Professor Robert Williamson, Professor of Biochemistry at St Mary's Hospital Medical School in London as the next Director of the Institute. As Professor Williamson was able to take up the appointment in April 1995, David Danks elected to advance his retirement to March 31, 1995. On behalf of the Board and all associated with the Institute I wish to thank David Danks for his energy and determination which initially led to the establish ment of the Institute, and then its strong growth in recent years. We have all gained great benefit and enjoyment from working with him over these years and greater detail on his career and role in establish ing and directing the Institute is set out later in this report. The Board has been most impressed by Professor Williamson's great energy and breadth of knowledge and we look forward to working closely with him in the next phase of the Institute's development. 5ome changes are inevitable as we are moving from a "Founding Director" to a Director who we have recruited and is scientifically rather than medically trained. Although there is this difference we are delighted to find that Bob Williamson is just as deter-

The 1994 setback in financial markets made funding of the Institute an even greater problem than usual. Unfortunately our investments showed a negative return for the year, although performance since estab lishing our fund in 1986 has still been very positive. We are therefore very pleased to learn of recent deci sions by the Murdoch family, the Miller Foundation and the Directors of the Brockhoff Foundation to con tinue their generous support of the Institute. The Murdoch family have undertaken a further donation to $250,000 for the 1994/95 year and Dame Elisabeth has personally pledged a huge sum of $470,000 a year for the following three years with the particular purpose of ensuring that Professor Williamson's own work can be established satisfactorily. The Miller Foundation has extended their annual support at the level of $50,000 a year for an indefinite period, and the Brockhoff Foundation has promised a generous allocation of $250,000 for 1995 and will talk about further support when Professor Williamson has settled into his role. The Danks Trust has been a significant contributor to the Institute since its foundation and has contributed a further $250,000 to coincide with David Danks' retirement in order to endow a Postgraduate Scholarship for a PhD student at the Institute. David Danks has also added funds accumulated to his cred it in the Special Purposes Fund over his career. People are the key to the success of any organisation and on behalf of the Board I would like to congratu late David Danks and all his colleagues for the mag nificent contribution they have made during 1994 and wish everybody a successful future under the leader ship of our new Director.

Laurence G Cox Chairman

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rofessor

avid

^Jenetics Towards2000

anks

Founder and Director of Murdoch Institute, 1986-95

Professor David Danks AO, the Founding Director of the Murdoch Institute retired at the end of March 1995, concluding a notable career in Paediatrics, Human Genetics and Medical Research. The greatest of Professor Danks's many achievements was the establishment of the Murdoch Institute in 1986. His own personal research interests focussed on inborn errors of metabolism including phenylke tonuria. It was Professor Danks who recognised that copper deficiency was the basis of Menkes disease. The team he built around him to work on copper defi ciency went on to be one of the three teams which simultaneously reported the cloning of the Menkes gene. Professor Danks returned to Melbourne in the early 1960's after post-graduate training in genetics and paediatrics at Newcastle-upon-Tyne, London and Baltimore. He returned to the Royal Children's Hospital to a joint appointment as a paediatrician and research fellow in genetics in the Clinical Research Unit, and from here he developed the research group which was to form the nucleus of the Murdoch Institute. Known originally as the Genetics Research Unit, it expanded and achieved independence as the Birth Defects Research Institute in 1981 following a most favourable report from an international peer review conducted by Professor Cedric Carter of London, Professor Leon Rosenberg of Yale and Professor Chev Kitson of Brisbane. The Birth Defects Research Institute was short-listed as a Commonwealth Research Centre of Excellence late in 1981 and awarded an NH&MRC Program Grant in 1982. Following a successful fund raising drive in

1984/85 which resulted in an initial capital raising of $9M (including $5M from the Murdoch family) the Murdoch Institute for Research into Birth Defects was formerly established in May 1986, receiving an NH&MRC Block Grant in November 1986. Throughout this period Professor Danks had a contin uing association with the University of Melbourne first as a Reader in Human Genetics (1967-75) then as the Stevenson Professor of Paediatrics (1975-1982) and finally as the Professor of Paediatric Research (19821995). The establishment of the Victorian Clinical Genetic Services in July 1988 was the culmination of Professor Danks's vision of a network of clinical genetic services side by side with a genetics research institute in the State. The VCGS brought together the major compo nents of an integrated genetics service - newborn metabolic screening tests, clinical diagnostic work, cytogenetics, biochemical and DNA laboratory tests, and genetic counselling. Professor Danks's diverse interests included the application of modern tech nologies and lead to the development of the POSSUM/OSSUM computer systems for the diagnosis of birth defects syndromes, which is now sold in over 50 countries.

SCIENTIFIC MEETING HELD TO HONOUR PROFESSOR DAVID M. DANKS, AO ROYAL CHILDREN'S HOSPITAL 16TH - 17TH MARCH 1995 This conference was held to mark the retirement of Professor Danks as Director of the Murdoch Institute and the Victorian Glinical Genetics Services. It attract ed several important overseas and interstate visitors, including three world renowned geneticists, Professor Victor McKusick, (Johns Hopkins Hospital, Baltimore), Professor Malcolm Ferguson-Smith (Gambridge University) and Professor Charles Scriver (McGill University, Montreal). Professor McKusick gave the inaugural David Danks Oration, "OMIM: A genetics knowledgebase in the service of clinical medicine and the human genome project".

ing current work and looking towards future develop ments in human genetics. Most of David's colleagues from genetics units and departments around Australia were able to attend and the Ella Latham Lecture Theatre was full at all times. Video facilitates in an adjacent meeting room were arranged in order to cater for those who were unable to find a seat in the Lecture Theatre.

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Meeting registrants, Institute staff and special guests and friends of David's and the Murdoch Institute were present at a dinner held to honour him in the Great Hall of the National Gallery of Victoria on Thursday 16th March. Tributes to David's lifelong contribution to clinical genetics were made by Dr. Dick Cotton, Dr. John Rogers and Professor Victor McKusick. Among the guests to celebrate this occasion were Dame Elisabeth Murdoch, her grandson Mr Lachlan Murdoch, many other members of the Murdoch fami ly, members of tbe Brockhoff Foundation, and Mr. Noel Miller and his family.

The scientific sessions were based on the major research interests of the Murdoch Institute, highlight-

Professor Danks has had a major influence in the development of clinical genetics and genetic research in Australia. His efforts in establishing the Murdoch Institute and the Victorian Clinical Genetics Services have been honoured by many awards including the Gold Medal of the Royal Children's Hospital in 1989 and the Order of Australia in 1990.

t. From left:

Victor McKusick, Charles Scriver, David Danks, John Rogers, Malcolm Ferguson-Smith

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irector's Ri eport

An important event of 1994 was the appointment of Professor Robert Williamson as Director of the Institute, following my retirement on March 31, 1995. By the time this report is published the changeover will have occurred, on April 3, 1995. A more detailed account of Professor Williamson's career will be found on page 8. He has been one of the most notable contributors to the development of the disci pline of human molecular genetics in Britain; notable for his skill in selecting and training outstanding young scientists and for anticipating new directions in the development of human genetics. Naturally, the long process of selecting the new Director has had an influ ence upon the day to day working of the Institute, causing some anxiety about future directions and pri orities. Now that the matter is settled staff feel more able to get on with their projects, comfortable that they have a new leader who shares their aspirations and approach to research in human genetics and the provision of high quality genetic services. The conversion of the North-West Wing of the 10th Floor into laboratories is about to commence and will be well underway by the time of the Annual General Meeting. The area will house the DNA Diagnostic Laboratory, the Cytogenetics Laboratory, the Newborn Metabolic Screening Laboratory and a new research laboratory. The convergence in technology between DNA diagnostic work and cytogenetics has been remarkable during the last few years and the way that these two groups of scientists will be housed together in shared laboratories will encourage further conjoint development. This integration could not have been imagined 3 or 4 years ago. It is possible because of the flexibility of thinking that Dr Sue Forrest and Dr Howard Slater have shown during the planning stages, and the skill of Mr Barry Holt and Dr Dick Cotton in guiding the planning. Dr Andy Choo has also played an important role over the last 5 years in building

bridges between molecular genetics and cytogenetics. The research laboratory area will be suitable for Professor Williamson's own particular interest in gene therapy, but would be equally suited for any of our major research groups if a re-location of groups should prove more appropriate. These alterations will cost $1.34 million and include many items of laboratory equipment which were not included in the previous initial estimate of $1 million. Unfortunately our financial situation has deteriorated over the intervening year since we determined that this alteration should go ahead. In common with most investment funds we experienced a negative yield on our investments in 1994. In addition, there will be a number of new costs in both the Institute and the Clinical Service associated with the change of Director. The Board was facing a very tight budgetary situation for 1995, but still decided that it must go ahead with the alterations. Without them, the Institute could not maintain its present level of activity, let alone expand. Once again the generous support of our major donors, especially the Murdoch Family, has eased the problem. Dame Elisabeth Murdoch has pledged wonderful new support - $470,000 in each of the years 1995-97. The Brockhoff Foundation will continue its support in 1995 with a $250,000 contribution towards the research laboratory in 10 West and the Miller Foundation has agreed to continue its present level of support for an indefinite period. We are most grateful to all these wonderful people. We are pressing the Victorian Government for a contribution to the cost of the diagnostic laboratories. In the 1993 report we talked at length about the importance of DNA diagnostic testing in a variety of adult onset genetic diseases. This whole subject has moved ahead quite rapidly in the last 12 months, especially in relation to inherited cancers. Four genes responsible for different inherited forms of colon can cer have been isolated by overseas researchers. One gene (BRCA1) responsible for inherited breast and

ovarian cancers has been isolated with a second (BRCA2) identified but not yet isolated. These discov eries have attracted great media attention and urgent discussions about development of testing and coun selling are going on in various Anti-Cancer Councils around Australia, in State Health Departments and in the Australian Cancer Network. The Victorian Clinical Genetics Service has a strong role to play in this activ ity, especially in genetic counselling and in the organ isation and integration of services. This topic is dis cussed further in the section devoted to the Victorian Clinical Genetics Service on page 10.

when he returned to Melbourne in May to help in the care of our patients with metabolic diseases. He trained with us in the 1980's and then went to Montreal before returning to take up a position as the sole clinical geneticist and metabolic physician in Brisbane. The workload proved overwhelming and he decided to accept our offer of moving to Melbourne. We would have liked him to come on a permanent basis, but are most grateful for the fact that he is help ing us out for 18 months. We have satisfactory plans in place to cope with the work over the next two years.

The establishment of the Metropolitan Hospitals Planning Board by the Victorian Government has pro vided an opportunity for us to express these views in an appropriate manner. In our research laboratories, the work of the groups led by Dr Julian Mercer and Dr Jim Camakaris (Department of Genetics, University of Melbourne) on the Menkes disease gene has pro gressed well and Dr Andy Choo's group has made fur ther steady progress towards isolating the crucial DNA components of the chromosomal centromere. We were all pleased to hear that Julian Mercer had been appointed a Principal Research Fellow of the NH&MRC - a well deserved recognition of his many years of excellent research on the molecular genetics of copper transport. This brings to four the number of our senior scientists holding personal Research Fellowships from the NH&MRC. Dr Cotton's paper on mutation detection by enzyme cleavage of DNA mismatch attracted editorial attention in most of the major scientific journals when it appeared in the Proceedings of the National Academy of the USA in January, 1995. The realisation that speedy and cheap methods of detecting mutations must be capable of detecting all possible mutations has redirected interest towards his previously described chemical cleavage method, as well as focusing attention on his new method. One or other may yet achieve general accep tance. This subject is discussed in our feature article in this Report.

Professor David Sillence, Head of Clinical Genetics at the Children's Hospital, Camperdown, Sydney, is on sabbatical leave in the Orthopaedic Research Unit of the Research Foundation and the Institute. A world expert on genetic bone dysplasias, and one of our past trainees, he has been collaborating for many years in the production of OSSUM, our computer/laser disk information system on these conditions, and it is good to interact with him on a daily basis.

We were very pleased to welcome Dr Jim McGill

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The new combined POSSUM/OSSUM Version 4.0 was very well received at the Annual Meeting of the American Society of Human Genetics in Montreal in November, but not released to our subscribers until just before Christmas. It is too early to be certain of the commercial success of the new version, but the

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rate at which we are receiving orders is very hearten ing. If it is as successful as we hope, then we will move on to a major technical revision of the system, integrating the systems completely, rather than just combining them, and exploring the possibility of con verting it to an on-line system through Internet.

all Members of the Boards and Investment Committee. Of course, the wonderful opportunities of the last 10 years would never have existed, but for Dame Elisabeth's second intervention in my career as the Institute's Patron and principal financial supporter, along with her very generous family.

Once again the Friends of the Murdoch Institute (President Mrs Ann McFarling) have continued their excellent work in putting the name of the Murdoch Institute before many members of the public and rais ing funds for our work in the process.

I was also very fortunate to meet the late Sir Jack Brockhoff (whom I knew only too fleetingly) through Dr James Guest and am most grateful to them, the other Directors of the Brockhoff Foundation, Mr Noel Miller and his family, the Trustees of The Scobie & Claire Mackinnon Trust, Mr Darvell Hutchinson and other Trustees of the Helen Schutt Foundation and our many other individual and corporate supports. These I have singled out because without them my career would never have developed as it did and the Institute would not exist.

This will be my last report as Director of the Institute and it is hard to know where to start in thanking the very many people to whom I am indebted. I cannot hope to thank everybody who has contributed, but I must identify a few people to whom I owe special gratitude. Dr Howard Williams and Dame Elisabeth Murdoch played the most important roles in setting me on a career in research, and genetic research in particular. Dr Williams influenced me greatly as a stu dent, resident and research registrar, and later after my return to Melbourne, helping me to realise that med ical research was the career I wanted. He also encouraged me to look at genetics as one of several possible new disciplines to enter when I went over seas in 1959. Dame Elisabeth's strong support of research and innovation as President of the Committee of Management of the RCH created an atti tude which made it possible for me to receive finan cial support for training in clinical genetics in London. Dr Cedric Carter and Professor Victor McKusick, my guides through the mysteries of genetics and my long term friends, were the next to play important roles. Dame Patricia Mackinnon was a great supporter dur ing my years as Stevenson Professor of Paediatrics and later as Director of the Research Eoundation and in the establishment of the Murdoch Institute. Dr Dick Cotton was an exciting colleague and intellectual sparring partner, especially in the period 1968-87. Mr Neil Walford and Mr Laurie Cox have provided friend ship and guidance, as Chairmen of our Board, as have

Nor would it have been possible without the continu al support and tolerance of my wife, June. Many, many others have contributed to making the Institute develop well - the most notable among these have been our Business Manager, Anne Cronin, and Laboratory Manager, Barry Holt. It is difficult, to know where to start and where to stop in acknowl edging individual contributions to research and clini cal work and invidious to try. I did actually try, indeed I tried several approaches - naming the key people in our major project areas and adding a few well chosen comments, listing all substantial contrib utors to the research and clinical activities - none seemed to really work. So, in the end, I will just thank most sincerely all those colleagues who have let me share their successes and their frustrations over the last 33 wonderful years as we have together built an inter nationally significant research institute and a very effi cient network of clinical services.

David M. Danks

Robert W/iilliamson

DIRECTOR OF THE MURDOCH INSTITUTE 1995 Professor Robert Williamson, previously Professor and Head of the Department of Biochemistry and Molecular Genetics at St. Mary's Hospital Medical School, University of London commenced as Director of the Murdoch Institute for Research into Birth Defects in April 1995 following the retirement of the founding Director, Professor David Danks. Professor Williamson is a scientist of outstanding international reputation in human genetics and mole cular biology and one of the leading world figures in the field of gene therapy. He was one of the very first scientists to clone a human gene, the beta globin gene, in 1978. Using the newly developed molecular techniques he went on to study diseases such as Duchenne muscular dystrophy, cystic fibrosis, myotonic dystrophy and Friedreich's ataxia, child hood diseases caused by the dysfunction of a single gene. More recently his research interests have turned to multi factorial and polygenic diseases such as hypercholesterolaemia, cleft palate and spina bifida, and Alzheimer's disease. Professor Williamson has always worked in close col laboration with clinicians to apply his research find ings. He initiated the first diagnostic use of DNA analysis of chorion villus samples for the prenatal diagnosis of the muscular dystrophies, cystic fibrosis, and Friedreich's ataxia. This was followed by the introduction of presymptomatic diagnosis and carrier testing for these diseases. He is one of the editors of the new Journal, Gene Therapy and a collaborator in a number of clinical trials of somatic gene therapy cur rently in progress. His intention is to set up his own

research group at the Murdoch Institute as soon as possible to combine these researches, especially into the use of genes for therapy, which he sees as a promising route for the treatment of children's dis eases. Prior to his appointment Professor Williamson also held the position of Deputy Dean at St. Mary's Hospital Medical School, was a member of the Steering Committee of the Cystic Fibrosis Genetic Mutation Consortium, a member of the AFRC Plant and Genome Analysis Board, and many MRC and Wellcome Trust Committees.

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In recognition of his outstanding reputation in the field he was awarded the Wellcome Award in 1983, the prestigious King Eaisal prize for medicine in 1994 and the Belgian Eranqui Award for 1995. Professor Williamson has published over 300 papers in refereed journals. The Board and staff of the Institute welcome Professor Williamson and look forward to working with him in this new and exciting phase in the growth of knowl edge of genetics.

i Professor Bob Williamson

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eport on the

vccs

The appointment of Professor Williamson, a scientist, not medically qualified, as Director of the Institute made changes necessary in the Clinical Service. The Board has appointed Professor Williamson as Executive Director, Dr Agnes Bankier as Director of Clinical Services and Dr Les Sheffield as Director of Education and Training. This seems to have been a year of endless discussion and debate about genetic services, especially services relating to inherited cancers and the new executives will be kept busy with continuing debate in the next year. The media attention given to the discovery of four different genes which can cause inherited colon cancer and two genes concerned in hereditary breast cancer has led to a flurry of activity in various hospi tals, in Anti-Cancer Councils in each State and in national cancer bodies. We have been taking a consistent line through all of these debates. We argue that every hospital that treats substantial numbers of patients with colon or breast cancer will need to set up special clinics to give advice to families with multiple affected members, to identify true hereditary cancers and help the families who have these problems. The need for personal ser vices to patients to be available in every hospital does not mean that every hospital needs to be able to do all of the gene tests that will be required. Quite the con trary, it will be much more efficient and economical to set up just a small number of laboratories and to ensure that between these laboratories there is no duplication of tests for any one cancer gene, at least until a great deal of experience has been accumulated or a huge workload has been identified. Blood sam ples from patients are easily transportable from one laboratory to another. We are arguing that clinical geneticists have a great

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deal to offer in the establishment of the clinics that will be needed and that, in general, these clinics should be staffed by oncologists with a special interest in familial cancers, cancer counsellors, genetic coun sellors and clinical geneticists, each in numbers appropriate to the workload. The system that we have established in the VCCS of a central organisation that employs the clinical geneticists and genetic counsel lors, and seconds them in appropriate numbers to the various hospitals where their services are needed, will prove just as efficient in dealing with hereditary can cers as it has for the genetic diseases of childhood.

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The very recent establishment of the Metropolitan Hospitals Planning Board, with a charter that includes giving advice on the most efficient way of introducing major new technologies into the health system, has given us an excellent opportunity to argue our case. One serious concern is that the excitement about inherited cancers may lead the major adult hospitals to ignore the 10 to 15 other important genetic diseases of adult life, diseases that cause progressive brain, muscle, kidney or liver disorders. These are what one might call the classical genetic diseases of adult life which are passed from generation to generation and cause symptoms only at an age when most people are finishing their families. Earlier presymptomatic diag nosis provides the opportunity for these people to know about their condition before they start a family and, in many, there are treatments which will delay, or even prevent, the onset of symptoms. We calculate that work with these conditions in each adult hospital would occupy a full-time genetic counsellor and a half-time clinical geneticist for the next 2 or 3 years and could efficiently overlap work with inherited can cers. After the backlog of families has been worked through the workload will drop to quite low levels. The same will happen with hereditary cancers, but the scale of work will be 5 to 10 fold greater. Considerable technical advances are needed to render a full scale attack on inherited cancers affordable. The Murdoch Institute researchers are among the leaders

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in making these technical advances. During the year our new clinics at the Royal Melbourne Hospital and St Vincent's Hospital finally commenced. Unfortunately we are only able to send Mac Gardner and Mary-Anne Young to each of these hos pitals for one half day a week and they can i spend only the miniI mum additional time ' needed to deal with the

Mary-Anne Young

patients seen in that half day. Already we are building up substantial backlogs of family members to be seen.

& Mac Gardner

At the Royal Melbourne Hospital the principal inter actions are with neurologists, especially Dr Elsdon Storey, and with gastroenterologists and colon cancer surgeons. The particular focus in colon cancer is upon familial adenomatous polyposis (FAP) a precancerous disease which has long been known to be inherited from generation to generation and to be identifiable by colonic examination. The big defi ciency of the past approach has been the difficulty in proving that a family member does not have the dis ease - colonic examinations at one or two yearly inter vals were required for 10 or 20 years. Now with the gene test we can make this decision by a single blood test performed at any age. In practice it is usually appropriate to do the test in the mid teens, the age at which colonic examinations have traditionally started.

At St Vincent's Hospital the principal relationships are with the neurologists (Professor Ed Byrne and col leagues) and a breast cancer surgeon (Mr Michael Henderson). Our researchers have collaborated with Professor Byrne for many years over a common inter est in mitochondrial diseases. Our clinic at Monash Medical Centre has also begun to work with breast cancer surgeons.The demand for our services is still increasing in the paediatric/obstetric field, especially at the Royal Women's Hospital. The demand for a

second genetic counsellor became so acute that a sec ond counsellor, Clara Gaff, has been employed with funds from the Hospital and fees paid by the privately referred patients. Tasmania is another place in which the demand for services is increasing faster than we can handle. We really need to be holding monthly clinics over there, but are having difficulty arranging the staff to meet this demand. Staffing of our service for metabolic diseases in babies and children was inadequate for 12 months until Dr Jim McGill arrived in Melbourne in May 1994. During this period Professor Danks had to cope with the whole work load on his own and it was cer tainly a great relief for him to have such a good col league with whom to share the work. Dr McGill trained in Melbourne and Montreal before attempting to cope with the whole load of clinical genetics and metabolic diseases in Brisbane single handed. Over a number of years the work load became quite impossi ble to handle and the State Government refused to heed his pleas for assistance until they found them selves with no staff at all after he moved to Melbourne. The situation there has been improved and he will probably return to V Brisbane at the end of ^ 1995. II meantime. Dr p'jfw.JI Maureen Cleary has ‘mv come from Manchester r to take over Professor Danks' share of the work load after his retirement. Other Maureen Cleary plans are being made for the & Jim McGill period of 1996 onwards. The Huntington disease service continues to feel the ben efits of the much improved DNA testing for this dis ease. The figures speak for themselves - 123 patients counselled and tested in the last 18 months, compared to 33 in the previous 3y2 years. We, and others, had felt that the rather low uptake of counselling and test ing by family members (less than 15%) might be indi cating that people really preferred not to know what

was ahead of them in regard to this disease. However, it is now apparent that the unsatisfactory nature of the previous test may have been a major factor. Family members start with a 50% risk of developing the dis ease and the previous testing could move this figure to less than 5% or greater than 95%, but never to 0 or 100%. The new test does achieve just this. In addi tion many family members who could not use the old test because key relatives were no longer alive, or would not cooperate, can now be tested. This experi ence is important as the prospect of testing families for inherited cancers approaches because the need for tests which are 100% diagnostic will be paramount in the diseases.

able DNA test has been available and all of these tests are conducted in our laboratory. Other DNA based tests that have been performed on a regular basis in the Cytogenetics Laboratory are those for the PraderWilli syndrome and Angelman syndrome, and for the Di George syndrome and related heart abnormalities. Prader-Willi syndrome and the Di George syndrome were particularly difficult to diagnose in the past because the clinical features were not always very clear cut, especially in younger children and because the previous chromosome method of diagnosis was positive in only a small proportion of cases. The Angelman syndrome is more readily recognised by a clinician.

The introduction of molecular techniques into the Cytogenetics Laboratory is continuing apace. The demand for testing of children with intellectual dis ability for the fragile-X mutation has been very heavy in 1994, partly because some surveys have been con ducted at Day Training Centres and Special Schools. The proportion of positive tests has been rather lower than previously. This may indicate that past testing has identified most of the families with this condition. Once that stage has been reached we would expect most new cases to be diagnosed prenatally or by early postnatal testing of new babies born into known affected families. Although the old chromosome test for fragile-X syndrome was not very good for detecting affected females it was very reliable in detecting affected males and had been in systematic use in Victoria since 1980. The number of families using prenatal diagnosis has increased since the more reli-

Our Metabolism/Enzymology Laboratory provides enzyme diagnostic tests and DNA analyses for defects in mitochondrial energy production. Experience is showing that these conditions are quite a deal more frequent than have been realised. This is partly because the range of clinical effects that these condi tions can produce is wider than had first been thought. This work began as a research project that has become a national clinical laboratory testing resource. The tests are complex and costly and there is no sign of new funds available from government sources so, with Health Department approval, we have begun to charge hospitals other than the RCH for these tests. Now that the testing has passed from a research phase into clinical diagnostic use, we have moved the DNA part of the work into the DNA Diagnostic Laboratory.

The Cytogenetics Group From left: Lynda Phillips, Ian Brooks, Anne Robertson, David Francis, Marie Thorpe, Howard Slater, Julie Garratt, Vida Petrovic, Sue Dale, Trent Burgess, Melissa Curtis, Catherine Vaux, Louise Hills, Lucille Voullaire, JIa Fang Shi, Ralph Oertel

Page 11

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■A

Research in P rogress

1 This section is written for our general readers to give them an idea of the research that is going on in the Institute. Our scientific colleagues may prefer to look at the more detailed project descriptions in the separate Research Studies volume.

A A

IThe Olive Miller Hrotein

I Research Group

Head:

Dick Cotton

Scientific Officer:

Ian Jennings

Postdoctoral Fellows:

Rima Youil Simon Hufton (from February)

Research Assistants:

Rania Horaitis George Makris (to January) Michelle O'Brien (to November)

PhD Scholars

MSc Scholar

Susan Ramus has completed her study of gene muta tions (faults) in PKU patients born before effective dietary treatment was available. She found both mutations in all but two patients and the final results confirm her preliminary findings of wide variation in the degree of intellectual disability in different patients with the same gene mutations. Similar conclusions are being reported in other genetic diseases and remind us that mutant genes act within a very com plex background of other genes and life time experi ences.

Susan Ramus Jeff Babon (from March) Tamara Gough

being achieved in collaboration between Ian Jennings and Dr Bruce Kemp from St Vincent's Research Institute. Our hope is that the results might show that one small part of the molecule is critical for its func tion and that this part alone might be used as a treat ment for the condition. We know that only about 510% of the normal amount of enzyme function is real ly needed to prevent the accumulation of phenylala nine in the blood which causes brain damage in this disease and we hope that a small part of the enzyme might retain enough activity to be useful in treatment. The traditional treatment with a complex diet is effec tive, but very cumbersome and costly. Unfortunately biochemical results obtained in our own laboratory argue that the minimum functional portion of the enzyme will still be too large to be used in this way, but ultimately the crystal analysis is needed to be sure.

Rania Horaitis, Susan Ramus, Simon Hufton, Rima Youil, Ian Jennings, Dick Cotton

Another project involves a careful study of an anti body which was made for a certain phase of the study of the PAH, but turned out to have properties that may be useful in cancer therapy. PAH requires another chemical which we call a co-factor to function prop erly and this co-factor is chemically similar to folic acid, an important cell nutrient. The antibody in ques tion interferes with the transport of folic acid into cells. A number of the best chemotherapy agents kill cancer cells by interfering with their ability to use folic acid and Dr Cotton thinks that this antibody might have a similar effect on cancer cells, depriving them folic acid. To be sure of this property it is necessary to analyse very carefully the way in which the antibody has its effect. Dr Simon Hufton is leading this work.

R ‘N

PTERIN ,

His 290

For a number of years one of the principal targets of our research has been to make sufficient quantities of the enzyme (PAH) which is at fault in phenylketonuria (PKU) for crystallographers to analyse its detailed structure. Crystal production is tantalisingly close to

The other major project in this laboratory involves the development of methods of detecting mutations in genes and is the subject of our feature article in this year's Report.

Glutamate ? His 285

From left:

I CHj- C—COOH PHENYLALANINE

NH,

A possible model for the active site of phenylalanine hydroxylase

j-i

Page 13

Page 14

.T'ii

iggigm::

Centromeres / Transgenic Mice

...a

Head:

Andy Choo

Scientific Officers:

Elizabeth Earle Anna Michalska (to July) Kerry Eowler (from August)

Postdoctoral Fellows:

Clara Gaff (to August) Michael Cancilla (from November) Helen Trowell (maternity leave since November) John Martyn (supported by AMRAD Ltd)

PhD Scholars:

Desiree Du Sart Camille McQuillan (to January) Paul Kalitsis Damien Hudson (from February)

Page 15

The principal aim of this research group is to identify the particular sequences of DMA which are responsi ble for the special function of the centromere of each human chromosome. The centromeres are specialised regions of chromosomes which cause pairs of chro mosomes to come together in the cell divisions that form germ cells (eggs and sperm) and enable spindle to fibres attach to the chromosome p-arm and to move the two chro mosomes of a pair apart along the Centromere spindle fibre at the end of cell division. Errors in this process cause conditions ci'flrm like Down syndrome. Eor several years Dr Choo's group has been analysing very carefully the repeated DNA sequences which make up the bulk of the region of a chromosome which can be recognised under the microscope as a centromere. They have shown that there is a definite pattern to the arrangement of large blocks of repeated DNA in this region and that this arrangement is spe cific to a particular pair of chromosomes and differs from the arrangements in most other chromosome pairs. They were interested to find strong similarities between the arrangements in those chromosome pairs which sometimes interact with one another erro neously. Unfortunately the large bulk of repetitive DNA also makes it difficult for scientists to find the smaller segments which are probably more critical in determining the way in which the centromere works. This expectation is based largely upon studies of cen tromeres of different strains of yeast. In one strain a quite simple sequence of just 125 base pairs is suffi cient to provide normal centromere function. In

another strain this smallest segment that is functional is about 100 times larger and contains a great deal of repetitive DMA. A patient whose chromosomes were studied because of mental retardation proved to have one chromo some which has lost its centromere. Another very small region of this chromosome appears to have assumed the function of the centromere and is per forming this function perfectly well without any errors occurring in cell division, yet it contains no detectable repetitive DMA. Elegant molecular manipulation has allowed a fragment of DMA about 50,000 base pairs long to be isolated from this region and Dr Choo is confident that the region that is causing this centromeric function must reside within this fragment. The next task is to find a way of testing blocks of DNA for centromeric function. All of the essential elements of a chromosome excepting a centromere will be put together and candidate fragments of DNA will be added. The regions of yeast chromosomes which are called centromeres were defined in this way, produc ing yeast artificial chromosomes (YACs) which repli cate satisfactorily for hundreds of divisions in yeast, even when they have had large fragments of human DNA inserted. However, they will not replicate in human cells. It seems very likely that insertion of a piece of DNA that contains the human centromere into a structure that contains all the other components of a human chromosome (which are available) should form a human artificial chromosome (HAC) capable of replicating in human cells, and perhaps in some other mammalian cells, but not in yeast. Another reason for developing HACs is that they may prove to be very satisfactory vectors for carrying into the cells of patients a normal human gene which might correct the harmful effects of some genetic disease (somatic cell gene therapy).

need for transgenic mouse work has increased greatly and we really want to have a laboratory in which a number of transgenic mice could be made each year for different research groups. Kerry Fowler, who was in charge of our Tissue Culture Laboratory a number of years ago, and has since been working extensively with transgenic mice technology at the Ludwig Institute, returned to the Institute to take over this role. Her initial projects are with Dr Henrik Dahl and Dr Andy Choo.

From left:

M Is

II"

David Zang, Paul Kalitsis, Elizabeth Earle, Damien Hudson, Desiree Du Sart, John Martyn, Kerry Fowler, Michael Cancilla, Andy Choo

It'd

During the year Dr Anna Michalska who was our expert in transgenic mouse production moved on to the Veterinary Research Institute where she will have more opportunity to develop her own projects. Our

’I

Page 16

dsmwmm^ ^

a Defects of S/iitochondrial Function i i

and Other Metabolic Studies

human mitochondrial disease into the mitochondria of transgenic mice.

are the ordinary nuclear genes like those that control the rest of the body and its functions. This dual genet ic control makes investigation more complex. Functional assays for the various components of the energy production system have been set up, plus methods of detecting those mutations in mitochondri al genes which have been described previously as the cause of clinical problems. The laboratory acts as a national reference centre for the diagnosis of these dis eases.

'■.ffiPIS

Senior scientists:

Henrik Dahl David Thorburn

Clinicians:

David Danks Jim McGill (from May)

Postdoctoral Fellow:

Rozanne Blok (Helen Schutt Fellow)

Scientific Officers:

Wendy Hutchison Denise Kirby

Research Assistants:

Clinical suspicion of a mitochondrial disease arises when functional abnormalities are present in 2 or more of the following organs - brain, muscle, heart. liver, kidney, retina or pancreas, or hearing defects. Another feature suggesting mitochondrial disease is gradual progressive deterioration over the years of childhood with episodes of more rapid deterioration associated with illnesses which stress the body such as viral infections. One particular pattern of disease observed in babies or young children, is known as Leigh syndrome, and a systematic study of 67 patients with definite Leigh syn drome or features which are suggestive of this diagno sis, but not definitive, resulted in a firm diagnosis of the underlying defect in 40% of cases. About two thirds of these were diagnosed by functional assays

From left:

Henrik Dahl, Rozanne Blok, Laraine Peters, Georgia Polidoros, Moira Graham, Wendy Hutchison

and one-third by examination of their mitochondrial genes. We now regard this phase of exploration of clinical features which can be caused by mitochondr ial diseases as no longer research, but are continuing to offer a clinical service. Our new research approach is to try to understand more about the dynamics of the balance between normal mitochondrial genomes and abnormal ones (heteroplasmy) in different cells and organs by trying to introduce the mutations found in

Abnormal Mitochondria Normal Mitochondria

Effie Tsostsis Kaye Seller

Cell Nucleus Random

PhD Scholar:

Laraine Peters

BSc Hons Scholar:

Georgia Polidoros

Mitochondria generate the majority of the energy that is available for cellular function. They are tiny organelles within cells which are most unusual because they have their own DNA molecules which encode 13 of approximately 100 proteins involved in the energy generating system. The remaining genes

During the year an unusual opportunity to study the problem of heteroplasmy arose. We had identified a particular mutation in the mitochondrial genome of three young brothers from New Zealand, all of whom had quite severe neurological disease. In their muscle cells the abnormal mitochondria were considerably more numerous than normal ones, although both were present. Studies of their mother's blood showed a small proportion of abnormal mitochondria among a majority of normal ones and she was quite healthy. The circumstances suggested that there was a high risk that any further children she might produce would be similarly affected and she therefore requested tubal ligation. She understood that scientists do not really understand how the balance of normal and mutant mitochondria can change from mother to children and suggested that we might be able to gain some knowl edge of this process if we were to ask IVF doctors in New Zealand to give her drugs to stimulate her ovaries to release multiple egg cells and harvest these egg cells at the time of performing her tubal ligation. This was arranged with the collaboration of Dr Debbie Cook, a world expert on egg manipulation from the Royal Women's Hospital. To our surprise all the eggs we tested showed either a very high or a very low pro portion of mutant genes. Now we have to work out a plausible explanation of this result.

From left: David Thorburn, Denise Kirby, Kaye Seller, Effie Tsostsis

Normal

Cell

Segregation

Severely Affected

Cell

Illustration of mitochondrial heteroplasmy. When a cell with normal and abnormal mitochondria divides, its daughter cells will contain varying levels of abnormal mitochon dria. Severely affected calls and organs are likely to have a high proportion of abnormal mitochondria.

Page 18 Page 17

ill

and both produce proteins of a very similar structure it seems likely that these two genes have evolved togeth er to suit the different needs for copper excretion in the liver and in the other body cells. The liver is the organ which controls the levels of copper in the body by varying the rate of excretion into the bile and it is not surprising that this organ should have developed a special method of copper excretion.

I he jcobie and C/a/re jVlackinndr Trace Element Research Group

Head:

Julian Mercer

Senior Associate:

Jim Camakaris (University of Melbourne)

Scientific Officer:

Andrew Grimes

Postdoctoral Fellows:

James Spencer (to August) Sharon La Fontaine (from December)

Research Assistants:

Sharon Horton Jenny Paynter (maternity leave from April) Paul Lockhart

Technical Assistant:

Leanne Bailey

PhD Scholars:

Loreta Ambrosini Michael Petris (from February) Michael Theophilos (from February)

Good progress has been made in identifying the muta tions in the various strains of mice that have distur bances of copper transport very like those in Menkes disease. All that have been studied adequately have

From left: Jenny Paynter Paul Lockhart Sharon Horton Sharon La Fontaine Michael Theophilos Andrew Grimes Julian Mercer

been shown to have mutations in the murine equiva lent of the Menkes disease gene. In Chinese hamster ovary cells rendered copper resistant by growing them in increasing concentrations of copper, as many as 100 copies of the gene have been found, conferring a greatly increased capacity for copper excretion. Other members of the group have worked out the exact structure and organisation of the gene.

.'A

Outline of copper pathway in mammals

Small ^ Intestine Transcuprein

albumin amino acids

Lysosomfi

This group continues to focus upon developing a full understanding of the copper transport proteins encod ed by the genes which are defective in Menkes disease and Wilson disease. The emphasis has been upon the Menkes disease gene which was first isolated in this laboratory three years ago. Since this gene is clearly involved in excreting copper from cells it was reason able to expect that increased levels of copper in the cell might stimulate production of the protein it encodes. This is not the case, nor is the production of the protein reduced in copper deficient situations. However, we have been able to show that the distrib ution of the protein within the cells is dramatically altered by copper loading and this raises a number of very interesting suggestions about the way the process of copper excretion may operate. Since the Menkes disease gene is active in all organs excepting the liver and the Wilson disease gene is active only in the liver

■A

Tissues /

illi mi

-Cu

T' T3S!

Cu out

Lysosome ceruloplasmin

;:X

Liver

GSH = glutathione WND = Wilson disease gene product MNK= Menkes disease gene product

Page 20 Page 19

■A

>■;

encountered and these took many months to resolve. However, the process is back in full swing again and more interesting results are expected in the near future. mmk

Technique Development in DNA

Embryology Group

Angelman syndrome are now routine as are the DNA methods for fragile-X syndrome. The fragile-X syn drome is common and about 800 children with intel lectual disability need to be tested each year. PraderWilli syndrome is less common, but equally difficult to diagnose with confidence without a specific test.

nd Chromosome Laboratories

> ■J

l'0l

Head:

Don Newgreen

Postdoctoral Fellow:

Susan Sevan

Research Assistants:

From left:

Richard Kerr Joseph Minichiello

Susan Sevan, Richard Kerr, Don Newgreen, Joseph Minichiello

The major project of isolating messenger RNA mole cules which are produced by neural crest cells at one stage in their migration, but not a few hours earlier or a few hours later, has progressed rather slowly during the last year. A number of technical difficulties were

Sfi

Leaders:

Conversion of embryonic epithelial cells to mesenchyme can be modelled in cell culture, and Involves a loss of a cell adhesion molecule (N-cadherin; green) and a gain of a specific carbohydrate (HNK-I; red). Cell nuclei are shown in blue.

Dr Howard Slater (Cytogenetics)

Work on a complex glycoprotein (protein with sugars attached) which seems to play an important role in keeping cells apart during certain stages of embryonic development, has also gone through a difficult stage, but is now progressing well again. Richard Kerr, who has been doing this work, has now enrolled as a full time PhD student. His current project will be very appropriate for this purpose. On the other hand, a project on the factors controlling transformation of epithelial cells into mesenchymal cells, an important step in the initial formation of dif ferent tissues and organs, has moved ahead well, joe Minichiello has developed a tissue culture assay with which he hopes to be able to define the individual chemical changes involved.

Dr Sue Forrest (DNA Diagnostic)

The tempo of discovery relevant to DNA diagnostic work continues its breakneck pace. Every week or two another disease-causing gene is isolated and the possibility of diagnostic testing for mutations arises.

Our staff have been remarkably successful in intro ducing new technical developments which have allowed the same number of scientists to process many more samples. We have recently learned from visiting overseas experts that our laboratory is proba bly the first in the world to get the recently described protein truncation test working in a true diagnostic mode for presymptomatic diagnosis of patients with familial adenomatous polyposis (FAR), an important precancerous disease.

From left:

StevenNasloulas, Susan Forrest, Karina Forshaw, Janet Shaw

Similar claims can be made by our Cytogenetic Laboratory which has been quick to incorporate DNA techniques into its daily use. Very efficient testing processes for the Prader-Willi syndrome and the V

Page 21

Page 22

Ji t- -i

fOSSUM/OSSUM

>1 sM:

mmmmmmssimim

David Danks Moshe Chemke David Si Hence

Staff:

Agnes Bankier Cathie Rose Sofia Mercer Anne Cronin

Version 4.0 which combined POSSUM and OSSUM for the first time was ready in time for display at the November meeting of the American Society of Human

Genetics. We had some disappointing delays over copyright permission from some publishers and with the production of the NTSC disc required for the US market. This delayed release of the system to our sub scribers until just before Christmas. Consequently, we do not yet know how many of our subscribers will take up the new system. The early sales are encour aging. In this first combined system we have really just put the two sets of pictures on the same video disc, loaded both programs and databases into the computer and made them accessible from a single menu. The user still has to move out of one system into the other in order to search the second database. In Version 5.0, we would like to merge the two systems completely with one operating program and one combined data base, but this will be expensive and we must be cer tain of the success of Version 4.0 before incurring this cost. We are also exploring the possbility of an on line database which can be updated continually and accessed worldwide.

from our reporting system as well as information avail able through the Victorian Birth Defects Register. Her supervisor, Professor Judith Lumley, was previously Director of this Register, a role which Jane herself is fulfilling on a part-time basis since Professor Lumley moved away from Melbourne. We congratulate Jane on obtaining her PhD and this acting appointment.

Jtudies Kelated ta r renatal

One interesting question that she examined was the factors which might determine whether women decide to undergo prenatal testing for Down syn drome or not. Some information which was initially available as a by-product of this study later bec*ame a major study in its own right - namely the analysis of the frequency of Down syndrome in women of vari For many years the Institute has accepted the respon ous ages who did not undergo amniocentesis. A care sibility for monitoring the performance of prenatal ful analysis of this data enabled Jane to develop the diagnostic tests in Victoria. The detailed monitoring best estimates yet available for the frequency of mis has been confined to the tests that involve fetal sam carriage of Down syndrome pregnancies between the pling, by amniocentesis and chorion villus sampling, time of CVS (10 weeks gestation), amniocentesis (16 without attempting to achieve a full assessment of the weeks gestation) and full term delivery. Those who effectiveness of diagnosis by obstetric ultrasound. have analysed prenatal diagnostic results have all This widely used approach has impacted upon our noticed that the proportion of pregnancy shown to be evaluation only when abnormalities observed on affected by Down syndrome by prenatal tests is high ultrasound led on to some forms of sampling fetal test. er than the frequency that used to be observed at term delivery before there were any prenatal tests available. The initial concern was over the safety and reliability Most have assumed that quite a number of the Down of tests when they were novel. These aspects have syndrome pregnancies identified by these tests would shown to be up to world standard and very satisfacto have terminated spontaneously if no action had been ry for many years and the focus has moved on to other taken, but there was also the alternative possibility questions such as utilisation and the impact upon the that some systematic change in the incidence of frequency of the diseases in the community. Ever Down syndrome had occurred during the years since since the 1970's Jane Halliday had these tests were introduced. Jane's results confirm that played a central role in these analy the former explanation is correct. The most recent ses and the data collection and iis analysis of prenatal diagnosis in Victoria, based on analysis of this information, i 1993 results, show rates of utilisation of testing for Obstetricians performing fetal « Down syndrome in older women which are mong the sampling procedures and the I ; ^^1 highest anywhere in the world, a quite remarkable laboratories to whom the sam- | result when one considers that we have never deliber pies were sent for testing con- I If ately publicised the availability of testing. In analysing iiilH tributed very generously to the « the 1994 figures attention will once again be focused work. Over the last three years ' on the complication rate because there has been a Jane has been undertaking studies widespread move to performing amniocentesis for at towards a PhD in epidemiology, 14 weeks gestation rather than 16 weeks. using some of the data made available

From left:

Back row Middle row Front row

Moshe Chemke, David Danks Sofia Mercer, David Sillence Cathy Rose, Agnes Bankier, Anne Cronin

■;

I 5

Jane Flalliday

K Page 23

Page 24

etect

ethod to

Safety of Drugs in Pregnane)

me. mmt m.

Dr Les Sheffield and Mr Ron Batagol, (recently retired from his position of Chief Pharmacist at the Royal Women's Hospital) are continuing their work towards developing a method of evaluating new and potent drugs that come into use in an obstetric practice for teratogenic effects on babies. They believe that it will be possible to use linkage of the computerised pre scription records of the major obstetric hospitals and the birth defects register to devise a simple and cheap method of monitoring for untoward effects of drugs upon the unborn baby. This would certainly be a great advance over the existing standards methods which are very tedious and expensive.

Our clinical geneticists are constantly alert for obser vations in individual patients or in families with genet ic diseases which may give new understanding of the disease concerned or its inheritance. A number of the ideas that arise in this way are worked over within the Institute or VCGS laboratories, but in some instances it proves more efficient to collaborate with an over seas laboratory which is already a leader in the research on the disease concerned. Examples of both types of activity are to be found in the scientific reports and publications accompanying this report.

Genes control the production of proteins in our bodles. Proteins are the making and doing molecules which give our body shape and strength and make it work. They make up the bulk of muscle, bone, skin and other organs and they control the biochemical reactions which make our bodies work, converting our foods into fuels that our cells can use to generate ene rgy and then converting this energy into mechani cal forces which allow our bodies to move. Even thinking depends on proteins. Inherited diseases are caused by faults (mutations) in genes which prevent the production of proteins or cause proteins to be improperly formed so that they do not function satis factorily. Our genes are generally passed faithfully from cell to daughter cell and from generation to generation with out any errors. Every time a cell divides a new copy of all the genes has to be made and new copies of all the genes are also required for every egg cell and sperm cell. Eaults (mutations) are rare, but can occur during the process of making a new copy of the genes or at other times.

The

■ e 'of yVfi Importance f

edition

From left:

Page 25

Back row - Jim McGill, Agnes Bankier, Mac Gardner Front row - Les Sheffield, John Rogers

utation

The possibility of identifying mutations in genes only started to become anything more than a dream a little over 20 years ago when scientists first learnt to isolate genes and examine them in the laboratory. Until 10 years ago the identification of a mutation in a gene was a major research project. During the last decade the methods of identifying mutations have improved

aults m

enes

immensely, making mutation detection a feasible method of diagnosis in some of those diseases, espe cially if the gene is quite small and in diseases in which most patients have the same fault in the gene. Unfortunately most genes are large and complex with hundreds of different mutations capable of causing a rather similar disease. At first the focus of mutation detection was upon the relatively rare genetic diseases of early childhood with the objective of offering couples prenatal diagnosis so that they could avoid the 1 in 4 risk present in future pregnancies after producing an affected child. Collectively these diseases affect nearly 1% of all births, but individually each of the thousands of dis eases is quite uncommon. In addition, the risk of fur ther children with the diseases is generally confined to those children of a particular couple and it may be dif ficult to justify the large amount of work that is neces sary to find a mutation in order to develop a test which will be used in just one or two pregnancies. Recently there has been a considerable increase in interest in mutation detection because the genes that are involved in many of the adult onset genetic dis eases have been isolated. There are 15 or 20 adult onset genetic diseases which are 5 to 10 times as fre quent as the individual paediatric genetic conditions and are inherited in a different way, so that there are generally 5 or 10 different family members who are at risk of having affected children. This means that a test developed for one member of the family will be used many times over. Although these adult onset diseases do represent a bigger "market" for mutation detection tests they incited only a moderate interest in this field. In the last 2 or 3 years it has become clear that among the thousands of adults who develop cancer each year there are several hundreds in whom the cause is an inherited fault in a single gene. Eaults in any one of five different genes can cause colon cancer. Two genes involved in breast cancer have been identified and several others are known to exist. Similar sub groups of inherited cases are found within melanoma

Page 26

and in cancers of the prostate, bladder, uterus, ovary, and lung. In each family with an inherited cause of cancer there will be 5 to 10 individuals who have inherited the gene and whose children will need to be tested, just as in the other adult onset genetic diseases. However, the demand fortesting of the mutations will be much greater than this because only mutation detection can really distinguish patients with inherited cancers from patients with forms of the disease that are not inherited. Ultimately we will need to test every patient who develops cancer. To be able to afford this approach we will need tests that are at least 100 times more efficient than the present ones. A fur ther problem is that most of these cancer genes are turning out to be very large and complex, and subject to many different mutations. Mutation detection is also a crucial component of most of the modern methods of identifying the genes causing the various genetic diseases. Scientists have developed rapid methods of localising the gene caus ing a particular disease in a certain family to a partic ular region of a chromosome. The next step of finding the responsible gene within this region of the chromo some and proving that it is the correct gene is more difficult. The ultimate proof that the correct gene has been isolated requires demonstration of mutations in each patient in the family and not in those without the disease. The task of finding a mutation is like search ing a 5 to 20 page long chapter of an instruction man ual for a typographical error. The classical method, called sequencing, reads each letter and compares it with the letter that should be present. Even though this technique has been automated it is still time con suming and also error prone, so that the process is just as likely to make an error as to find a mutation. To

Normal DNA

imiiniiiiiiii

Mutant DNA

llllllllllllllll M llllllllllllllll M

These difficulties have led to the development of scan ning methods in which segments of the sequence are compared with a normal sequence in a manner which only recognises the presence of a difference between the two. If a difference is found in a particular seg ment of a gene the scientist then can sequence just that segment to find the mutation. These methods are more rapid and cheaper than sequencing.

Methods

scanning

Mutations

fon

iiaiiaasii

The current methods fall into two groups - the physi cal methods which determine only whether a piece of DNA contains a mutation, and chemical and enzymic methods which not only determine whether a muta tion is present, but locate it approximately within the segment that has been assayed. The latter methods are also generally able to test longer stretches of DNA than the physical methods.

TTTTifhnTTnrM iiiiijjiiiiim

In 1985 when the first scanning methods were pub-

lished, they were only about 70% effective. During 1986 and 1987 Dick Cotton spent a sabbatical leave in Oxford where he worked with Dr Duncan Campbell and developed a new method of scanning for mutations based upon chemicals which can cut the DNA where there is a mismatch between the two strands. This method was published in 1988 and later patented, and was featured in our Annual Report in 1989. It is known as the Chemical Cleavage Method (CCM) and a number of improvements have been made in our laboratories over the intervening years so that it can now detect almost 100% of mutations and, indeed, detects each mutation in two slightly different ways, giving a double check on the result. Two prob lems deterred some laboratories from using the method - it involves a number of steps and consider able experience is needed to become quick at per forming the method, and the chemicals used are quite toxic.

Cologne, was thought to be a candidate. Dr Cotton and his associate, Dr Rima Youil, talked to Dr Kemper and started a collaboration which led to the identifi cation of this enzyme as very useful in mutation detec tion. A US company, set up specifically for the devel opment of mutation detection methods, has shown great interest in the method and a business agreement has been made over the further development towards an automated system.

Two recent developments have refocussed attention on this method in that last few months. The first has involved attaching the DNA that is being studied to magnetic beads allowing the reactions to be carried out in solution and the fragments of DNA to be sepa rated quickly. This reduces handling and lends itself well to automation diminishing the problem of toxici ty. Secondly an automatic sequenator has been used by a Paris group to study the reaction products more quickly and accurately. This French publication attracted the attention of the principal manufacturers of DNA sequenators and they are working to adapt their equipment to perform the test even more rapidly and cheaply.

We remain very hopeful that either the CCM or ECM may emerge as the standard method for scanning human genes for mutations with a particular application to genes cancers. causing inherited However, we must realise that it is a very competitive field with many scientists around the world trying to develop better methods of direct detection of mutations or else using a functional approach to the recognition that genes contain a mutation. Only time will tell which of these approaches is bet ter. Certainly there are many rea sons for needing a much better method than we have - at least 100 fold better.

To date the new enzyme cleavage method, although able to detect almost all mutations, has a small prob lem in that the detection signal is not strong with some mismatches between DNA strands. We anticipate finding ways of solving this problem. In the meantime the method has been applied to detect the mutations in cancer genes and also in some of the genes that cause childhood inherited diseases with which we are very familiar. P53 Mutation Detection

If there were one really satisfactory method for muta tion scanning it would be used in all laboratories and we would not need to talk about 5 or 6 current meth ods. Each of the current methods has some deficien cy, such as less than 100% detection of errors, a need for special equipment, a requirement for multiple tedious manipulations, an ability to scan only limited lengths of the gene or the use of toxic chemicals.

Own Research

Hybridization

Improperly zipped hybrids cleaved at bulge by chemicals or an enzyme Cleavage detected by size analysis

Page 27

overcome this problem it is generally necessary to sequence a gene at least twice.

.I..

Although CCM has many good features, the disadvan tages mentioned led Dr Cotton to look for less toxic chemicals or other methods that might be used to recognise the point at which the two strands of DNA fail to match. Other groups have examined enzymes which check newly synthesised DNA for errors and correct them, but these have not been satisfactory. One virus enzyme, 14 Endonuclease VII, being stud ied in a basic manner over 10 years by Dr Kemper of

The arrows indicate site of mutation

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Page 28 i-'”

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urdoch Institute 1994

Scientific Director:

Clinical Scientists

David Danks, A.O., M.D., B.S., F.R.A.C.P. (to 31 St March 1995) Robert Williamson, Ph.D.,FRCPath., Hon. MRCP, Hon.M.D. (Turku) (from 1st April 1995)

Agnes Bankier, M.B., B.S., F.R.A.C.P. John Rogers, M.B., B.S., D.C.H., F.R.A.C.P. Mac Gardner, M.B., Ch.B., M.Sc. F.C.C.M.C., H.G.S.A.C.C.G.

Deputy Scientific Director: Richard Cotton, B.Ag.Sci., Ph.D., D.Sc.

Business Manager: Anne Cronin, B.Sc., B.Bus.(Acc.), A.S.A., C.P.A.

Laboratory Manager: Barry Holt, B.App.Sci.(M.T.), A.A.l.M.L.S.

i Postdoctoral Fellows Susan G. Bevan, Ph.D. Rozanne Blok, B.Sc.(Hons.), Ph.D. (Helen M. Schutt Fellow) Michael Cancilla. B.Sc.(Hons.), Ph.D. Clara Gaff, B.Sc.(Hons.), Ph.D. (to 29/8/94) Jane Halliday, B.Sc.(Hons.), Ph.D. Simon Hufton B.Sc. (Hons.), Ph.D. Sharon La Fontaine. B.Sc. (Hons.), Ph.D. John Martyn, B.Sc.(Hons.), Ph.D. Anna Michalska, M.Sc., Ph.D.(Adelaide) (to 29/7/94) James Spencer, B.Sc.(Hons.), Ph.D. (to 1/8/94) Helen Trowell, B.Sc.(Hons.), Ph.D. Rima Youil, M.Sc., Ph.D.

Scientists (Senior)

Clinical Fellows

Richard Cotton, B.Ag.Sci., Ph.D., D.Sc. Jim Camakaris, B.Sc.(Hons.), Ph.D. K.H.A. Choo, B.Sc.(Hons.), Ph.D. Henrik Dahl, Ph.D. Julian Mercer, B.Sc.(Hons.), Ph.D. Donald Newgreen, B.Sc.(Hons.), Ph.D. Les Sheffield, B.Med.Sci., M.B., B.S., M.Sc., D.C.H., F.R.A.C.P.

Martin Delatycki, M.B., B.S., F.R.A.C.P. (Part 1) Catherine Rose, M.B., B.S.

Research Fellows Susan Forrest, B.Sc.(Hons.), D.Phil.(Oxon.) David Thorburn, B.Sc.(Hons.), Ph.D.

Richard Kerr, B.Sc. (Hons.) Denise Kirby, B.Sc.(Hons.) Paul Lockhart, B.Sc.(Hons.) George Makris B.Sc.(Hons) Helen McNeil, M.I.Biol. Sofia Mercer, S.R.N. Joseph Minichiello, M.Sc. Michelle O'Brien, B.Sc. (Hons.) (to 16/11/94) Jenny Paynter, B.Sc.(Hons.) Kaye Seller, B.App.Sci. Janet Shaw, B.Sc. (Hons.) Effie Tsotsis, B.Sc.

Ph.D. Scholars Loreta Ambrosini, B.App. Sci. Jeffrey Babon B.Sc.(Hons.) Desiree Dusart, B.App.Sci. Damien Hudson, B.Sc.(Hons.) Paul Kalitsis, B.Sc. Laraine Peters, B.Sc.(Hons.) Michael Petris B.Sc.(Hons.) Susan Ramus, B.Sc. (Hons.) Michael Theophilos B.Sc.(Hons.)

Editorial Assistant, Human Mutation Julie Cross, B.Ed.

Administration Sue Nash, B.Bus.(Acc.) (to Assistant Accountant: 4/11/94) Personnel Assistant: Debbie Zombolas Personal Assistant to the Director: Lee Jackson Receptionists: Fiona Keltie Olga Wilson Secretaries: Debbie Davis Valerie Mehl Kristine Yeomans

Accounts Clerk:

')■' ■

Christine Keenan Cathy McMillan

B.Sc.fHons.) Student

Photography/Graphic Design:

Georgia Polidoros, B.Sc.

Michele Winsor

Scientific Officers and Research Assistants 1

Leanne Bailey Tina Colgan, S.R.N. Marjorie Crawford, A.R.M.I.T. Elizabeth Earle, A.A.l.M.L.S. Kerry Fowler, M.App.Sci., M.Sc. Tamara Gough, B.App.Sci. Andrew Grimes, B.App.Sci. Joanne Hill, B.App.Sci. Ourania Horaitis, B.Sc. Sharon Horton, B.Sc., Grad.Dip.Diet. Wendy Hutchison, B.App.Sci.(App.Biol.) Ian Jennings, B.Sc.

Technical Assistants :S

■

Leonie Anastasiou Evelyn Boyer Robyn Breslin Sophie Gazeas Moira Graham Michelle Guneratne Catherine Quilici

Page 29

Page 30

;

■v

ictorian

enetics

ervices

Executive Director:

Scientists - Cytogenetics

Neonatal Screening Laboratory

David Danks, A.O., M.D., B.S., F.R.A.C.P. (to 31 St March 1995) Robert Williamson, Ph.D.,FRCPath., Hon. MRCP, Hon.M.D. (Turku) (from 1st April 1995)

Howard Slater, B.Sc., Ph.D., Dip.R.C.Path., H.G.S.A.C.C. - Scientist -in-charge Trent Burgess, B.Sc.(Hons.) Melissa Curtis, B.Sc. Sue Dale, B.Sc.(Hons.) Julie Davies, B.Sc., H.G.S.A.A.C. Dean Foster, B.App.Sc. (to 24/6/94) David Francis, B.Sc.(Hons.) Julie Garratt, B.Sc.(Hons.) Yvonne Harney, B.Sc.(Hons.), Ph.D. (to 15/7/94) Louise Hills, B.Sc. Arthur Ma, B.Sc., R.T.(C.G.), C.L.S.P.(C.G.) (to 29/6/94) Ralph Oertel, B.Sc., H.G.S.A.A.C. Vida Petrovic, B.Sc., H.G.S.A.A.C. Anne Robertson, B.Sc., H.G.S.A.C.C. Marie Thorpe, B.Sc.(Hons.) Cathryn Vaux, B.Sc. Lucille Voullaire, M.Sc., H.S.S.A.C.C. Susan White, B.Sc, Dip. Ed. (to 2/12/94)

Ivan Francis, B.Sc., Dip.Comp.Sci. - Scientist-inCharge Leonard Bonacquisto, B.Sc.dHons.), Dip.Comp.Sci. Mona El-Masri Nella Napolitano Maureen Ryan (to 10/6/94) Nick Tzanakos, B.App.Chem.

Clinical Geneticists: Agnes Bankier, M.B., B.S., F.R.A.C.P. John Rogers, M.B., B.S., D.C.H., F.R.A.C.P. Les Sheffield, B.Med.Sci., M.B., B.S., M.Sc., D.C.H., F.R.A.C.P. Mac Gardner, M.B., Ch.B., M.Sc., F.C.C.M.G., H.G.S.A.C.C.G. Geoff Woods, M.D., Ch.B., M.R.C.P. (to 25/11/94)

Metabolic Physician

Business Manager Anne Cronin, B.Sc., B.Bus.(Acc.), A.S.A., C.P.A.

Laboratory Manager Barry Holt, B.App.Sci.(M.T.), A.A.I.M.L.S. /■

Secretary Joanne Hogg (to 7/7/94) Lorraine White

Administrative Assistant Sharon Vandersluis

From left:

James McGill, M.B., B.S., F.R.A.C.P., H.G.S.A.C.C.G.

Leonard Bonacquisto, Nella Napolitano, Nick Tzanakos, Mona ElMasri, Ivan Francis

Technical Assistant Scientists - DNA Diagnosis Susan Forrest, B.Sc.(Hons.), D.Phil.(Oxon.) - Scientist in charge Michaela Balnaves, B.Sc.(Hons.) (to 27/10/94) Janice Brasch, B.Sc.(Hons.), M.Sc. Karina Forshaw, B.App.Sci. Andrea Twomey, B.Sc.(Hons.)

Lynda Phillips Genetic Clinic Co-ordinators/Genetic Counsellors Sue Casanelia, S.R.N. Clara Gaff, B.Sc.(Hons.), Ph.D. (from 5/9/94) Margaret Olsen, Dip.App.Biol. Ann Robertson, S.R.N. Jo Wells Mary-AnneYoung, S.R.N.

Laboratory Assistant Ian Brooks Bozena Jezierski Jia Fang Shi

Social Workers 'i,

)

Page 31

Sue Mansie, S.R.N., B.S.W. Margaret Sahhar, B.A., Dip.Soc. Studies

Page 32

Acknowledgements The Murdoch Institute for Research into Birth Defects Limited acknowledges the following donations: Color scanning by Wilke Color.

PRINTERS

Printing by Pac-Rim Direct

Pac-Rim Direct \ /

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The Murdoch Institute for Research into Birth Defects Limited Royal Children's Hospital Flemington Road PARKVILLE VICTORIA 3052 ACN 006 566 972

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Postal Address: Post Office Box 1100 PARKVILLE VIC 3052 •i

Telephone: Facsimile:

(03) 345 5045 (03) 348 1391

Page 33 k

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Murdoch Institute for Research into Birth Defects Limited

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1994 Annual Report

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Financial Statements and Reports

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31st December 1994 f

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The Directors present their report together with the accounts of the Murdoch Institute for Research into Birth Defects Limited "the Company" and the consoli dated accounts of the economic entity, being the Company and its controlled entity, for the year ended 31 December, 1994 and the auditors' report thereon.

Age 53 ' Director of the Department of Gastroenterology, Royal Children's Hospital. Clinical and Scientific Advisor, Royal Children's Hospital Research Foundation. Dr. Barnes represents the Hospital on the Institute's Board. Director since 1986.

Directors Mrs. J. Calvert-Jones The Directors of the Company in office at the date of this report are:

Chairman (Non-Executive Director) Age56 Chairman of Potter Warburg Limited. Director since 1986 - appointed Chairman 1993.

Non-Executive Director Age 56 Chairman of the Herald and Weekly Times Limited. Chairman of the Advisory Council for Children with Impaired Hearing (Vic). Mrs Calvert-Jones represents Cruden Investments Pty Ltd on the Institute's Board. Director since 1986.

Mr. W.H. Hodgson

Dr. R.G.H. Cotton, B.Ag.Sci., Ph.D., D.Sc.

Deputy Chairman (Non-Executive Director) Age 65 Formerly Deputy Managing Director of the National Australia Bank Limited, an appointment which com pleted a long career with the Bank. Mr Hodgson is a Director of various public and pri vate companies. Director since 1986.

Deputy Scientific Director Age 54 Senior Principal Research Fellow, National Health & Medical Research Council. Dr. Cotton, acts for the NHMRC in the Assigners and Regional Grants Interviewing Committees. Director since 1986.

Mr. L.G. Cox, B.COiti., A.S.A., F.S.I.A.

Mr. I. Davies, B.H.A., F.A.I.M., F.C.H.S.E. Professor J.A. Angus, B.Sc.(Hons), Ph.D. Non-Executive Director Age 46 Professor Angus hblds the Chair of Pharmacology at the University of Melbourne. He represents the National Health & Medical Research Council (NHMRC) on the Institute's Board. Director since 1991.

Non-Executive Director Age 54 Chief Executive Officer, Royal Children's Hospital. Mr. Davies was formerly the Chief Executive Officer of the Princess Margaret Hospital for Children in Perth. Director since 1991.

Corporate Affairs adviser to some of Australia's largest corporations. Director since 1986.

Professor Phelan is the Stevenson Professor of Paediatrics at the University of Melbourne and a distinguished thoracic physician. Director since 1986.

Mr. P. Griffin, B.Comm.(Melb) Professor C.W. Tregear, B.S.c., PhD., F.R.A.C.I.

Non-Executive Director AgeSS , Chairman of the Institute's Finance Committee. Mr. Griffin is an investment banker and a director of N.M.Rothschild & Sons (Aust) Pty Ltd Group companies, various public and private companies, industry and community groups. Appointed during 1993.

Non-Executive Director Age 54 Associate Director, Howard Florey Institute of Experimental Physiology and Medicine. Professor Tregear represents the NH&MRC on the Institute's Board. Appointed during 1994.

Mr. j.S. Guest, A.M., O.B.E., V.R.D., B.Sc., M.B., B.S., F.R.C.S., F.R.A.C.S.

Professor G.B. Ryan, A.C., M.D., B.S., Ph.D., F.R.C.P.A., F.R.A.C.P.

Non-Executive Director Age 78 Mr. Guest is a distinguished Melbourne surgeon and the Chairman of the Jack Brockhoff Foundation. Director since 1986.

Non-Executive Director Age 56 Dean of the Eaculty of Medicine, Dentistry and Health Sciences, University of Melbourne. Director since 1986.

Mrs. I. McFarling

Professor R. Williamson, PhD., F.R.C. Path., Hoh. M.R.C.P., Hon.M.D. (Turku)

Non-Executive Director Age 57 Mrs. McFarling is a successful public relations advi sor. She is the President of the Friends of the Murdoch Institute, the successful Fundraising Auxiliary of the Institute. Director since 1988. Mr. A.S. Murdoch Non-Executive Director Age 54 President of the Royal Children's'Hospital. Director since 1993.

Scientific Director Age 56 Executive Director of the Victorian Clinical Genetics Services. Professor of Medical Genetics, University of Melbourne. Director since 1995. Professor A.J. Pittard retired as a Director of the Comi^ny during the year. Professor D.M. Danks retired effective 31 March 1995.

Mr. J.A. Fitzgerald Dr. G.L. Barnes, M.D., Ch.B., F.R.A.C.P. Non-ExeCutive Director

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Non-Executive Director Age 63 Mr. Fitzgerald is a public relations consultant. He is

Professor P.D. Phelan, B.Sc., M.D., B.S., F.R.A.C.P. Non-Executive Director Age 58

Pages

Directors^ Meetings The number of directors' meetings and number of meetings attended by each of the directors of the Company during the financial year are: No of Meetings

No of Meetings

Attended

Held *

Mr. L.G. Cox

Mr. W.H. Hodgson

Professor J.A. Angus

Dr. G.L. Barnes

Mrs. J. Calvert-Jones

Dr. R.G.H. Cotton

Professor p.M. Danks

Mr. I. Davies

Mr. J.A. Fitzgerald

Mr. P. Griffin

Mr. J.S. Guest

Mrs. I. McFarling

Mr. A.S. Murdoch

Professor P.D. Phelan

Professor A.j. Pittard

Professor G.B. Ryan

Professor G.W. Tregear

Director

Events Subsequent to Balance Date

Principal Activities

■

There has not arisen in the interval between the end of the financial year and the date of this report any item, transaction or event of a material and unusual nature likely, in the opinion of the Directors of the Company, to affect significantly the operations of the economic entity, the results of those operations, or the state of affairs of the economic entity, in subse quent financial years.

The principal activities of the economic entity during the course of the financial year were to promote and , undertake medical research into the understanding, prevention and treatment of birth defects, and to pro vide services for the diagnosis and treatment of genetic diseases and other birth defects. No signifi cant change in the nature of these activities occurred during the year.

Likely future developments and expected results

Dividends The Company is a company limited by guarantee. As such it has no share capital, and no dividends are paid.

The scope of the alterations to the 10th floor of the main building of the Hospital planned for the near future has been reduced. It is anticipated that refur bishment of the area which will accommodate the Cytogenetics Laboratory, the DNA Diagnostic Laboratory and the Neonatal Screening Laboratory will commence early in 1995 at an estimated cost of $1 .-3 million.

Consolidated Result The consolidated net deficit of the economic entity for the financial year ending 31 December 1994 was $388,015.. (1993 $112,401 surplus). No provision is required for taxation as the Company and its con trolled entity are exempt from Income Tax.

Directors'Interests and Benefits Since the end of the previous financial year, no Director of the Company has received or become entitled to receive any benefit (other than a benefit included in the aggregate amount of remuneration received or due and receivable by Directors shown in the consolidated accounts) because of a contract made by the Company, its controlled entity, or a related body corporate with the Director or with a firm of which the Director is a member, or with an entity in which the Director has a substantial interest.

Review of operations A review of the operations of the Company and its controlled entity during 1994 has been included in the Report of the Board.

* Reflects the number of meetings held during the time the director held office during the year. ^ . :■

Significant changes in state of affairs

Dated at Melbourne this 12th day of April, 1995 Signed in accordance with a resolution of the Directors:

LAURENCE a cox : Directors

In the opinion of the Directors there were no signifi cant changes in the state of the economic entity's affairs during the financial year under review not oth erwise disclosed in the report or the consolidated accounts.

WILLIAM H. HOD8SON

-A

Page 4

Pages

THE MURDOCH INSTITUTE FOR RESEARCH INTO BIRTH DEFECTS LIMITED AND ITS CONTROLLED ENTITY

THE MURDOCH INSTITUTE FOR RESEARCH INTO BIRTH DEFECTS LIMITED MD ITS CONTROLLEL) ENTITY

Profit and Loss Accounts for the year ended 31 December 1994

Balance Sheets as at 31 December 1994

Note

Operating Profit/(Loss) before Income Tax Income tax attributable to Operating Profit

Consolidated

The Company

1994

1993

1994

1993

' $

(388,015)

112,401

(434,991)

34,827

(388,015)

Operating Pr6fit/(Loss) after Income Tax Accumulated Eunds at beginning of the

112,401

(434,991)

34,827

9,029,562

8,917,161

8,982.502

8,947,675

8,641,547

9,029,562

8,547,511

8,982,502

financial year Total available for appropriation Aggregate of amounts transferred to reserves

Accumulated funds at the end of the financial year

35,000

8,606,547

8,512,511

CURRENT ASSETS Cash Receivables Investments Inventories TOTAL CURRENT ASSETS

8,982,502

1993

28,686 628,829 809,668

The Company 1994 1993

20,771 350,291 505,141

1,467,183

876,203

64,188 176,160 280,454 13,848 534,650

1,087,500 7,705,604 , 225,564 9,018,668

1,160,000 8,115,072 229,482 9,504,554

1,087,500 7,705,604 213,076 9,006,180

1,160,000 8,115,072 214,219 9,489,291

10,485,851

10,622,317

9,882,383

10,023,941

871,552 683,676 1,555,228

644,885 585,282 1,230,167

680,528 429.152 1,109,680

450,613 365,634 816,247

63,884

137,396

63,884

137,396

TOTAL LIABILITIES

.1,619,112

1,367,563

1,109,680

816,247

NET ASSETS

8,866,739

9,254,754

8,772,703

9,207,694

8,606,547 260,192 8,866,739

9,029)562 225,192 9,254,754

8,512,511 260,192 8,772,703

8,982,502 225,192 9,207,694

4 5 6

non-current assets Receivables Investments Plant & Equipment TOTAL NON-CURRENT ASSETS

4 5 7-

TOTAL ASSETS

NON-CURRENT LIABILITIES Creditors and Borrowings

TOTAL NON-CURRENT LIABILITIES The profit and loss accounts are to be read in conjunction with the attached notes to and forming part of the financial statements set out on pages 9 to 18.

Consolidated

1994

69,513 418,408 615,994 . 13,848 1,117,763

CURRENT LIABILITIES Creditors and Borrowings Provisions TOTAL CURRENT LIABILITIES

35,000

9,029,562

Note

MEMBERSHIP FUNDS Accumulated Funds Reserves TOTAL MEMBER’SHIP FUNDS

'x-

The balance sheets are to be read in conjunction with the attached notes to and forming part of the financial statements set out on pages 9 to 18.

C--

Pages

-TV

(•

THE MURDOCH INSTITUTE FOR RESEARCH INTO BIRTH DEFECTS LIMITED AND ITS CONTROLLED ENTITY

•

The Company

1994

1993

1994

1993

Inflows

(Outflows)

CASHFLOWS FROM OPERATING ACTIVITIES Payments to suppliers and employees

(5,715,812)

(5,642,054)

(3,445,812)

(3,621,479)

Government Grants received

3,099,527

3,236,609

1,439,527

1,701,209

Donations received

1,000,928

922,048

1,000,928

922,048

Other receipts

1,141,120

811,595

579,408

356,117

9,657

■ ^

8,887

Interest received

NET CASH PROVIDEDAUSED) BY OPERATING

. '

(425,949)

(642,105)

79,847' 511,246 169,786 207,573 8,841,731 7,550,970 (8,389,932) (8,082,714) (.LTZ,429J J.T32,680)

65,314 207,573 8,241,731 (7,789,970) (1J.Z,429)

506,226 169,786 7,550,970 (7,883,369) _(13:2,660)

ACTIVITIES (Note 10(ii)) CASH FLOWS FROM INVESTING ACTIVITIES Interest received Dividends received Proceeds on sale of investments Payment for investments Payment for property, plant and equipment NET CASH PROVIDED BY INVESTING ACTIVITIES CASH AT THE BEGINNING OF THE REPORTING ‘

210,953

(645,517)

181,270

(431,152)

_486,J 62

,1,333,679

._344,642

^7Z5,Z9_4

642,602

486,162

525,912

156,440

NET INCREASE IN CASH HELD PERIOD

60Z,219.

62.T,Z9.0

^1.6,628

CASH AT THE END'OF THE REPORTING PERIOD (Note 10(i))

.Pages

STATEMENT OF SIGNIFICANT ACCOUNTING POLICIES

Basis of Preparation The financial statements have been drawn up in accordance with applicable Accounting Standards, the Corporations Law and Schedule 5 to the Corporations Regulations. They have been prepared on the basis of his torical costs and do not take into account changing money values or, except where stated, current valuations of non-current assets. ; ; The accounting policies have been consistently applied by the entities in the economic entity and are consistent with those of the previous year. The carrying amounts of all non-current assets are reviewed at least annually to determine whether they are in excess of their recoverable amount at balance date. If the carrying amount of a non-current asset exceeds the recov erable amount, the asset is written down to the lower value. In assessing recoverable amounts the relevant cash flows have not been discounted to their present value. '

Principles of Consolidation The consolidated financial statements combine the financial statements of the Murdoch Institute for Research into Birth Defects Limited, being the chief entity, and its controlled entity Victorian Clinical Genetics Services Limited, for the twelve months ended 31 December 1994. All balances and transactions between the chief entity and the controlled entity have been eliminated. Investments Investments are stated at the lower of cost or recoverable amount. Dividends are brought to account as received.. Property, Plant and Equipment Items of property, plant and equipment are recorded at cost. The depreciable amounts of all iterns bf property, plant and equipment are depreciated over their useful lives commencing from the time the asset is held ready for use. The straight line method of depreciation is used. Prepayments Item's of expenditure having a benefit or relationship to more than one accounting period are amortised over the periods;to which they relate. ; "

344,642

The statements of cash flows are to be read in conjunction with the attached notes to and forming part of the finan cial statements set out on pages 9 to 18.

The significant policies which have been adopted in the preparation of these financial statements are:

The financial statements of the Company and its controlled entities reflect all entries affecting the Company and its controlled entity, and include transactions that were specifically recorded in the bank accounts of the Company and its controlled entity. -

(662,145)

(465,350)

‘

Notes to and Forming Part of the Financial Statements for the year ended 31 December 1994

Statements of Cash Flows for the year ended 31 December 1994

Consolidated

Employee Entitlements The provision for employee entitlements relates to amounts expected to be paid to employees for long service leave and annual leave and is based on legal and contractual entitlements. Current wage rates are used in the calculation of the provisions.

'■;Rage^0:-

The Company

Consolidated Income Tax The Company and its controlled entity are exempt from income tax under section 23(e) of the Income Tax Assessment Act 1936 The Company

Consolidated 1994 $

1994

1993

1994

1993

257,500 2,692 260,192

222,5.00 2,692 225,192

257,500 2,692 260,192

222,500 , 2,692 225,192

2,692

2,764

2,692

2,764 2,692

■

3. RESERVES

1993

1994

1993

2. OPERATING PROFIT Operating Profit before Income tax has been determined .after-

Building Development Fund Social Work Fund BALANCE AT END OF YEAR MOVEMENTS IN RESERVES

fa) CREDITING AS REVENUE

SOCIAL WORK FUND

1,260,302 1,787,091 210,492 1,125,928 87,659 207,573 42,293 132,207 847,823 5,701,368

1,299,014 1,879,221 140,725 922,048 520,903 169,786 174,747 114,869 , 714,468 5,935,781

1,260,302

1,299,014

163,249

245,997

210,492

140,725

1,125,928

922,048

67,794

506,226

207,573

169,786

42,293

174,747

132,207

114,869

263,663

258,990

3,473,501

3,832,402

4,077,872

3,978,170

2,461,137

ErripIoyee entitlements

98,394

; 77,624

63,518

Laboratory Consumables

546,080

596,731

546,080

Refurbishment Costs

32,069

18,898

32,069

Repairs & Maintenance

61,246

53,252

61,246

Travel .

63,216

103,697

63,216

2,460,985 59,961 596,731 18,898 53;252 103,697

Clinical Research

9; 758

9,758

3,09()

Grants-NHMRC Grants- H&CS Grants - Other Doriations Interest - other persons -

Dividends - other persons Net Gain on sale of investments

POSSUM SALES Income - Other

Balance at beginning of year

balance at end of year

(72)

Transfer to revenue

2,692

222.500 35,000 257.500

222,500

222,500 35,000 257,500,

BUILDING DEVELOPMENT FUND Balance at beginning of year Transfer from revenue BALANCE AT END OF YEAR

222,500

222,500 222,500

4. RECEIVABLES

(b) charging AS EXPENSE SalariesAA/ages, inch superannuation

3,090 .

329„205

288,252

Central Services & Administration

562,253

486,128

Depreciation

121,346

140,232

Patient Care Services

POSSUM

Proceeds from Sale of Investments

CURRENT

125,000

Accrued Income Amount Owing by Controlled Entity

125,000

, Debtors

415,971 87,858 628,829

332,733 85,675 418,408

137,433 87,858 350,291

50,000 40,485 85,675 176,160

1,087,500

1,160,000

1,087,500

1,160,000

Prepayments

non-current

187,944

77,306

6,089,383

5,823,380

364,953 118,571 187,944 3,908,492

8,841,731

7,550,970

8,241,731

286,198 137,457 77,306 3,797,575 7,550,970

Prepayments

Page -7 7

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/' Consolidated

The Company

Consolidated

1994

1993

1994

1993

1994

1993

1994

1993

Plant & Equipment - at cost

640,927

523,499

613,176

495,748

Accumulated Depreciation

415,363 ^

294,017

400,100

2£!1,529

225,564

229,482

213,076

214,219

5. INVESTMENTS AT COST

7. PLANT & EQUIPMENT

Current Bank Bilh

95,752

99,308

Bond

100,000

,100,038

Short Term Deposit'

613,916

416,648

505,141

280,454

TOTAL CURRENT INVESTMENTS

.809,668

615,994

5.05,141

280,454

TOTAL

8. CREDITORS & BORROWINGS Non current CURRENT

Shares - Listed on a prescribed stock exchange Unlisted

2,158,051

1,942,119

2,158,051

1,942,119

2,158,051

1,942,119

2,158,051

1,942,119

Government Bonds - Listed on a prescribed stock exchange - Unlisted

Interest in Trusts

29,900

Royal Children's Hospital

486,933

504,711

326,721

282,132

Sundry Creditors

354,719

140,1.74

323,9.07

168,481

871,552

644,885

680,528

450,613

TOTAL 3,619,541

3,292,079

3,619,541

3,292,079

3,619,541

3,292,079

3,619,541

3,292,079

NOTE: Royal Children's Hospital

2,880,874

This is a suspense account which is used for payments to creditors.

1,928,012

2,880,874

1,928,012

29,900

Unearned Income

The Hospital pays the creditors on behalf of the Institute, TOTAL NON-CURRENT INVESTMENTS ToVaL INVESTMENTS

7,705,604

8,115,072

7,705,604

8,115,072

8,515,272

8,731,066

8,210,745

8,395,526

and the Institute subsequently reimburses the Hospital. NON-CURRENT 63,884

137,396

Annual Leave

210,667

198,696

113,368

118,934

Long Service Leave

473,009

386,586

315,784

246,700

683,676

585,282

429,152

365,634

Special Purpose Funds MARKET VALUE OF LISTED INVESTMENTS

2,456,731

3,381,939

2,456,731

3,046,399 9. PROVISIONS

6. INVENTORIES Raw Materials & Stores - at cost

CURRENT 13,848

13,848 7 / TOTAL

Page 12

Page 13

Consolidated

Note

1994

1993

The Company 1994 1993 $

1993

1994

1993

. $

16,000

13,000

9,000

5,000

16,000

13,000

9,000

5,000

116,985

112,187

116,985

112,187

No.

15 '

1994

The Company

Consolidated

10. NOTES TO THE STATEMENTS OF CASH FLOWS 11. REMUNERATION OF AUDITORS (i) RECONCILIATION OF CASH.

Amounts received or due and receivable by the Auditors:

For the purposes of the Statements of Cash Flows, the entity

For auditing the accounts.

' considers cash to include cash on hand and at bank and

For other services

short term deposits at call. Cash as at the end of

- TOTAL

the reporting period as shown in the Statements of Cash Flows is reconciled to the related items in the Balance Sheets as follows: CASH, 28,686

69,513

SHORT TERM DEPOSIT

613,916

416,649

505,141

280,454

642,602

486,162

525,912

344,642'

20,771

12. DIRECTORS' REMUNERATION

64,188

Total income received or receivable by the Directors of the Company from the Company or related

(ii) RECONCILIATION OF NET CASH PROVIDED BY OPERATING

bodies corporate excluding amounts included under

ACTIVITIES TO OPERATING PROFIT AFTER INCOME TAX. Operating Profit/(Loss) after Income Tax

(388,015)

112,401

(434,991)

34,827

Depreciation & Amortisation

193,846^

212,731

191,071

209,956

Amounts set aside to Provisions

112,596

100,975

68,601

63,208

Gain on sales of investments

(42,293)

(174,747)

(42,293)

(174,747)

Dividends received

(207,572)

(169,786)

(207,572)

(169,786)

Interest received

(76,292)

(511,246)

(65,314)

(506,226)

retirement payments.

AddALess) Non Cash Items Superannuation Benefits Superannuation contributions paid in respect of directors are

AddALess) Items classified as Investing Activities

included-in total income received. The directors-believe that the provision of full particulars would be unreasonable. The above amounts (including the comparatives) are disclosed in accordance with an ASC class order dated 13/10/94.

AddALess) Changes in Assets & Liabilities (lncrease)/Decrease in Debtors

(46,949)

(lncrease)/Decrease in Accrued Income

(125,000)

11,527

(2,183)

(lncrease)/Decrease in Prepayments/Receivables

(179,581)

(lncrease)/Decrease in Inventory

13,848 ‘ .

IncreaseADecrease) in Creditors

(90,121)

IncreaseADecrease) in Grants in Advance IncreaseADecrease) in Provisions/Accrued Expenses

145,584

IncreaseADecrease) in Unearned Income

29,900

(80,917)

Number of Directors of the, holding company whose total income from the Company or related bodies corporate

2,327

13,848

2.327

(35,043)

45,758

(20,675)

3,591

falls within the following bands:

$0 - $9,999 $10,000 - $19,999 $70,000 - $79,999 $90,000 - $99,999 $100,000 - $109,999

3,591 (20,104)

145,584 29,900

IncreaseADecrease) in Reserve NET CASH PROVIDED BY OPERATING ACTIVITIES

(46,949)

(72) (465,350)

(662,145)

(72) (425,949)

(642,105)

1 1

The individual remuneration received by the fifteen Directors in the band $0 - $9,999 was nil.

PageJ4

; Page 16. ■

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Directors of the holding company in office at any time during the year:

employee superannuation fund. Employee contributions are based on various percentages of their gross

Professor J.A. Angus

Mr. I. Davies

Professor P.D. Phelan

salaries. All employees are entitled to join the fund. Fund members are entitled to benefits oh retirement, dis ability or death.

Dr. G.L. Barnes '

Mr. J. Fitzgerald

Professor A.j. Pittard

The fund provides defined benefits based on years of service and final average salary. The Company and

Mrs. j. Calvert-Jones

Mr. P. Griffin

Professor G.B. Ryan

Dr. R.G.H. Cotton

'Mr. J.S. Guest

Professor G. Tregear

other controlled entity are under no legal obligation to make up any shortfall in the fund's assets to meet pay ments due to employees.

Mr. L.G. Cox

Mr. W.H. Hodgson

Mr. A.S. Murdoch

Professor D.M. Danks

Mrs. I. McFarling

An actuarial assessment of the fund as at 31 December 1991 was carried out by Mr C J White FIA, FIAA. The assets of the fund are sufficient to meet all benefits payable in the event of the fund's termination, or the vol untary or compulsory termination of employment of each employee of the Company and other controlled entity.

Professor A.J. Pittard retired during the year. 16. SEGMENT INFORMATION 13. LIABILITY OF MEMBERS

In accordance with the Articles of Association, in the event of the company being wound up, members may be called upon to make a subscription not exceeding ten dollars. As at the 31 December 1994 the number of

The Company and its controlled entity operates predominantly in a single industry, being research into causes, diagnosis and treatment of genetic diseases and other birth defects, within a single geographical segment, being Australia.

members of the company is 76. 17. PARTICULARS IN RELATION TO CONTROLLED ENTITY

14. RELATED PARTY DISCLOSURES

As at 31 December 1993, the Company was owed $50,000 by its controlled entity Victorian Clinical Genetics Services Limited which was repaid during the year ended 31 December 1994. No interest was charged on the loan.

The Company is the only member of its controlled entity, Victorian Clinical Genetics Services Limited. No consideration was paid for this ownership, but in the event of the controlled entity being wound up, the Company may be called upon to pay an amount not exceeding ten dollars. The directors of the controlled entity are appointed by the Company:

Some directors made donations to the Company during the year.

Contribution to

, Mr. L.G. Cox is a director of Potter Warburg Ltd. which manage part of the investments of the controlled entity on normal commercial terms.

‘

Consolidated Profit/Loss

Financial assistance is provided by the Company to the controlled entity by way of infrastructure and over heads.

The Murdoch Institute for Research into Birth Defects Ltd

1994

1993

(434,991)

34,827

46,976

77,574

(388,015)

112,401

Controlled entity: 15. SUPERANNUATION COMMITMENTS

Victorian Clinical Genetics Services Limited

The Company and its-controlled entity contribute various percentages of employees' gross salaries to an

Page 16

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i'i

INDEPENDENT AUDITORS'REPORT TQ THE MEMBERS OF THE MURDOCH INSTITUTE FOR RESEARCH INTO BIRTH DEFECTS LIMITED

THE MURDOCH INSTITUTE FOR RESEARCH INTO BIRTH DEFECTS LIMITED AND ITS CONTROLLED ENTITY

Scope

Statement by Directors

We have audited the financial statements of The Murdoch Institute for Research into Birth Defects Limitec^ for the financial year ended 31 December 1994, consisting of the profit and loss accounts, balance sheets, statements of cash flows, accompanying notes, and statement by directors set out on pages 6 to 1 5. The financial statements comprise the accounts of the Company and the consolidated accounts of the economic entity, being the Company and its controlled entity. The Company's directors are responsible for the preparation and presentation

1. In the opinion of the Directors of The Murdoch Institute for Research into Birth Defects Limited:

(a)

the financial statements set out on pages 6 to 14 are drawn up so as to give a true and fair view of the results and cash flows for the financial year ended 31 December 1994, and the state of affairs at 31

of the financial statements and the information they contain. We have conducted an independent audit of these financial statements in order to express an opinion on them to the members of the Company.

December 1994, of the Company and the economic entity;

(b)

Our audit has been conducted in accordance with Australian Auditing Standards to provide reasonable assurance as to whether the financial statements are free of material misstatement. Our procedures included examination, on a test basis, of evidence supporting the amounts and other disclosures in the financial statements, and the evaluation of accounting policies and significant accounting estimates. These procedures have been undertakento form an opinion as to whether, in all material respects, the financial statements are presented fairly in accor dance with Australian accounting standards and statutory requirements so as to present a view which is consistent with our understanding of the Company's and the economic entity's financial position and the results of their operations.

the consolidated accounts have been made out in accordance with Divisions 4A and 4B of Part 3.6 of the Corporations Law; and

(c)

at the date of this statement, there are reasonable grounds to believe that the company will be able to pay its debts as and when they fall due.

2. The financial statements have been made out in accordance with applicable Australian Accounting Standards.

The audit opinion expressed in this report has been formed on the above basis.

Audit Opinion In our opinion, the financial statements of The Murdoch Institute for Research into Birth Defects Limited are prop erly drawn up:

Dated at Melbourne this 12th day of April, 1995.

(a) so as to give a true and fair view of: i) the state of affairs of the Company and the economic entity at 31 December 1994 and the results and cash flows of the Company and the economic entity for the financial year ended on that date; and ii) the other matters required by Divisions 4, 4A and 4B of Part 3.6 of the Corporations Law to be dealt with in the financial statements;

Signed in accordance with a resolution of the Directors:

(b) in accordance with the provisions of the Corporations Law; and

- I

LAURENCE G. COX

KPMG Chartered Accountants

Directors

P. Lorn - Partner

WILLIAM H. HODGS

Rage 18

Page 19

Acknowledgements I

I 1

The Murdoch Institute for Research into Birth Defects Limited acknowledges the following donations: Color scanning by Wilke Color.

PRINTERS

Printing by Pac-Rim Direct

Pac-Rim iHrect

Page 20

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Annual Report "C. i