PathWay_Issue#12_2

redefining diagnosis, disease and drug therapy GENETICS: A REVOLUTIONARY DISCOVERY HAEMOCHROMATOSIS: PHARMACOGENETICS: TAILOR-MADE TREATMENTS IGNORANCE IS NOT BLISS Autumn 2008 | Issue #15 PCR TESTING: $7.50 (inc. gst) PathWay Autumn 2008 - Issue #15 Genetics: REDEFINING DIAGNOSIS, DISEASE AND DRUG THERAPY ALTERNATIVE’ | PHARMACOGENETICS: TAILOR-MADE TREATMENTS | PCR TESTING: A REVOLUTIONARY DISCOVERY | HAEMOCHROMATOSIS: IGNORANCE NOT BLISS PRINTPOST APPROVED PP60630100114

ADVISORY BOARD Contents Dr Debra Graves (Chairman) Chief Executive, RCPA Dr Tamsin Waterhouse Deputy CEO, RCPA Dr Edwina Duhig Director of Anatomical Pathology QHPS (Prince Charles Hospital) PATHWAY Dr Andrew Laycock Autumn 2008 Chairman Trainees Advisory Committee, RCPA Issue #15 Dr David Roche New Zealand Representative, RCPA Wayne Tregaskis S2i Communications PUBLISHER Wayne Tregaskis EXECUTIVE EDITOR Dr Debra Graves COVER STORY EDITOR A perfect fit: Pharmacogentetics 8 Dr Linda Calabresi Advances in genetics are making it possible to tailor treatments to the individual patient. ART DIRECTOR Jodi Webster FEATURES ADVERTISING SALES DIRECTOR Sue Butterworth Disciplines in depth: Back to basics 12 PUBLISHING CO-ORDINATOR Pathology’s newest subspecialty, genetics looks set to change the Andrea Plawutsky future of medicine’s approach to disease and treatment. PathWay is published quarterly for the Royal College In profile: Family matters 16 of Pathologists of Australasia (ABN 52 000 173 231) by S2i Communications, Level 9, Dr Graeme Suthers’ drive and vision have had a major influence 16 Spring St Sydney 2000 on Australia’s familial cancer services. Tel (02) 9251 8222 Fax (02) 9247 6544 Testing testing: The ABC of PCR 20 PrintPOST approved PP60630100114 Bianca Nogrady reports on how PCR testing has changed the face of medical diagnosis. Spotlight on disease: Metal detectors 26 Haemochromatosis: easy to diagnose and treat but still often going undetected until too late. The Royal College of Pathologists of Australasia Tel: (02) 8356 5858 Cutting edge: High expectations 32 Email: rcpa@rcpa.edu.au Prenatal genetic screening is becoming commonplace in S2i Communications Pty Ltd Australia. Dr Kathy Kramer looks at its benefits, limitations and Tel: (02) 9251 8222 potential. Email: wayne@s2i.com.au Foreign correspondence: Wisdom in the Solomons 35 PathWay Email: pathway@rcpa.edu.au Australian expertise is behind the setting up of the Solomon http://pathway.rcpa.edu.au Islands’ first anatomical pathology laboratory. FOR FURTHER INFORMATION ON THE ROYAL COLLEGE OF PATHOLOGISTS OF AUSTRALASIA OR ANY OF THE FEATURES IN THIS ISSUE OF PATHWAY CHECK OUT THE WEBSITE www.rcpa.edu.au PATHWAY_1

Key Incident Monitoring and Management Systems (KIMMS) Pathology in Australia has been a KIMMS Objectives: leader in accreditation and quality N To establish a national data set assurance. Recent studies in many for pathology incidents countries have shown that the majority N To develop the data set to enable of adverse patient incidents occur in the participants to measure and monitor non-analytical phase of the test-request- pathology incidents report cycle. N Utilise the data to set achievable national benchmarks for good pathology practice in the pre- and post- To minimise the risk of errors and analytical phase of testing incidents in pathology, the pre- and N Work with participants, by ex- post- analytical phase of testing need to changing information, to educate be measured and monitored. KIMMS is laboratories on methods to reduce designed to provide pathology practices errors with the tools for continuous N Raise awareness of safe work measurement and monitoring of key practices which in turn will reduce incident indicators. errors and increase patient safety N Set standards for best practice in the pre– and post-analytical areas of KIMMS provides the means by which laboratory work laboratories can be encouraged to monitor rate of adverse incidents affecting patient safety and welfare; KIMMS offers pathology laboratories: through benchmarking against peers N Data and graphical analysis, show- and state-of-the-art, a mechanism is ing trend analysis provided for the systematic risk N Benchmarking against peers management and improvement of N Educational content performance in agreed key areas. For further information contact: Penny Petinos KIMMS Coordinator pennyp@rcpa.edu.au Ph: +612 8356 5814

REGULARS IMAGES OF IRAN PAGE 46 From the CEO 4 Welcome from RCPA CEO Dr Debra Graves Under the microscope 6 News + views LIFESTYLE 6minutes news 30 Interesting news from around the world Travel: O Paradiso 44 Pangkor Laut Resort in Malaysia is a heady combination of beauty, Finance finesse 38 Financial advisor, Greg Lomax gives serenity and luxury. some timely tips on superannuation investments. Travel: Images of Iran 46 Judy Myers finds a country rich in history, culture, colour and hospitality Conference calendar 42 Postscript 64 Fairy tales and feral carbon: Dr Pam Travel doc 49 Rachootin proposes pathologists are On the trail of the tiger: Dr Harsha Sheorey has the experience of a ideally placed to save the planet lifetime while on safari in Central India WISDOM IN THE Private passions 52 Doing the hard yards: Mike Ralston’s hankering for hiking has certainly seen him cover some ground. SOLOMONS PAGE 35 Recipe for success 54 Expelled to greatness: Carolyn Alexander meets lauded chef, Andrew McConnell, the talent behind Melbourne’s Three, One, Two. Dining out 57 Food with a view: Combining a spectacular view with fabulous food makes for a truly memorable dining experience The good grape 61 Chic sherries: Ben Canaider explains why sherry is enjoying a renaissance around the world Rearview 62 Racing to unravel the mystery of AIDS: Who discovered AIDS? Dr George Biro looks at one of the great feuds of our time PATHWAY_3

from the CEO Welcome to the 15th Edition of PathWay In our article “The ABC of PCR”, the A revolution started in medicine in 1953 when Watson and Crick discovered DNA. use of Polymerase Chain Reaction (PCR) to The other very exciting area of genetics that we look at is that of predicting a detect the genetic make up of organisms is person’s responsiveness to a particular Over the ensuing 55 years many outlined. Developed in the early '90s, the medication. This is explored in the article “A advances have occurred in the field of technique of PCR testing allows scientists perfect fit: Pharmacogenetics”. Genetics which have had profound effects to produce or amplify genetic material to a Already there are a number of genetic on our understanding of disease and our sufficient “volume” to enable the detection tests that are being used to determine a response to it. of particular base pair sequences in genes patient's suitability for particular treatments. This edition of PathWay focuses on the that code for particular conditions or And the number of new tests becoming “Genetic Revolution” examining specific organisms. available over the next few years is likely to areas where genetic testing impacts on In the article “Family Matters”, we increase dramatically. This will have healthcare and the challenges that lay profile Dr Graeme Suthers who is the head tremendous benefits for patients as they will ahead for countries dealing with this of the South Australian Familial Cancer receive much more targeted treatments, and phenomenon. Service, which is doing remarkable work in also has the potential to save considerable For many people genetic testing is a this important area of genetic testing. amounts of money with people only being brave new world and perhaps even a little Dr Graeme Suthers, a genetic offered a drug if it is known they will be abstract, with concepts such as “predictive pathologist and Chair of the College's responsive to it. testing” and its far reaching consequences. Genetics Advisory Committee is one of a But the reality is genetic testing is here and In the pharmacogenetics article, number of pathologists driving the already contributing significantly to the another major area of genetic testing - the College's push for a National Framework in advancement of medicine. testing of the genetic make up of cancers Genetics in Australia. As a result, it is time for politicians, themselves - is discussed. Variations in the As is so often the case with new health care administrators and the general genetic profile of cancer cells compared to technologies, the funding, workforce planning, and medical communities to be better normal cells is a key area of research and regulatory, ethical and quality/standards need informed about genetics and what we need indeed in a number of areas is already used to be planned in a systematic way to ensure a to do to ensure the healthcare system is in routine diagnostic practice. Greater high quality appropriate service is delivered. well-equipped to deal with this revolution. understanding of these differences offers Compared to the UK, many countries Perhaps the most widely known form of benefits in diagnosis, prognosis and including Australia are slow in addressing genetic testing is that involved with prenatal treatment of cancer. these issues. In the UK, over 300 genetic screening, looking for conditions such as By understanding the exact type of tests are funded by the NHS, in Australia the Down syndrome. Medical Benefits Schedule includes only ten, tumour present more targeted therapy can This type of testing and the issues be provided, the classic example being the with some States funding some genetic surrounding it are explored in the article by effectiveness of trastuzumab (Herceptin) in tests in a somewhat ad hoc manner. Dr Kathy Kramer, “High Expectations”. HER2 positive breast cancer. While a very important area it must be The College thinks it is time for urgent action to be taken to keep Australia at the We hope you enjoy this exciting very stressed that this is only one application of genetic testing, and only the tip of a very forefront of the medical world. important edition of PathWay. large iceberg. In the feature “Metal Detectors”, we Other major areas of genetic testing that examine another area of genetic testing for will be explored include predictive testing in the condition known as haemochromatosis. adults for susceptibility to disease and We talk with Professor David Ravine about responsiveness to drug therapy, the genetics this very important genetic test and explore of cancers and genetics of organisms the question of population screening for the Dr Debra Graves causing infectious diseases. disease. CEO, RCPA 4_PATHWAY

Symbion Pathology is fast becoming one of Australia’s leading private pathology groups, performing more than 10 million patient episodes each year. With a national network of distinguished pathology providers positioned throughout Victoria, New South Wales, Queensland, Western Australia and the Northern Territory, our highly experienced pathologists and medical scientists have access to state-of- the-art technology and automated work ow systems to enable high throughput and fast turnaround of analyses and reports. At Symbion Pathology we remain at the forefront of delivering innovative and improved pathology practices. We recognise our responsibility to the patients, medical practitioners and communities we serve and are committed to delivering a service based on superior quality and customer satisfaction. Our National Network of Pathology Providers ( 03 9244 0444 ( 03 5174 0800 ( 02 9005 7000 At Symbion Pathology, everything we do is ( 08 9317 0999 driven by one goal - to help people achieve health and wellness. Why? ( 07 3121 4444 Because life matters® www.symbionhealth.com Symbion Health Ltd ABN 56 004 073 410

under the microscope: news + views Australia Day honours T hree Australian pathologists were among those recognised on this year’s Australia Day honours list. Boost for Dr Colin Laverty (pictured right) was awarded a Medal of the Order of Australia Hep C/HIV (OAM) for his service to medicine, particularly gynaecological cytology and histopathology. research He established the role of human papillomavirus in cervical cancer and has helped advance cervical screening H epatitis C and HIV research has been given a significant boost with the announcement of $17.7 services in Australia. The award also acknowledged Dr Laverty’s contribution to million in funding being awarded to art, particularly Indigenous art, both in the University of NSW by the Australia and overseas. Former chief executive officer of the National Health and Medical Immunologist, Professor Paul Gatenby, WA Centre for Pathology and Medical Research Council (NHMRC) to foundation dean of ANU medical school Research, Dr Keith Shilkin was also made advance understanding of the two was made a Member of the Order of a Member of the Order of Australia (AM) Australia (AM) for service to medicine in for his work in developing WA’s public diseases. the field of clinical immunology as a sector pathology services. His The grant, the largest in clinician and researcher, to the contributions to professional organisations Australia’s history, was announced advancement of medical education, and as well as to the Jewish community were also recognised. last month by the Minister for Health through professional organisations. and Ageing, Nicola Roxon. Professor David Cooper from the National Centre in HIV Epidemiology and Clinical Research (NCHECR) will More anatomy for Sydney lead a nine person team from across Australia, combining researchers in Uni med students virology and immunology with those who have expertise in translating fter a year-long review of its curriculum, findings in the laboratory into human A Sydney University has more than clinical trials. doubled the teaching time devoted to Part of the grant has been anatomy as part of its graduate medical allocated to fund a five year project course. The four year course will now to develop new strategies to prevent include reportedly 1200 hours of anatomy and treat hepatitis C, which is study, significantly more than the 500 hours currently affecting more than allocated in the previous curriculum. 260,000 Australians. The move is believed to be in in Leading the project, University of response to complaints from many in the medical community, including the students Adelaide virologists Dr Michael themselves, that graduates of the course Beard and Dr Karla Helbig, along were inadequately trained in a number of with colleagues from the University the basic medical sciences, including of NSW, hope to identify antiviral anatomy. It is believed that the revised proteins that can work effectively curriculum, the first revision in 11 years also against the hepatitis C virus with the contains increases in the teaching time aim of developing vaccines and allocated for other sciences such as treatments for the disease. pathology. 6_PATHWAY

Australian innovation GPs ordering advances genetic more path technology tests A new type of RNA microarray chip developed by Australian scientists has been licensed to one of the world’s largest life sciences technology companies, Invitrogen. A ustralian GPs are ordering significantly more tests and investigations, particularly pathology tests than they were Dr Marcel Dinger and Professor John Mattick from the University of Queensland’s six years ago, new data show. Institute of Molecular Bioscience designed the proprietary technology that will help analyse which genes are being expressed at any one time in a particular cell. Findings from a report released by the Australian Institute of Health and Welfare Each cell in the body contains a full set of genes, however different cells express show GPs ordered 44% more tests (or different subsets of these genes. Previously it was believed these genes only coded batteries of tests) per 100 patients in mainly for proteins via the production of ‘messenger RNAs’. However it has been 2006-07 compared with 2000-01. discovered that many other genes produce non-coding RNAs, the functions of which Researchers suggest incentives for are yet to be determined. improved care of people with chronic The newly licensed RNA microarray chip can uniquely identify tens of thousands of diseases such as diabetes may, at least coding and non-coding RNA sequences. For the first time, one product can identify partly be responsible for the increase. large numbers of both types of RNAs and the new technology has the potential to The report, General Practice Activity make a significant impact in the areas of cancer and stem cell research where RNAs in Australia 2006-07, reports the results have been implicated. from the ‘Bettering the Evaluation and The technology has been licensed through IMBcom, University of Queensland’s Care of Health’ (BEACH) program’s company for the commercialisation of intellectual property arising from research national survey of 100,000 GP-patient conducted at the Institute of Molecular Bioscience. encounters. PATHWAY_7

cover story A perfect fit Pharmacogenetics GENETICS CAN PREDICT A PERSON’S RESPONSE TO A DRUG EVEN BEFORE THEY’VE TAKEN IT. PETER LAVELLE LOOKS INTO THIS BRAVE NEW WORLD. 8_PATHWAY

University of South Australia. “A drug is a It was a lot better to be born at the end of last century than at the beginning. In 1900, life expectancy wasn’t much over 30 molecule that goes through a journey in someone’s body, and that journey depends Fortunately, many of these mutations can be tested for and identified, thanks to advances in genomics and in genetic years of age. But we ended the 1900s with on interactions with different proteins,” he testing. a life expectancy of 77 years for men and says. “Those proteins are encoded by There are two ways of testing for 83 for women. genes, and those genes vary from person genetic mutations affecting drug Better sanitation, hygiene and nutrition to person and so the journey differs in each metabolism, says Professor McKinnon. played a big part. But it was the person. In most cases the differences One involves looking for the faulty emergence of the pharmaceutical industry won’t mean much but in others these genes themselves; that is to do genotypic that gave us vaccines, antibiotics, differences can have a dramatic impact.” tests to look for the abnormal DNA bases anaesthetics and host of other drugs, that The genetic differences themselves (single nucleotide polymorphisms or SNPs) helped bring the killer diseases of centuries seem minor on the face of it. using polymerase chain reaction (PCR) past under control. In most cases they are just mutations techniques. These tests can be done on So we’ve a lot to be grateful for. in single bases of DNA known as single blood samples or cheek swabs. Still, drug treatment is a clumsy nucleotide polymorphisms (SNPs) - The other approach is to look for the business. It's mostly trial and error; a variations that occur when a single consequences of the abnormality, by doing doctor prescribes a certain drug, hoping it nucleotide (A, T, C or G) in the genome assays of the enzyme(s) that break the will work, and if it doesn’t, tries another. sequence is altered. drug down in the body, or of the There’s not much certainty - one person In some individuals, there may be metabolites of the drug - these are blood responds well to a drug while another is multiple different single base mutations, or tests. resistant to it, or develops side effects so multiple copies of the same mutated Professor Ross Pinkerton is a the drug has to be stopped. sequence. paediatric oncologist at Royal Children's Why? Some people may have inherited the Hospital, Brisbane. We’ve known since the 1950s that people react differently to different drugs; mutations from one parent (this is called heterozygous) or from both parents (homozygous). > and that a person's age, sex, weight, and ethnic background all influence how he or But the consequences can be she will react. dramatic, says Professor McKinnon. But what’s becoming clearer in the Genes that code for proteins that beginning of the 21st century is how affect the way a drug is metabolised may important an individual's genetic makeup is be altered so they work differently or they in determining a person’s reaction to a don’t work at all. particular drug. If, for example, the mutation produces Thanks to an emerging discipline called enzymes that are less effective in breaking ‘pharmacogenetics’, clinicians are down a drug into its metabolites, the increasingly using genetic testing to person will have abnormally high levels of identity who is suitable for a particular that drug in the body, causing toxicity and treatment - enabling clinicians to tailor drug side effects. treatments to particular individuals. If the mutation produces more of the It's not a new concept - the term enzyme than normal, this may lead to pharmacogenetics was coined in 1958 - faster metabolism of the drug, and the but what is new are the advances in our drug is less effective than in the normal understanding of the human genome and population. the technologies we now have to detect Where there are several copies of the abnormalities in individual genetic profiles. same abnormal gene, or the person is Professor Ross McKinnon is Professor homozygous for the altered gene, then the of Pharmaceutical Biotechnology in the effect can be especially dramatic. School of Pharmacy and Medical Sciences PATHWAY_9

One of the drugs he uses to treat children with acute lymphoid leukaemia Identifying the (ALL) is 6-mercaptopurine, a thiopurine drug that is usually well tolerated and used as a maintenance drug. enemy Normally 6-mercaptopurine is broken down in the body by thiopurine methyltransferase (TMT). But some n the world of tailored medicine there are two sides to the equation. I Isolating variations in a person’s genetic profile to see whether a treatment will be effective is an important component of customising therapies. children don’t have this enzyme. “In these children [6-mercaptopurine] is toxic. They get severe neutropaenia, However, on the flipside it is often equally important to know the genetic that is they get dangerously low white cell make up of the disease that is to be treated. counts that leave them susceptible to One area of medicine where this is particularly true is cancer. infection.” The ‘genetic revolution’ has enabled a greater understanding of a whole Other children have greater than range of cancers. normal levels of TMT and in these In lymphoma for example, advances in genetics have led to greatly children, the drug doesn’t have the improved diagnostic accuracy, says Clinical Professor Dominic Spagnolo from therapeutic effect it normally should. the University of Western Australia. The faulty gene can be detected using “Being able to identify antigen receptor genes in B and T lymphocytes genotypic testing, or by testing for the has allowed us to be more definite in difficult-to-diagnose cases of levels of metabolites of 6-mercaptopurine. lymphoma,” he says. “Those kids without the enzyme have Advances in this discipline have also led to the identification and low levels of metabolites, while those with assessment of genes that control cell growth, differentiation and death. higher than normal levels of the enzyme “In lymphoma the inappropriate switching on or off of these genes have high levels of the metabolites,” he correlates with the progression of the disease and indicates how aggressive says. the cancer is likely to be,” says Professor Spagnolo who is also consultant These tests aren’t routinely done on pathologist at PathWest Laboratory Medicine, Perth. children commencing treatment with The presence of such genetic markers therefore has become predictive of 6-mercaptopurine, but they will be done if patient outcomes and hopefully will enable the tailoring of future lymphoma a child shows neutropaenia or isn’t therapies, he adds. responding to treatment. If the test shows In other cancers the use of genetics to determine suitability of particular a faulty gene and/or abnormal levels of treatments is already well advanced. metabolites, the dosage of Breast cancer is a classic example says Dr Adrienne Morey, senior staff 6-mercaptopurine is adjusted. specialist in anatomical pathology at St Vincent’s Hospital, Sydney. Many of the advances in “It is becoming increasingly apparent that breast cancer is not a single pharmacogenetics have been in oncology disease but a group of diseases with different molecular profiles that are (diagnosis and treatment of cancers), linked to specific genetic defects.” largely because of the important role “New therapies are being developed which target different subgroups of genetics plays in the genesis and the disease, the most widely known probably being trastuzumab (Herceptin) inheritance of cancers. and lapatinib (Tykerb) which are indicated only in cancers that have an over- But it is by no means confined to expression of the HER-2 protein to which the drug binds,” she says. oncology. Only one fifth of all breast cancers have this over-expression. Genetic It is now being used in the prevention testing to identify this subgroup ensures these new (expensive) treatments are of blood clots, in inflammatory bowel only given in cases where they will be most effective, Dr Morey says. disease management, in the treatment of As the genetic profiles of more and more cancers are identified, advances high blood pressure and in viral illnesses. in diagnosis, prognosis and effective therapies look set to follow. Genetic testing is already being widely In addition to breast cancer and lymphoma, cancers of the colon, prostate used in the treatment of hepatitis and HIV, and ovary are just some of the many malignancies that are currently the where the genotype of the virus is being subject of genetic research. used to predict the response to drugs, Dr Morey predicts that down the track, more targeted therapies will be says Professor McKinnon. developed and pathologists will be increasingly asked to identify the genetic Some people have an exaggerated profile of individual cancers as such knowledge becomes a fundamental response to the anti-clotting agent, component of determining treatment. warfarin. They may not metabolise it or they may have a gene that increases 10_PATHWAY

“We are still unravelling the genetic differences that underlie the variation in response from person to person. So there are plenty of challenges” warfarin's effects on the clotting cascade. available from the larger pathology labs at “The drug itself may be subsidised by These people are at risk of catastrophic a cost of a few hundred dollars. But others the Pharmaceutical Benefits Scheme but bleeding. Both types of mutations can be can cost thousands of dollars and are only the test isn’t covered by Medicare, so there identified with gene testing, and the available through research centres. needs to be a better alignment of funding dosage of warfarin can be adjusted Conversely, there are huge potential for the drug and the test,” he says. accordingly. Another issue is how well and how cost savings in the form of fewer drugs Psychiatry is another area where being prescribed that don’t work in certain quickly GPs and other clinicians will adapt pharmacogenetics will play an important patients, and less treatment needed for to using pharmacogenetics. It means more role in the future, Professor McKinnon toxic side effects in others. training for GPs who’ll need to improve believes. Clinicians will be able to match their understanding of genetics to get to There are some drugs where it’s differences in a person's biochemistry - the point where they become used to generally accepted that it makes sense differences in their levels of chemical ordering genetic tests for drugs as an aid from a cost benefit point of view to screen neurotransmitters in their brain for to prescribing. individuals before giving the drug, says example - using genetic testing, so their Associate Professor Leslie Sheffield is Professor McKinnon. use of antidepressants and other drugs a clinical geneticist with Genetic Health can be customised. They include mercaptopurine and Services Australia, and at the Royal azathioprine (another thiopurine used in the It is expected that pharmacogenetics is Children's Hospital in Melbourne. He has treatment of solid tumours and other going to be most useful where a drug has been interpreting genetic tests for 25 conditions such as inflammatory bowel serious side effects at a dose not much years. He says there are now tests disease). “With these drugs there's a good greater than the therapeutic dose, where a available for about 30 per cent of all the drug is particularly expensive (so it’s argument that we should be doing genetic drugs in a physician’s armoury (most not important to know the drug will work), and testing before we start treatment to give us yet commercially available but used in where there is known to be a great deal of an idea of how the patient is going to react research labs). variation in a drug’s effectiveness. to them,’ he says. He predicts GPs will eventually Nevertheless genetic testing of drugs is But for most other drugs, there isn’t yet embrace pharmacogenetics because it will still a relatively new field and isn't yet in enough evidence that pre-treatment take much of the hit-and-miss out of widespread use. screening saves money in the longer term. prescribing. “We need more studies done before we There are many issues still to be sorted He’s in the process of setting up a can make those decisions,’ he says. out; such as what drugs should be tested service that will give GPs and other and at what stage of treatment. “We are still unravelling the genetic clinicians access to information about what Also - does the cost justify the benefit? differences that underlie the variation in pharmacogenetic tests are available and Some, such as the older tests involving the response from person to person. So there for what drugs. The service will be cytochrome P450 (CYP) family of liver are plenty of challenges” he says. accessible via a web site that he hopes will enzymes, (which break down many To complicate matters, most of these be online about April this year. The address commonly used drugs) are commercially tests aren’t eligible for a Medicare rebate. is www.genesfx.com. PATHWAY_11

disciplines in depth Back to basics THE MOST RECENTLY RECOGNISED OF THE PATHOLOGY DISCIPLINES, GENETICS IS SET TO HAVE A MAJOR IMPACT ON THE FUTURE OF MEDICINE, AS LOUISE MARTIN-CHEW FINDS OUT. Over recent years, medical success of the Human Genome Project. G enetics is described in the RCPA history, Pathology: Professional professionals will have noticed the increasing interest in this area, with almost This international tour de force, Practice and Politics, as the “Cinderella of coordinated by the U.S. Department of disciplines”. every conference now featuring a genetic Energy and the National Institutes of strand. Yet this discipline has only been a Health, brought scientists together It is a surprisingly apt analogy with its recognised part of pathology and the between 1990 and 2003, to identify the “rags to riches” connotations. Following RCPA since 1996. 20,000 genes in human DNA. what Dr Ron Trent, the inaugural The training program in laboratory It also determined the sequences of Chairman of the Genetics Advisory genetics is available in three different Committee, RCPA, describes as the the three billion chemical base pairs that areas - cytogenetics, biochemical “genetics to genome revolution”, the sub- make up human DNA. genetics and molecular genetics. Since speciality is poised to give a unique and The information from the project has 1996 the diversity of the training required new focus to important health issues in in genetics has grown with the curriculum been stored in extensive databases and the community, becoming an integral part now including the need to understand research is ongoing. of every medical discipline. clinical genetics, which includes aspects The Human Genome Project’s success “Genetics will change the future for of genetics counselling and analysis of has stimulated the creation and rapid inherited disease absolutely”, says Dr genetic information in the clinical setting. growth of the field of genomic medicine Michael Buckley, chief examiner in The exponential increase in interest in within pathology making the development Genetics for the College. genetics can be tied intrinsically to the of an understanding of genetic material on 12_PATHWAY

PHOTO CREDIT: ELIZABETH ADAMS Marcus Hinchcliffe 4th year trainee a large scale possible. Importantly, the Registrar in Molecular Genetics, Project has also resulted in the development of improved tools for data Royal Prince Alfred Hospital, Sydney analysis. In the area of molecular medicine, the Ihave always been interested in molecular genetics and was keen to understand the science better, so after my residency at new knowledge base has already led to the Royal Brisbane Hospital I went back to university to do a an improved diagnosis of disease. Masters in Molecular Biology. I began training in molecular Increasingly, detailed genome maps genetic pathology at the Department of Molecular and Clinical are aiding scientists seeking genes Genetics at the Royal Prince Alfred Hospital in Sydney in 2005. associated with a myriad of genetic Genetic knowledge is rapidly expanding, there’s a lot to keep conditions. These include, for example, up with and I find that very stimulating. Increasingly, molecular myotonic dystrophy, fragile X syndrome, genetics will become central to medicine. Personal genome inherited colon cancer, Alzheimer's profiles will become standard within the next ten years. There disease, and familial breast cancer. will be wide impacts upon diagnostics, cancer profiling and Diagnosis based on the presence of individualised prescribing. specific genes heralds a new era of molecular medicine - characterised less It still amazes me that the complexity of life can be simplified by treating symptoms and more by to the combinatorics of a four letter DNA code. looking to the most fundamental causes The clinical side of our department consults with families of disease. mainly on an outpatient basis. I work on the diagnostic side. Dr Buckley has a special interest in Blood/DNA is sent off to the relevant laboratory. (In Australia muscular dystrophy where genetics is part each lab specialises in a number of tests). At RPA we specialise of routine management. in the haemoglobinopathies, as well as a number of other “Parents want to know first what it is, heritable conditions. secondly if they can stop it happening I will complete my training in 2010. My exams are mid 2008 again and thirdly if it is a consequence of and then I’ll do the PhD component of the RCPA molecular their actions. So far we can answer genetic course. I will be looking at non-coding RNA in the questions one and two. We classify the disease according to gene mutation. If human brain using high throughput sequencing technology. parents are willing to go down the track of falling pregnant and having the necessary analysis and termination, yes we can stop it happening again.” > PATHWAY_13

“Genetics will change the future for inherited disease absolutely”, says Dr Michael Buckley, chief examiner in Genetics for the College. PHOTO CREDIT: PAUL JONES But diagnosis is just part of the information now available, according to Dr preventative or control measures, such as genetics story. Trent. is the case with women with the BRCA1 Understanding the role of certain The trend to automate analysis and and BRCA2 genes for breast and ovarian genes and the significance of their the development of microarray analysis cancers. presence, medical researchers will also be has allowed, researchers to identify As Dr Trent suggests, “[Because of able to devise therapeutic regimens based individual genes, to look at any single this technology] we can predict the on a person’s genetic profile. They will be gene and have access to the information possible consequences for the individual, able to augment or even replace defective from it concerning particular disease. and this possibility, for genetics, is huge. genes through gene therapy. Rational Previously this was too complicated or A handful of conditions have marker drug design, control systems for drugs time consuming. It was also vulnerable to genes, and as the technology improves and pharmacogenomics “custom drugs” human error. even bigger profiles of people’s genetic are other benefits currently under In Australia, new machinery has make up will be a possibility.” development. allowed developments in the revolutionary But this is far from a straightforward areas of personalised medicine and process. Added to the difficulties inherent As Dr Trent notes, the sequencing of predictive medicine. in identifying the genetic markers of the human genome began with modest Personalised medicine, working with disease, researchers have to also ambitions but has had revolutionary by- an individual’s genomes, allows the determine how well that genetic marker products, albeit more complex than development of drugs and medications predicts the disease and whether any originally anticipated. that work best for that individual. Given action can or should be taken. And then “Humans have 20,000 genes. The there is the ethical debate about the risks their genetic profile, the practitioner may pinot noir grape, just sequenced, also has versus benefits of this type of testing. select which category of drugs puts them 20,000 genes. Humans are obviously at least risk and maximum benefit. While the way forward is not without more complex. We need to ascertain how Predictive medicine allows analysis of its challenges, Dr Trent says informatics it all works, how it interacts with the an individual’s DNA to identify genetic will have an important role to play. The environment. We need answers to these markers that signal that person’s sequencing of a genome and the questions.” depositing of this information within a predisposition to particular diseases. Advancements in genetics have been Identification of such genetic mutations database still requires interpretation, and possible in a large part by the technology prior to the disease causing any today, most of the genome information in developed to manage the bonanza of symptoms, enables a person to take the databases remains unintelligible. He 14_PATHWAY

Kym Mina 1st year trainee indicates that better informatics and Registrar in Molecular Genetics, algorithms will make more sense of this PathWest, Perth information in the future, and more training in the clinical genetics area will be required to interpret the vast amount Istudied medicine at The University of Western Australia and completed my intern year in 2000. I worked as a resident at the Royal Perth and Sir Charles Gairdner Hospitals but then took of data that will be generated. some time away from medicine and had two children (now two While there has been a small increase and five years of age). At the same time I worked toward my in the number of trainees in this field of PhD (completed end 2006) in Public Health (epidemiologic pathology, there are insufficient trainee methods). My training and work as a registrar in Molecular positions funded by governments to cope Genetics immediately followed. the demand for genetic pathologists. I am employed by PathWest which has laboratories (for both “The workforce will have to be molecular genetics and cytogenetics) in the public hospitals here educated, to become more savvy in Perth, so I rotate through different hospitals for my training. At concerning genetic issues. Otherwise the the moment I am working at Sir Charles Gairdner Hospital, but I level of testing required and the numbers have also worked at Royal Perth Hospital and King Edward of clinical geneticists needed will become Memorial Hospital during 2007. unsustainable. There are important While there was no direct relationship between my PhD topic questions which need to be addressed in and laboratory genetics, when the opportunity to do this job terms of these workforce issues as arose I found it irresistible. I have always found molecular genetics becomes part of every medical biology and genetics interesting, even at school, but had not discipline,” Dr Trent says. worked in the area previously. I am naturally analytical and Genetics, as the Cinderella of the methodical and hence genetics and laboratory work fit well with pathology disciplines, has well and truly both my personality and interests. Genetics is also very arrived at the ball. appealing because of its relative newness in comparison to other As a direct result of all the advances fields of pathology and its growing medical relevance and in knowledge and technology, genetics is applications. playing an increasingly important role in I have now been working in this position for one year and I the diagnosis, monitoring and treatment am enjoying it immensely. This is a new position and as a result of diseases. Its revolutionary nature and we’re all learning; primarily about how best to train a genetic importance is such that genetics is pathologist, but secondly about how such a pathologist might fit poised to become arguably the foremost into a complex and expanding genetics workforce here in WA. science of the 21st century. PATHWAY_15

in profile Family matters IF YOU OR YOUR GP HAS EVER SUSPECTED THAT YOUR DNA MIGHT INCLUDE A HEREDITARY RISK OF CANCER, THEN YOU’VE PROBABLY BEEN REFERRED TO A FAMILIAL CANCER SERVICE. AND EVEN IF YOU DON’T LIVE IN THE SAME STATE, THERE’S A GOOD CHANCE THE SERVICE YOU HAVE VISITED HAS BEEN INFLUENCED BY THE WORK OF THE SOUTH AUSTRALIAN SERVICE, JUSTINE COSTIGAN MEETS GRAEME SUTHERS, THE MAN BEHIND THE CUTTING EDGE APPROACH TO FAMILIAL CANCER. riginally specialising in paediatrics in O Sydney, where he grew up, Graeme But it’s his work in the field of familial cancer that has clearly dominated the last ten years of his career. In 1998 he Suthers wasn’t thinking of pursuing a career in genetics. But after a young established the Familial Cancer Service in patient with homocystinuria (an inherited South Australia where he remains deficit of amino acid metabolism) piqued Program Director to this day. his interest, Dr Suthers changed track to “By the mid 1990s, there was growing specialise in the field that has since awareness that a tendency to develop inspired a life-long interest in DNA and cancer could be familial,” says Dr Suthers, gene technology. explaining the reasons for establishing the Australia, as elsewhere, there was a rising service. “And instead of clinical Combining an interest in both clinical tide of referrals to talk about familial geneticists always being paediatricians and research work, Dr Suthers went on breast cancer and familial bowel cancer.” dealing with children and reproductive to complete a PhD in Fragile X syndrome When Dr Suthers established the issues and so on, the geneticists had to at the Women’s and Children’s Hospital start making some linkages with the service it was one of Australia’s first and in Adelaide and further research at clinicians and services operating out of quickly became a leader in its field - an Oxford University. Returning to clinical adult hospitals. And that was novel. That achievement that his peers readily work, he was subsequently accredited as really hadn't happened very much. We attribute to Dr Suthers’ powerful a specialist clinical geneticist in 1993 also saw a growing demand from patients combination of vision and drive. and, more recently, as a genetic saying we want to come and get our “Graeme saw very quickly that clinical pathologist in 2002. genetic situation sorted out. In South genetics was becoming a sub-specialty,” 16_PATHWAY

“It was Graeme’s vision that got [the Familial Cancer Service] going and he has worked very hard and very successfully to bring so many different people together to work at such a very high standard.” PHOTO CREDIT: TONY LEWIS says Professor Eric Haan, Head of the Haan, “and Graeme’s delivery of an being confronted with the thought of a South Australian Clinical Genetics Service integrated service to patients has been pending serious disease can be daunting. who first met Dr Suthers when he came to one of his most important contributions Not only does the idea of a potential (or South Australia to do his PhD. (to genetics) so far.” actual) health threat cause alarm, but “It was Graeme’s vision that got [the At the heart of the Familial Cancer understanding the genetic process and Familial Cancer Service] going and he has Service is the role clinicians and the risks to yourself or your family can be worked very hard and very successfully to counsellors play in helping people come a challenge. bring so many different people together to to terms with the knowledge they may One of Dr Suthers’ strategies to help work at such a very high standard.” have an increased risk of cancer. his patients understand how genetics “The Familial Cancer Service has been For those with only a basic works is to highlight the universality of an Australian leader,” continues Professor understanding of science or medicine, mutations. When patients understand that PATHWAY_17 >

“Cancer is generally perceived to be something that comes out of the blue and strikes people at random. A more realistic view is to recognise that cancer is the result of a slow burning fuse, and we all have a fuse that is burning.” the corrosion of one’s individual genetic heritage is intrinsic to every one of us, it can help minimise the anxiety of a birth defect or the word ‘cancer’. RCPA urges As he laconically explains it, “Your genes are becoming rusty.” National Genetics Framework “I think that we still have a major job to do in terms of giving cancer better press, if I can put it that way,” says Dr T he RCPA is calling on the federal government to develop a National Genetics Framework to deal with urgent issues relating to the future of the specialty including; regulation and external quality assurance for genetic Suthers. testing; the collection and interpretation of data; the development of an “Cancer is generally perceived to be appropriate framework for making ethical decisions; and the creation of a something that comes out of the blue and national register of funding for genetic tests. strikes people at random. A more realistic Also the College is concerned at the lack of long term planning for the view is to recognise that cancer is the management and growth of genetics. result of a slow burning fuse, and we all Currently there are eleven qualified Genetic Pathologists in Australia, with have a fuse that is burning. And the thing few training positions available and a lack of Clinical Geneticists and Genetic that varies is the rate at which it burns, or Counsellors. how long the fuse is. Cancer is an inevitable consequence of being alive. Genetics is a rapidly changing specialty and the potential for it to Cancer is one of the ‘privileges’ that challenge how we look at healthcare is considerable. comes from living in a peaceful developed Testing DNA for the degree of genetic fragility and degradation is now society.” possible (though still experimental) and has the potential to reduce the burden One of the most rapidly changing of degenerative diseases in the community. Yet who will benefit from this specialties, keeping up to date with technology, and who should pay for it? advances in technology and new Although many of these issues are currently being addressed by the information is a necessity. NHMRC Human Genetics Advisory Committee, the AHMAC Clinical, Technical “It’s a bit scary to see how quickly and Ethical Principal Committee, the RCPA Quality Use of Pathology Project and the PSTC/RCPA Alternative Funding Proposal, the RCPA is urging the your carefully nurtured skills and Government to create a National Genetics Framework to ensure consistency knowledge become out of date in this of testing and ethical guidelines across Australia and to develop a national field. You have to keep reinventing framework for planning. yourself. Once you’re a cardiologist or a respiratory physician, you’re always pretty much a cardiologist or a respiratory physician. But in genetics, you need to reinvent how you perceive your discipline want to know about the sorts of ethical himself occupied until retiring a year ago, and your skills. And it does require quite concerns, training and mindset that was Dr Suthers “looks at the big picture and constant footwork, I think, to maintain being inculcated by those at the forefront your usefulness as a clinician.” takes on the issues with drive and of research during the 1980s.” The speed of change also impacts the enthusiasm - which is what you need if The ethical considerations of DNA challenges for the specialty as a whole. testing is just one of the many reasons you are going to take on the hospital While ethical frameworks for the medical why Dr Suthers is promoting the concept system.” profession are being developed and of a National Genetics Framework (see refined, private enterprise simply speeds Dr Graeme Suthers is the program director of ahead. box) as part of his role as Chairman of the the South Australian Familial Cancer Service, RCPA Genetics Advisory Committee. “It hasn't taken long for the field to senior visiting consultant in clinical genetics to explode well outside the reach of clinical Professor of Molecular Genetics at the a number of teaching hospitals in Adelaide, geneticists. We now have all sorts of University of Sydney, Ron Trent, says that and consultant genetic pathologist to the health care providers and laboratories and Dr Suthers has always showed leadership. State’s largest public sector laboratory (IMVS) commercial companies doing genetic As the incoming Chairman of the and is the Chairman of the RCPA Genetics testing and they don’t necessarily know or Committee, a position Professor Trent Advisory Committee. 18_PATHWAY

NT-proBNP The Power of Standardisation “NT-proBNP... showed the best power, compared with the other immunoassays... for separating healthy individuals from patients with mild symptoms of heart failure.” 1 Acute diagnosis/differentiation of CHF 2 Prognosis of CHF and risk prediction 4 Diagnostic aid for LV Dysfunction 3 Monitoring of CHF therapy 5 1000 951 900 Roche Elecsys proBNP 800 BNP/NT-proBNP Levels (pg/mL) 700 600 500 400 Abbott AxSYM BNP proBNP cut-off – 125 pg/mL 342 300 266 222 200 Biosite Triage BNP 133 130 100 95 BNP cut-off – 100 pg/mL 64 Bayer BNP 0 Normals NYHA I NYHA II Data taken from Product Package Inserts Troponin T, NT-proBNP assays standardised from Point-of-Care to high throughput systems. cobas® 6000 cobas h 232 Elecsys® Point of Care High throughput results in laboratory test 12 minutes Roche Diagnostics Australia Pty. Limited ABN 29 003 001 205 PO Box 955 Castle Hill 1765 Australia Ph: (02) 9860 2222 1. Clerico et al. Clinical Chemistry 2005;51(2):445-7. 2. Januzzi JL et al. Am J Cardiol 2005;95:948–954. 3. Gustafsson F et al. Heart Drug 2003;3:141-146. 4. Kragelund C et al. New Engl J Med 2005;352:666-75. 5. Richards AM, Troughton RW. Eur J Heart Fail 2004;6(3):351-4. PB3299/02-08 COBAS and COBAS H are trademarks of Roche. ©2007 Roche Diagnostics

testing testing THE PCR OF

DISCOVERED BY ONE OF SCIENCE’S MORE COLOURFUL CHARACTERS, POLYMERASE CHAIN REACTION HAS CHANGED THE FACE OF MEDICAL DIAGNOSIS AND DNA DETECTION. BIANCA NOGRADY REPORTS.. Kary Mullis’ entire Nobel autobiography S ix months before the 1993 Nobel Prizes were due to be announced, is unusually dedicated to a portrayal of his Kary Mullis’ mentor, University of family and upbringing. At the very end of California Berkley biochemist Joe the document, a single, brief sentence Neilands, suggested to him that “you’d acknowledges his momentous role in make it easier for the [Nobel] committee scientific history: “I worked as a to give it to you if you didn’t talk to the consultant, got the Nobel Prize, and have press so much”. Not that Mullis’ work now turned to writing. It is 1994.” was in any way controversial - far from it. What this sentence fails to capture is He had developed the polymerase chain the significance of his discovery, and why reaction; a technique for amplifying it was judged worthy of one of science’s segments of DNA that was soon to greatest accolades. revolutionise molecular biology. “It has been absolutely What had Neilands on edge was his transformative,” says microbiologist Dr protegé’s openness about his use of LSD, David Smith, Head of the Division of and to a lesser extent, his enthusiastically Microbiology and Infectious Diseases at proclaimed fondness for women and PathWest Laboratory Medicine WA. surfing. Thankfully, the Nobel Committee PCR allows scientists to locate within saw fit to overlook these apparent a mess of DNA and RNA a short transgressions, and in 1993 awarded sequence of base pairs that is unique to Mullis the Nobel Prize in Chemistry for his the organism they are trying to detect. A discovery of the polymerase chain reaction is then set in motion to multiply reaction. this stretch of DNA or RNA over and over Mullis is an intriguing character. again until it reaches a concentration high Raised on a farm in rural North Carolina, enough to be detectable, or usable for he studied chemistry then completed a other purposes. PhD and lectured in biochemistry, before The ready identification of DNA and joining biotechnology company Cetus RNA through PCR testing has wide- Corporation as a DNA chemist. While ranging applications from prenatal working here, he made the discoveries screening to testing of adults for that led to the polymerase chain reaction. susceptibility to diseases such as breast But far more interestingly, he has also and bowel cancer. It can be used to help been tabled as an expert witness in the predict a patient's response to a O.J Simpson murder case (although was particular drug, or provide more accurate never called to the stand), has stirred diagnosis of diseases such as cancer controversy with his views on climate helping with prognosis and therapeutics. change and the link between HIV and PCR testing also enables rapid genetic AIDS, has been quite forthcoming about identification of infective micro-organisms, his use of LSD in Berkley during the 60s a process that is now standard for a and 70s, apparently believes in astrology, range of infections from chlamydia to and is a keen surfer. pertussis. PATHWAY_21 >

PCR is also extremely sensitive and extremely specific, meaning that it will detect even the smallest amounts of a DNA sequence, and will only detect that exact sequence. As simple as it may sound, this it can also provide a valuable source of While Mycobacterium tuberculosis approach has enabled a quantum leap in genetic material for use in other might be slow growing, at least it can be progress. Compared to conventional experiments - DNA cloning. “PCR can cultured. Other pathogens, such as detection methods, PCR enables also be used to generate material which hepatitis C, have proven extremely detection of organisms that are dead or you can use to further characterise that difficult to culture. However PCR’s ability degraded, difficult to culture, present in organism,” Dr Smith says. to detect even the tiniest amount of levels too low to detect with conventional In pathology, PCR has a number of bacterial or viral DNA without requiring methods, in a wide range of samples, and applications. It can be used to detect a culture means it has become essential for can now be done within a matter of hours. wide variety of genetic diseases, the diagnosis of diseases such as hepatitis C. The PCR process consists of two amplification enabling pathologists to It is also enabling researchers to, not stages (see box). In the first stage, the recognise insertions, deletions or only diagnose, but learn more about a DNA of the sample is heated to separate mutations that characterise certain pathogen, providing information that may it into single strands, then the mix is hereditary diseases such as Duchenne affect management of the infection. Drug cooled and special DNA primers are muscular dystrophy. resistance is a particular concern when added to seek out a short sequence of “It’s very useful for detecting bacteria treating diseases such as HIV. The DNA that is unique to the organism being or DNA viruses, because you can amplify prevalence of drug-resistant HIV is currently tested for. Once those primers find and the small amount of signal material there is estimated at around 10% of new infections, lock onto their target, an enzyme is added to give you a measurable piece of DNA,” so detecting that resistance early can make to create multiple copies of that particular says microbiologist Professor Peter Coloe, a significant difference to the choice and target. By repeating this entire process of head of Applied Sciences and professor of efficacy of antiretroviral medication. thermal cycling again and again, scientists biotechnology at Melbourne’s RMIT. “Researchers can do a virtual can amplify that unique DNA sequence to phenotype to work out the likely Even when that signal material is a level where it becomes detectable. resistance to antiretrovirals,” Dr Smith thousands or even millions of years old, The second stage involves adding PCR can still be used. In a Jurassic Park- says. “They use PCR methods to amplify DNA probes that will bind to that style scenario, DNA has been extracted up the viral RNA and then from the sequence, and which are tagged to allow sequence of that RNA they can tell from insects preserved in amber more their concentration to be assessed. whether it’s likely to be resistant or not.” than 20 million years ago, and amplified When PCR was in its early days, each up into useable quantities by PCR. The same technique has also been used of these steps was done separately and Ancient Egyptian mummies have also to determine whether a particular strain of would take several days to complete. been probed for the DNA remains of the the H5N1 influenza virus is likely to be “You used to have to put them into pathogens that plagued them, and PCR resistant to a particular neuraminidase the thermal cycler, then leave it to run for used to diagnose their ailments several inhibitor - a class of drugs that includes 30-40 cycles and then you took them out thousand years after they died. Using this oseltamivir (Tamiflu) and zanamivir of that machine and put them onto gels to technique, scientists have been able to (Relenza). read them,” Dr Smith says. “With real- posthumously diagnose tuberculosis from PCR is also extremely sensitive and time PCR machines it’s actually a tiny fragment of lung tissue taken from a extremely specific, meaning that it will monitoring as it goes through.” This mummy. detect even the smallest amounts of a means the machine is calculating levels of Unfortunately for this Egyptian, the DNA sequence, and will only detect that your target sequence as it replicates it, diagnosis may have come a little too late, exact sequence. and can alert you as soon as a target level but the diagnosis of tuberculosis in “In pathology, it’s going to give you has been reached. Cycling times have modern times has also benefited from ways of detecting very low levels of also improved considerably, so now each PCR. Mycobacterium tuberculosis - the organisms and you’ve got a level of thermal cycle to denature and anneal the bacteria that causes the disease - is specificity that you might not have had by DNA strands and primers takes around particularly slow growing, which means conventional microscopy or culture,” says one minute. Within just a few hours, the diagnosis by conventional means can Professor Coloe. “It gives you a high level original target sequence of DNA can be take a long time. In contrast, PCR doesn’t of specificity because you’re using copied several million times. require the bacteria to be cultured, so a primers that will only bind to specific This not only enables detection of diagnosis using nucleic acid detection regions where the DNA is a perfect organisms or features of those organisms, takes just a few hours. match.” 22_PATHWAY

What is PCR? “PCR is one of the techniques used for what we call nucleic acid detection test,” says Dr David Smith. “What that means is that we detect the RNA or DNA of the nucleic acid rather than, in the case of infectious diseases, the organisms.” The technique has a variety of applications. As well as diagnosing However that extreme sensitivity can hereditary and infectious diseases, PCR can also be used for DNA cloning also be a problem. “You can occasionally for sequencing, identification of genetic ‘fingerprints’ used in forensics and detect levels of organisms… in such low paternity testing including, as well as the functional analysis of genes. concentrations that they might not constitute a disease problem,” Professor Coloe says. “That becomes an issue But how is it done? when you’re dealing with things like water and looking for the presence of things like Giardia - there might be T o start with, you need to know the genetic sequence of the particular organism you are looking for in a sample. That information is easily obtainable from public ‘libraries’ of DNA and RNA sequence data, such as extremely low levels, you pick them up GenBank in the US, European Molecular Biology Laboratory's European but whether it constitutes a clinical Bioinformatics Institute and the DNA Data Bank of Japan. “You’re looking problem is questionable.” for parts of the sequence of the organism which are found in all strands of It also means PCR may detect the that organism and which are only found in that organism; usually an area presence of a dead organism that is long between 80-200 base pairs in length,” Dr Smith says. The next step is to past being a biological threat. “If the create smaller fragments of DNA about 20 base pairs in length that are organism is still there in the sense that it designed to pair with either end of your larger sequence - these are called hasn’t been degraded, the DNA is still primers. there but the organism is not alive, but you These two ingredients, plus the enzyme DNA polymerase, are then can still get a positive response,” he says. combined in a thermal cycler, which first raises the temperature high But, there is an upshot to this - PCR is enough so that the double-stranded DNA and primers denature, or peel particularly useful in situations where apart into single strands. The cycler then lowers the temperature to allow samples haven’t always been kept in the strands of primer to anneal, or bond, to their target at one or the other optimum conditions, according to Dr Smith. end of the target sequence on the larger DNA strands, creating a collection “The organism doesn’t have to be of single stranded DNA with a primer attached. alive, which means it’s particularly good Now the DNA polymerase comes into play. Starting from one end of for samples where there are difficulties in each primer, this enzyme reads back along the single strand of DNA, storage or transport,” Dr Smith says. “This copying as it goes. After repeating this process several times, the end is a big advantage in testing in remote result is two double-stranded copies of the target DNA sequence. The areas where it’s very difficult to get live whole process is then repeated again, and each time it is repeated, the organisms, particularly things like viruses target sequence is copied. which tend to be fragile.” “Commonly you’d use anywhere between 30-50 cycles, so you end up So what is the future for PCR testing? with a lot of material… but once you amplify it you have to know you’ve Dr Smith believes the next step will amplified the product you’re interested in,” says Dr Smith. This is done by likely be to make the test more adding in a probe that binds to a specific section of the DNA and is tagged transportable. “How do we make these with a particular enzyme label or fluorescent tag that can be easily tests more accessible?” he asks. “At the detected and measured. moment, they’re confined to relatively large laboratories, so how do we make them easier to deliver in small laboratories?” Making the test more transportable will also at the bedside you’re not going to go thanks to improvements in technology enable its use in very remote areas or even through a PCR amplification process.” and biochemistry. It’s hard to know in scenarios such as on the battlefield. However PCR may be used to produce whether the man who is credited with However Professor Coloe says PCR is the material that might be used in a hand- developing PCR could fully appreciate the not likely to reach the stage of being a held device, for example to detect the impact his discovery has since had on bedside test any time soon because of presence of herpes simplex virus in a cold biological research and medicine. the need for the amplification process. sore.” His reaction to the announcement that “Remember that PCR still relies on the temperature cycling,” he says. “In the PCR has come a long way in terms of he had won the Nobel Prize gives some pathology laboratory that’s easy to do but speed and efficiency since its invention, indication - he went surfing. PATHWAY_23

close up

Human chromosomes. Coloured scanning electron micrograph (SEM) of a group of human chromosomes. These structures occur in the nucleus of every cell in the body, carrying genetic information in the form of DNA (deoxyribonucleic acid), arranged in discrete segments known as genes. Apart from the sex cells, every human cell contains 46 chromosomes, 23 inherited from the father and 23 from the mother. The chromosomes shown here have replicated themselves during cell division and so consist of two identical strands (chromatids) linked at their centre by a structure known as a centromere. PHOTO CREDIT: ANDREW SYRED / SCIENCE PHOTO LIBRARY

spotlight on disease Metal detectors THERE ARE DISEASES WHERE THE CAUSE IS UNKNOWN, WHERE THE DIAGNOSIS IS DIFFICULT, AND WHERE THE TREATMENT IS COMPLEX AND EXPENSIVE. HAEMOCHROMATOSIS IS NOT ONE OF THESE DISEASES. SO WHY THEN, DESPITE A KNOWN CAUSE, A RELATIVELY STRAIGHTFORWARD TESTING PROCEDURE AND A SIMPLE TREATMENT, ARE THERE PEOPLE WITH THE DISEASE REMAINING UNDETECTED UNTIL THEIR ORGANS ARE IRREVERSIBLY DAMAGED, AND WHY ARE MILLIONS OF DOLLARS BEING WASTED ON THE INAPPROPRIATE TESTS? MATT JOHNSON INVESTIGATES. amount and, with no natural way to noticeable to debilitating and perhaps T hink of seven friends to whom you are not related. The odds are one of you is carrying a single mutation of C282Y. excrete that much iron, it can accumulate even eventually fatal. to levels more than 20 times what the The most common cause of iron C282Y is a common mutation of the body needs. overload, hereditary haemochromatosis, is HFE gene which, until the 1990s, lay There are now two known mutations also the most common genetic disorder in undiscovered on chromosome six, but Australia, affecting an estimated one in of the HFE gene: C282Y and H63D, and has, for millions of years, been controlling every 200 to 300 of the population. while a single mutation of either may how much iron is absorbed from food. Because of its genetic nature, as many as increase your iron absorption and storage, Individuals without the mutation 25% of the siblings of haemochromatosis it probably won’t accumulate sufficiently absorb only about 10% of the iron sufferers will also develop the disorder. to develop haemochromatosis, the contained in the food they eat: a The symptoms of haemochromatosis disease associated with too much iron. sufficiently wasteful process that are both common and vague, and don’t combined with a nutritionally poor diet But if you are homozygous - that is usually present in men until their mid 30s, puts many people at risk of iron you have two copies of the mutation, a decade or two before women who are deficiency. one inherited from each parent - then partially protected by the iron lost during In contrast, those with the C282Y it’s likely you will be struck with menstruation and pregnancy in their mutation absorb up to three times that symptoms that can range from barely reproductive years. The most frequent 26_PATHWAY

One North American study found one in three people with iron overload had met with more than 11 doctors before receiving the correct diagnosis. With so many of the initial symptoms being attributable to other conditions, and because excess iron damages organs slowly, the disease was often well established with irreversible organ damage having already occurred before the diagnosis was made. symptoms of haemochromatosis are joint clinical detail in the requests for his team prompted the test. You can have a very pain and fatigue, but they can also to provide an accurate interpretation of different report on the same result include abdominal pain, loss of sex drive, the result. depending on why the test was ordered,” and shortness of breath. “When it was created the HFE test he said. Because there are few characteristic was assigned a Medicare item number The problem, according to Dr Ravine or reliable symptoms that differentiate and laboratories set themselves up to is that the link between the gene mutation haemochromatosis from other conditions, conduct the test, so it very quickly and the disease is far less perfect than diagnosing the disease is notoriously became routine,” Professor Ravine people appreciate. difficult. explained. “It became like a routine “When the genetics of One North American study found one sodium test, but it’s actually a very haemochromatosis were first discovered in three people with iron overload had met different type of test.” the basic view was that it was one gene, with more than 11 doctors before > “The interpretation of this test is totally one mutation, and you’ve got iron receiving the correct diagnosis. dependent on the clinical indication that overload,” he explained. With so many of the initial symptoms being attributable to other conditions, and because excess iron damages organs slowly, the disease was often well established with irreversible organ Organs affected by damage having already occurred before the diagnosis was made. haemochromatosis Not surprisingly the discovery of the genetic cause of the disease and the establishment of an accurate test for the Liver As the major site of iron storage, the liver is often the first HFE mutations was expected to radically organ to display the effects of haemochromatosis. Pain, improve the management of the disease. swelling and cirrhosis can all develop and the disease But a misunderstanding about the increases the risk of liver cancer. test’s ability to link non-specific symptoms to a definitive diagnosis has led to widespread inappropriate use of the genetic test according to David Ravine, Professor of Medical Genetics at the Heart Cardiac failure can occur with very little tissue iron University of WA and genetic pathologist at PathWest at the Royal Perth Hospital. Professor Ravine and his team deposition but it can also occur suddenly once the iron recently conducted an audit of requests levels have reached extremely high values. Once it appears, heart function tends to rapidly deteriorate. for HFE testing submitted to their laboratory. The audit took 187 HFE test requests and, by referring to hospital notes or conferring directly with the doctor who Hormonal requested the tests, the audit tried to Diabetes is common in people with haemochromatosis as iron accumulates in the pancreas. People develop overt determine if the tests were appropriate diabetes mellitus requiring insulin therapy. Excess iron can and could therefore provide accurate results. The audit found that up to 57% of also cause pituitary dysfunction and reduced sex hormone HFE test requests are made for production that can lead to infertility. inappropriate reasons. And in more than a third of cases there was not enough PATHWAY_27

Haemochromatosis before Chronic Fatigue Researchers have called for doctors to exclude haemochromatosis before diagnosing and commencing treatment of Chronic Fatigue Syndrome (CFS). Although also a symptom of liver failure and cirrhosis, fatigue has proved the most common symptom present at diagnosis of haemochromatosis. “That’s not the case. The link between But the dilemma faced by Dr Ravine program had also proved very popular genotype and iron overload is not and his associates is to not create a with physicians. perfect,” he said. “There are actually situation where the prevalence of the “It’s a collaborative approach that several genes involved and since that first disease is underestimated. helps the doctor understand what are the discovery our awareness of the nuances “Significant iron overload may be best tests for the condition they are that go with that are increasing.” uncommon, but it’s still being seeking.” But he is pessimistic about it Interestingly, the message coming underdiagnosed, so we still want to get being introduced in Australia. from Dr Ravine’s and similar studies is for doctors thinking about it,” he said. The “The system doesn’t permit this sort doctors to use older tests to identify best chance patients have for a diagnosis of interaction here, and while it would be patients with iron overload before they is when they build a relationship with a expensive it’s probably not as expensive search for the cause of the accumulation. single doctor who can conduct tests in a as what we’re currently doing.” “Serious iron overload is pretty logical order. Compared with the complexity of uncommon when compared with the Professor Ravine has been interpreting genotype test results, treating number of people with HFE mutations,” Dr encouraged by the response of doctors to haemochromatosis is startlingly Ravine said. “One in four of us are carriers his study but is concerned there is no system in place to change the way the straightforward and effective. of the various mutations, so just testing for that will identify a lot people who don’t test is ordered. Ridding the body of excess iron actually have the disease.” “We identified a misunderstanding simply requires removing blood the same about the clinical utility of the genotype way it is drawn from donors at blood Dr Ravine’s position aligns with the Medical Benefits Scheme indications for test,” he said, “and having spotted that, banks. requesting a HFE test, with the return of the solution is to educate doctors. But Based on the severity of the iron at least two positive tests for elevated iron that’s a long term, major undertaking - a overload, 500ml of blood is to be taken result before requesting genotype testing. generational change and in the meantime once or twice a week for several months. we’re spending millions inappropriately.” Blood ferritin tests conducted periodically “If you’re thinking haemochromatosis, measure the iron first, then if that comes Massachusetts General Hospital in the monitor iron levels and when they reach back positive, then test for the gene,” USA also identified this problem and, the low end of normal the withdrawals are reinforced Professor Ravine. according to Professor Ravine, has reduced in frequency. The treatment instituted a better system. needs to continue indefinitely but it will The serum transferrin saturation test and serum ferritin concentration tests “They make sure someone talks to the usually prevent further organ damage. used to assess iron levels in the blood are doctor so we know why the test was Because early detection and treatment both sensitive and reliable tests that requested,” he explained. are so effective, a number of researchers geneticists described as phenotypic - that “This allows the pathologists to have proposed widespread screening for is, they show patients who actually have integrate the genotype results with the haemochromatosis would be cost- the disease rather than just having the clinical indications. It’s been hugely effective depending on the type of testing genes that can cause it. successful,” he said, adding that the conducted. 28_PATHWAY

Testing for blood iron is relatively indicated those who tested positive were The greatest impediment to screening inexpensive but it has to be done twice to not anxious about the result. remains cost. confirm a diagnosis while, as has already In a difficult process Professor Professor Delatycki has recently been been shown, HFE gene testing will Delatycki was also able to reach an capture a large number of people who granted funding to conducted a health agreement with the health insurers to not don’t have the disease. discriminate against these individuals. economic study into the cost benefit Associate Professor Martin Delatycki, “In the end it’s in everyone’s interest relationship of testing just such a group. Director of the Bruce Lefroy Centre at the to prevent the disease,” he said. But those results are years away and Murdoch Children’s Research Institute Since that study Professor Delatycki until then, Professor Delatycki is reinforcing and also Clinical Geneticist at Genetic has also been involved in a study which the need for early detection by GPs. Health Services Victoria, is one of the found 28 per cent of men in their 60s who many researchers trying to find the most were homozygous had very significant “There’s good evidence GPs are effective screening plan for disease. thinking more and more about haemochromatosis. This, according the Professor haemochromatosis, but we’d like to pick “One of the first issues raised in any Delatycki contradicted earlier studies that up more people earlier so we need to form of genetic screening is the stress of had predicted only 1% would by severely keep reminding doctors to have a very knowing you have a predisposition to a affected. low threshold for requesting iron studies,” condition that you may never develop, “It’s a strong indicator for genetic and that it might impact on your ability to he said. screening,” says Professor Delatycki who get insurance,” he explained. wants to take advantage of the fact “Until screening starts that’s still our But the results of the Haemscreen haemochromatosis is rare before 30 years best way of helping these patients.” study conducted by Professor Delatycki in of age. which 11,000 participants were assessed “Young males traditionally don’t go to for anxiety and health perception before GPs, so screening them in high school GPs NOTE: This article is available for and after genetic testing found a genetic may be feasible as it virtually captures the patients at http://pathway.rcpa.edu.au predisposition to haemochromatosis , entire population.” Your WORLD RECOGNISED ACCREDITATION Partner in Clinical Genomics Enabling Clinical Genomics Drug Metabolism / Pharmacogenomics Microbial Identi cation Cancer - Chromosome Copy Number - Linkage Analysis - Array CGH - Loss of Heterozygosity Email: appliedgenomics@agrf.org.au PATHWAY_29

In the eye of the beholder hile for many, the Renaissance W masterpieces are the epitome of fine art, for some scientists, the works represent a hidden fascination with the anatomy of the human brain. Writing in the Journal of the Royal Society of Medicine (2007;100:540-543), four UK scientists describe examples of hidden symbolism in Renaissance paintings by artists such as Rafael, Michelangelo and David. The theory is that the artists used the imagery to conceal their fascination with the The artistic anatomical representation anatomical discoveries being made at the time, as such interest was often was first suggested by another scientist, FL Mershberger, who believed the cloth Heart disease branded as sacrilegious by the clergy who were likely to have commissioned and figures behind God in Michelangelo’s Creation of Adam resembled the sagittal on the rise the artwork. section of the human brain. T he decline in coronary artery disease seen in western countries in recent times may have come to an end, trends seen in autopsy findings suggest. Epidemic of diabetes and In a US study of 425 autopsies of people who died of unnatural causes cardiovascular disease between 1981 and 2004, researchers found that the temporal decline observed in the grade of coronary disease ended drive to the nearest shop,” the article A Spam-fuelled epidemic of diabetes and cardiovascular disease is says. after 1995 “and possibly reversed after 2000.” rampaging through the South Pacific, the "Even if you go into a store in a The findings are based on data from UK’s Daily Telegraph reports. remote village you'll find shelves of Spam death certificates and pathology reports and corned beef," the piece quotes Dr among Olmsted County residents aged The Telegraph notes the tragedy of a Jan Pryor, the director of research at the 16 through to 64 years. Writing in the region once famed for its lithe inhabitants Fiji School of Medicine, as saying. Archives of Internal Medicine (2008;168: driven to health crisis by a luncheon meat World Health Organisation figures 264-270) the study authors say their “lampooned by Monty Python and show that eight of the world’s 10 most findings provide “some of the first data to spurned by British shoppers.” obese nations are in the region. support increasing concerns that “Where once islanders ate fish, declines in heart disease mortality may Nauru, former home to Australia’s vegetables and coconuts, burning off “Pacific Solution” detention centre, tops not continue.... The extent to which excess calories by casting nets from the table with 94.5% of adults defined as recent trends are attributable to the canoes and farming small plots of land, obese. Similar problems are repeated epidemics of obesity and diabetes now they eat tinned, processed food and across the South Pacific. mellitus awaits further investigation.” 30_PATHWAY

Prostate Glucosamine Magnesium predictor interaction prevents A genetic test for hereditary prostate cancer appears to be around the R gallstones egulatory authorities are warning doctors of an interaction between the alternative arthritis remedy glucosamine corner, with the successful identification of an array of gene markers for the and warfarin. M agnesium-rich foods such as nuts may help prevent gallstones, US researchers say. disease. In its recent bulletin (Volume 27, February 2008), the Adverse Drug In a prospective study of more than In a study of over 4000 Swedish men, Reactions Advisory Committee (ADRAC), 42,000 men over a 17 year period, researchers from the Karolinska Institute says it has received 10 reports of patients researchers at the University of Kentucky and their American colleagues found the showing an increase in their INR after found that men with higher intakes of presence of a number of genetic starting glucosamine. magnesium-containing foods had a variations, along with family history of significantly lower rate of symptomatic The mechanism behind this interaction prostate cancer increased the likelihood gallstone formation. is still unknown, but the effect of of the cancer more than nine-fold. glucosamine on warfarin activity is The findings, published in the They found 16 single nucleotide consistent with reports received by other American Journal of Gastroenterology polymorphisms, in five different regions of drug monitoring bodies overseas, (103:375-82), were supported by other chromosomes 8 and 17 were common to evidence that magnesium deficiency including the WHO Collaborating Centre men with prostate cancer. causes dyslipidaemia and insulin for Drug Monitoring. hypersecretion, which may promote While the findings published in NEJM ADRAC recommends patients on gallstone formation, said the study online (Jan 16, 2008) need to be warfarin should have their INR checked authors. validated and refined, efforts to develop a within a few days and no later than two 6minutes is a daily online newsletter and genetic test are underway, say the study weeks after they start or increase their website for Australian doctors, including authors. dose of glucosamine. general and specialist practitioners, published by Reed Business Information. GET MORE THAN JUST THE TAX BREAKS Convenient and flexible health insurance It’s great that there are two tax incentives working in your favour when you buy hospital insurance, but you still want to choose health insurance which provides simple and convenient financial protection when there is a healthcare incident in your life. Join your not-for-profit private health insurance fund which offers high quality health insurance with the flexibility for you to choose the hospital and extras insurance that works for you. With hospital insurance, from the very economical ‘Smart Starter’, to ‘Top Cover’ with the greatest medical benefits in Australia based on AMA List fees. The choice is yours. For all the information you need and to join visit www.doctorshealthfund.com.au. Contact us at info@doctorshealthfund.com.au or call 1800 226 126. www.doctorshealthfund.com.au PATHWAY_31

cutting edge High expectations DR KATHY KRAMER LOOKS AT THE ROLE OF GENETIC TESTING IN PRENATAL SCREENING FOR FETAL ABNORMALITIES - ITS BENEFITS, LIMITATIONS AND POTENTIAL. any pregnant women worry about whether the M baby is okay, and now doctors can offer so much more than soothing words. There aren’t tests for all the potential problems, but general screening for some serious conditions - and special testing for families with particular risks - have become a routine part of Australian prenatal care. In fact, the Human Genetics Society of Australia and the Royal College of Obstetricians and Gynaecologists both recommend that screening be offered to every woman. Professor Eric Haan is a clinical geneticist at the Women's and Children's Hospital in Adelaide and an expert on prenatal genetic testing. “There are basically two time points when screening is offered for Down syndrome, and the screening picks up some other abnormalities, such as trisomy 18.” “First trimester screening involves an ultrasound at 11 to 13 weeks looking at nuchal translucency (the width of a fluid-filled space at the back of the fetal neck) plus a blood test at nine to 13 weeks.” It picks up about 90% of Down syndrome pregnancies but falsely suggests one in twenty pregnancies is affected when really it is fine. The screening calls for a skilled ultrasonographer but also relies on the expertise of biochemists, like Dr Michael Sinosich, Scientific Director of Prenatal Testing at Sydney’s Sonic Health Care. “We really need both diagnostic modalities, biochemistry and ultrasound, monitoring different parameters to get an optimal performance in assessment of feto-placental wellbeing,” he says. 32_PATHWAY

In the laboratory, pathologists look at a range of different chemicals - known as markers - which are produced Another side of the story by the placenta or fetus, and are detectable in the mother’s blood. Marker levels can change when there is F etal genetic testing can also help women who have recurrent early miscarriages or a late miscarriage or terminated. Often there is little doubt about the diagnosis, and a post-mortem examination merely confirms, for an abnormality such as Down syndrome. The results are used to build stillbirth. example, that the fetus has features a picture of how likely it is that a Fetal pathologists have a particular consistent with Down syndrome. pregnancy is affected by the condition role in diagnosing lethal inherited However, anatomical pathology for which it is being screened. disorders. In these conditions, there is a comes into its own when the diagnosis 1-in-2 to 1-in-4 chance of future can only be made by examining specific There’s nothing magic about the pregnancies being affected. It’s tissues. For example, an ultrasound may number produced by screening, he important to distinguish these from identify cystic kidney disease but only a says, and different labs can produce chromosomal disorders, where the pathologist can determine which of the slightly different numbers depending on recurrence rate varies from 1-in-3 to 1- many disease types is involved. “We how many biochemical markers they in-100, and environmental, sporadic and look at the fetal tissues under the test for, what machines they use and uterine disorders which don’t tend to microscope and this can give us a very the software they employ. “For example, recur. clear idea, even though we don’t have a we use four markers but other units Dr Adrian Charles is a perinatal and specific genetic test, about what the may use two,” he says. paediatric pathologist at the King recurrence rate is, whether it’s 1-in-4 or Edward Memorial Hospital in Perth. 1-in-2 or pretty low.” Second trimester screening involves There are two scenarios that typically a blood test at 14 to 20 weeks (ideally “We try to get the abnormality clearly call for his services. 15 to 17 weeks). It picks up only about determined so the parents can be The first is where an apparently counselled.” 75% of Down syndrome pregnancies normal pregnancy ends in miscarriage or and wrongly identifies about 7% of Dr Diane Payton, an anatomical stillbirth and the parents consent to an normal pregnancies as being at pathologist, does similar work at the autopsy. “We say, this fetus has a range increased risk. Royal Brisbane Hospital. of abnormalities that amount to this type of syndrome and then we ask for that “If we can recognise an intact fetus, “Being told about an increased risk test to confirm the diagnosis. Sometimes we do an autopsy,” says. “If it is very often causes anxiety in women at the the parents are tested and/or future tiny, we look at the external appearance time and during the pregnancy and pregnancies are tested early in the and may attempt an internal examination even after the birth, and they often pregnancy with possibility of interrupting and certainly examine the cells. From remember it very vividly as something the pregnancy if it’s abnormal,” Dr around ten to twelve weeks, we can do that had a big emotional impact,” an excision and check the internal Charles says. Professor Haan says. organs.” A question arises over whether About 80% of women found to have chromosomal testing should be offered She takes tissue for basic genetic an increased risk choose to go on to after all pregnancy losses. “A large testing in most cases. When she has a invasive diagnostic testing, he says, and number of the first and early second specific diagnosis in mind - for example, most decide not to continue with the trimester miscarriages are due to such as cystic fibrosis - she may take pregnancy if the baby is affected. chromosomal abnormalities, so we could additional cells from relevant organs. check for these but the test costs a few However, careful thought is required, An ultrasound is also recommended hundred dollars and most of these will because there isn’t a screening test for for all women at 19 to 20 weeks. This is not recur, so is not indicated on every all the potential different genetic not part of Down syndrome screening; it case,” he says. problems. “Unless I can suggest what I checks the well-being of the pregnancy “There is growing pressure from want them tested for, there’s not much and can detect physical malformations we can do.” parents to try to find an answer: you in the baby, some of which may be due have to be thoughtful of the health dollar “This is a specialised area in which I to underlying genetic problems. but it does ease the parents’ minds to usually seek advice from clinical “Once you know your risk is high, identify a cause.” geneticists,” she says. “Many of the you have to decide, ‘am I going to sort The second scenario is where investigations are highly specialised and this out or not?’ And the main way to prenatal screening has identified an are only performed in selected sort out whether the baby does or does abnormality and the pregnancy has been laboratories in the country.” not have the condition after first > PATHWAY_33

trimester screening is chorionic villous sampling [CVS] at the end of the first trimester or amniocentesis at the beginning of the second Goodbye to invasive testing? trimester, or amniocentesis after screening in the second trimester.” If there is an increased risk of a B oth chorionic villous sample and amniocentesis can trigger a miscarriage, albeit very rarely, so researchers are looking for safer ways to perform fetal genetic testing. chromosome problem - say, because the “It is known that there are a small number of fetal cells, shed by the woman is more than 35 years old or because a placenta, that circulate in the mother’s blood,” geneticist Professor Eric previous pregnancy has had a chromosome Haan says. “And for many years attempts have been made to isolate abnormality - women can skip screening and these cells for genetic testing. It is clearly possible to do so, but so far go straight to a definitive (rather than screening) reliable, universally applicable and cost-effective testing in early chromosome test. This is either CVS from 10 to 11 weeks or amniocentesis at 15 to 16 weeks. pregnancy has not been developed.” Many couples choose CVS because the result Preimplantation genetic testing, performed on cells removed three is available at a much earlier stage in the day after fertilisation, is an evolving field which may allow couples to pregnancy. implant only embryos free of a particular gene. The most commonly performed genetic test IVF Australia, on its website, points out that this is really only is a chromosome test using cells taken from appropriate for couples where there are already family members with the placenta (via CVS) or shed from the baby serious inherited genetic disorders. “Worldwide researchers are and floating in the amniotic fluid (via questioning whether the same technology will allow improved embryo amniocentesis). “The chromosomes can be selection prior to embryo transfer, and hence improve pregnancy rates seen and counted, so it is a very reliable test per cycle for all couples having IVF treatment. The small studies for Down syndrome because they can see the performed so far have not been of a large enough size or been designed extra chromosome,” Professor Haan explains. to answer this question accurately.” DNA tests for literally hundreds of different heritable genetic conditions can also be done. The first such test was performed in 1978 for sickle cell anaemia, Professor Haan says. The most common tests these days are for thalassaemia, fragile X syndrome, cystic fibrosis, Duchenne muscular dystrophy and MIRAX LIVE RT infantile spinal muscular dystrophy. If doctors Combine the advantages of don’t know which gene is causing a problem, conventional microscopy with there may be other ways to test for the disease; the power of Live Robotic for example, if the disease involved a specific Telepathology enzyme, a chemical pathologist may be able to measure enzyme levels. However, prenatal genetic testing is not without risk. CVS and amniocentesis can Full remote slide access and microscope control. trigger a miscarriage, although the risk is small. An occasional problem with CVS occurs when some, but not all, of the placental cells contain a genetic mutation. This is called ‘mosaicism’. It usually affects only the placenta, not the baby, so amniocentesis is recommended to check the baby’s cells. However, even a normal amniocentesis does not definitely exclude mosaicism. “Also, some abnormalities may not be detected because they are too small to be seen reliably with a light microscope,” Professor Carl Zeiss Pty Ltd Haan points out. Unit 13, 2 Eden Park Drive North Ryde NSW 2113 Australia So, women and their partners need to know Nationwide: 1300 365 470 Email: micro@zeiss.com.au that chromosomal testing is not foolproof. http: www.zeiss.com.au 34_PATHWAY

foreign correspondence Wisdom in the Solomons SOLOMON ISLANDS PATHOLOGY IS SET TO COME INTO ITS OWN WITH A LITTLE HELP FROM SOME AUSTRALIAN FRIENDS. KIM COTTON REPORTS. for the mission included Dr Michael T he appointment of the Solomon Islands’ first indigenous pathologist last year brought an unexpected bonus. A Whiley, director of Pathology Queensland, Professor Konrad Muller, state director of The Solomons is made up of almost 1,000 mountainous islands and coral atolls divided by nine provinces spread group of top Australian pathologists and anatomical pathology, Bob Partridge, across 28,000 square kilometres. It has a medical scientists travelled from regional coordinator and Leigh Owen population of just over 500,000 with about Queensland to the South Pacific supervising scientist at Pathology 40 per cent aged less than 15 years. archipelago to establish an anatomical Queensland Central Laboratory, and Dr The NRH has about 280 beds and pathology laboratory. Stephen Weinstein, director of pathology about 20 medical staff. The NRH For more than 20 years, Pathology at the Gold Coast Laboratory Group. laboratory has haematology, biochemistry Queensland (a branch of Queensland Dr Weinstein, who has worked on and microbiology with a separate malaria Health’s clinical and statewide services) similar projects in East Timor and laboratory. Apart from Honiara, there are has been the Solomon Islands’ major Vanuatu, said the team operated as a two small laboratories in the provincial referral centre for pathology support. “well-oiled machine”. Tasks undertaken capitals of Auki (Malaita province) and Services have included general pathology included installation of histology Gizo (Western province). as well as diagnosis of surgical equipment and communication software, Dr Weinstein said the 750 annual histopathology and cytology specimens. staff training and the development of a histology cases that are produced in the However, with the appointment of Dr quality assurance program and support Solomons are likely to rise with the Roger Maraka to Honiara’s National framework for Dr Maraka’s ongoing operation of the local service. Dr Maraka Referral Hospital (NRH), it seemed logical professional development. also conducts about two forensic to the group that a laboratory be “For the first time ever the surgeons autopsies a month and runs a fine needle established, in which the pathologist and doctors can get the results then and aspiration clinic. could practise. there, and view their own tumours and Pathology Queensland donated The five experts who traveled to the cancers without having to have them sent equipment to fit out the histology unit, nation’s capital Honiara last September to Brisbane,” Dr Weinstein said. which was freighted with the support of PATHWAY_35 >

“Just the fact that the pathologist can function as an important member of the clinical team… that makes a difference for the hospital and the medical staff” the Lions Club. The donation was made assurance in Pap smear reporting present these [findings] in clinical possible by the Ipswich lab and Mr Owen procedures. meetings. was instrumental in organising the With the greatest morbidity in the “Just the fact that the pathologist can logistics of moving the equipment, Solomons being caused by infectious function as an important member of the including a processor, microtome and diseases, namely malaria and clinical team… that makes a difference for embedding station to the Solomons. Two tuberculosis, the unit was unlikely to have the hospital and the medical staff,” he local Solomons technicians who had been an “immediate earth shattering” effect on said. previously trained in Brisbane were the nation’s health, Dr Weinstein said. Another tenet of the project was the reskilled in operating the equipment as Also the benefit of having a local development of a strong continuing well as correct specimen handling and pathology service was hampered by the education model for Dr Maraka to ensure packaging, Dr Weinstein said. lack of radiotherapy and chemotherapy, his professional development remains “At the end of the week they were limiting the ability to treat diagnosed current and that he also feels supported producing diagnostic-quality histology collegially. malignancies beyond surgical excision. slides to the delight of Dr Maraka. This However, the fact that a resident “Continuing education for the will mean that the majority of histology pathologist can now discuss with pathologist himself is a major problem in a from the Solomons - all of which was colleagues diagnostic reports - and place like the Solomons because previously sent to Brisbane will be receive results much faster - will have a pathologists should ideally not practise reported locally in the future,” he said. alone. They should have a colleague to major impact on staff professional whom they can show interesting cases, Oral cancer, including cancer of the development and morale, he said. bounce them off and also cover for them buccal mucosa, tongue and gums, is one “For medical staff in the National when they go on leave,” Dr Weinstein of the most common malignancies in the Referral Hospital it’s important that they’re said. Solomon Islands - due to the popularity of not isolated, they feel they are not The pathologist will continue to send chewing the carcinogenic betel nut. Liver stranded without support,” Dr Weinstein to Brisbane all cases requiring second cancer is also common courtesy of the said. “Now they can come down and ask opinions and special stains, and in high prevalence of hepatitis. if they can see the tumour or have Dr addition send a randomly selected five Cervical cancer, still common due to Maraka point out an interesting feature per cent of his work for quality assurance poor screening practices, will continue to and discuss whether surgical margins are purposes. Twice a year, with the support be diagnosed in Brisbane - in part clear, did they excise it completely… they of the Pathology Queensland SERTF Trust because of the absence of a local can interact with the pathologist in the Fund, Dr Maraka will also visit Brisbane to cytoscreener and the issue of quality laboratory and the pathologist can also refresh his skills. 36_PATHWAY

Previous page: Young Solomon Islanders in traditional dress Blood sample being taken by a Pathology staff member. During the visit, Dr Whiley gave a Left to right this page: Selling taro at the market in Honiara presentation to the medical staff grand Mr Michael Aiko, histotechnologist preparing diagnostic slides; rounds on the relevance of point of care Dr Roger Maraka, Solomon Islands first Indigenous pathologist with testing and the Istat instrument to remote Professor Konrad Muller, Pathology Queensland's Director of Anatomical Pathology locations. Dr Weinstein presented recent Solomons’ histology cases reported in Brisbane and also breast cancer and screening. Such an experience for the Australian contingent brought an insight into the health problems and health system of a small developing country and “a great sense of satisfaction to help out there”, Dr Weinstein said. Fact file “Even be it in a very limited way and it The majority of Solomon Islanders (80 per cent) rely helps set up long term relationships on subsistence agriculture and fishing. which are valued greatly.” Dr Weinstein suggested opportunities There were 90,606 reported malaria cases in 2003 are available for Australian pathologists to with 71 deaths. take on unpaid locums in the Solomon TB rates in 2005 were 142 per 100,000. Islands as a means of experiencing a different health system as well as The prevalence of betel quid chewers is 76.8 per affording them a break from the normal cent. routine. Life expectancy for Solomon Islanders is 63 years Meanwhile, Dr Maraka reports the (at 2004). new lab is going well. Sources: AusAID, World Malaria Report 2005, WHO Global Health Atlas TB Dr Weinstein said. “He is able to Country Profile, American Journal of Tropical Medicine and Hygiene, Human repair any equipment locally; he is in Development Report 2006. email contact when he needs advice and is energetically getting down to work.” PATHWAY_37

finance finesse $$$ STEADY AS YOU GO - Super Planning It has been a roller coaster ride for investors in the share market this financial year. Not only has the year seen the start of the biggest changes to our superannuation system in 20 years but the share market has reached its highest levels in history and then tumbled by more than 20 per cent. This much anticipated correction to the share market had been expected for some time but the magnitude of the fall surprised many. Consequently because of various international influences the ride in the short term future looks anything but steady. However for superannuation investors it is perhaps not as alarming, as the effect of these corrections have been felt more by those investing money in a relatively short term volatile market. As superannuation is a longer term investment these fluctuations are expected in the overall investment Greg Lomax cycle and with a well chosen portfolio of investments, the magnitude of any fall can be cushioned by diversification. Greg Lomax is the CEO of Huthnance Lomax Accountants and Financial Advisors in Chatswood NSW. He is a regular columnist for It is important to remain calm and focused on the the Sydney Morning Herald and Melbourne underlying benefits that can be gained from Age and other professional magazines. choosing super as the number one investment strategy in today’s uncertain and volatile markets. 38_PATHWAY

2. REVIEW YOUR CURRENT 3. ACCESS TO SUPER AND SUPER ARRANGEMENTS RESULTING STRATEGIES The following four steps will help you utilise superannuation as your main investment choice: Now that most people are making super You can access your super from 55 years their main retirement vehicle, it is of age while you are still working. The 1. Achieve your maximum tax important to be aware of the manner of benefits you withdraw are taxable at your breaks via super for this and investment and type of fund you have. In marginal tax rate less a 15% rebate. Once future years. particular you need to be well aware of you turn 60 the benefits are tax free on your own risk profile and match this to the withdrawal. 2. Review your current super class of investments you use in your fund. The advantage in considering this is arrangements to ensure you are Many people are not aware of the that the underlying super benefits in your in the right fund and determine commissions and fees attached to every fund are placed into a tax free state. This if a self managed fund is right contribution. A statement of advice must means there is no tax on capital gains or for you be provided by an advisor when making a earnings of the fund whilst it is in this recommendation so be sure to read it pension mode. If you have a self managed 3. Understand the impact of closely as it must clearly state the way in fund in pension mode you can even get a accessing your super benefits which the advisor is paid and how the refund of the value of any franking credits and the hot tax strategies this investment is managed. the fund has received. creates for over 60’s. Self managed superannuation funds For a practitioner over 60 this is a are growing rapidly in popularity for good “must do” and presents some top tax 4. Review the basic estate reason especially since the introduction of strategy opportunities. An example is by planning issues involved with the new super rules. contributing up to $100,000 per annum, the increased financial The advantages of considering a self you receive a tax deduction against your resources now in super. managed fund strategy include: income and also have the ability to assist • The flexibility of controlling the type the funding for further contributions if of investments you have in super. needed by access to your super benefits. 1. ACHIEVE MAXIMUM TAX This is certainly a hot strategy as it allows • The ability to move into a pension a tax saving on the $100,000 of income BREAKS VIA SUPER mode, tax free without disposing of reducing the tax rate from 46.5% to less any of the fund’s assets. (i.e. no than 15 per cent. capital gains tax to pay). 4. REVIEW ESTATE PLANNING The new superannuation rules changed the maximum deductible contribution to • The ability to both receive an income ISSUES $50,000 per annum. However if you are stream from your super fund and 50 or over the maximum contribution is continue to make tax deductible $100,000 per annum until 2012. contributions to the same account The new super rules allow for super to be (i.e. no need to have separate super withdrawn tax free when you are over 60. This provides special opportunities funds or accounts) But if you die and do not have a surviving particularly for those employing their • The tax benefits from receiving spouse or financial dependents, the funds spouses in their business where tax income from fully franked investments will be taxed at 16.5% when passed to deductions for super contributions can be and offset the resulting tax credits your estate. up to $200,000 per annum. thereby reducing the tax rate in the It does not apply to after tax or Also self employed practitioners can fund. undeducted contributions you made to now enjoy full deductibility on their • Delay of tax payments until the the fund. This is an unfair and inequitable contributions compared to the old rule lodgement of the funds tax returns treatment and one that may well be where only 75% of the contribution was rather than paying 15% contribution changed in the future. In the meantime it tax deductible. tax on the day you make a is prudent to speak to your advisor about Some careful planning needs to take the best way for you to deal with this. place if you also receive a salary as well contribution. Most lawyers and financial advisors as self employed income. If the salary • Ability to access new products that recommend you not only have an up-to- income exceeds 10% of the overall gross will allow borrowing by self managed date trust deed, but an enduring power of income of the practitioner then tax super funds. These are called attorney together with a death benefit deductible contributions cannot be made. installment warrants and are allowed nomination in place to assist in the tax This can usually be avoided by a salary under new Government legislation free release of super benefits in cases of sacrifice arrangement or restructuring of that now extends the allowable terminal illness. Once released from super, the employment income. borrowings to any assets including the funds can be gifted to children, Additional contributions can be made property. relatives or other intended beneficiaries to super without claiming a tax deduction. While self managed super isn’t for directly or via an individual’s estate The limits on these contributions are everyone, it is certainly worth looking at without tax implications. $150,000 or $450,000 averaged over three the pros and cons as it affects individual years. There is no contributions tax on practitioner circumstances. these undeducted contributions. PATHWAY_39

RCPA update Snapshot of Pathology Update 2008 14- 16 March 2008 Sydney Convention and Exhibition Centre, Darling Harbour Innovation and PATHOLOGY UPDATE IS TRULY A UNIQUE CONFERENCE, Trainees Program WHICH BRINGS TOGETHER EIGHT DIFFERENT DISCIPLINES OF PATHOLOGY OVER A THREE DAY - Friday 14 March 2008 SCIENTIFIC MEETING, OFFERING SOMETHING FOR Innovations explores professional issues concerning pathology now and in the future. EVERYONE. The program starts with the RCPA Quality Assurance Program Symposium, which will profile a range of important developments in quality assurance, and culminates with a presentation by the eminent Dr Stephen Raab on practice redesign for patient safety. The Highlights of the 2008 program afternoon will showcase the inestimable Dr include: Chris Smith, sponsored by the Australasian Association of Clinical Biochemists (AACB), • Innovations Program on Patient who is speaking on the naked pathologist Safety (though he will be clothed as far as we know!). The afternoon continues with the • Trainees Program theme of patient safety in microbiology with Prof David Paterson and genetics with Dr • Seven international speakers Graeme Suthers. Trainees Day is a great opportunity to • Six cross discipline sessions address aspects of the curriculum that trainees might otherwise find difficult, as well • ‘Meet the Chief Examiner’ sessions as providing practical, exam-oriented sessions and workshops in the afternoon. Talks include critical appraisal, issues around • General Poster Display and a the handling and control of laboratory- combined discipline Abstract generated data and ethics and patient Publication. advocacy – all by prominent pathologists with extensive experience in these areas. There is also a session on using mindlfulness to help deal with the stresses of being a trainee by Craig Hassed, from Monash University who is internationally recognised for his work on the applications of meditation in medicine. The www.rcpa.edu.au/pathologyupdate afternoon includes workshops on electron and light microscopy as well as the AP exam review and the mock exam for part I Microbiology candidates. 40_PATHWAY

Scientific Programs - Saturday 15 & Sunday 16 March Anatomical Pathology has worked hard microbiology (genetics of susceptibility to Microbiology has internationally to put together a varied and interesting infection). But the novelty and broad recognised experts presenting in the areas program that will have “something for application of genetics also raises of hepatitis, meningococcal infections, everyone”. Dr Neil Lambie, from particular challenges in developing and and new ways of preventing these Christchurch, will present this year’s “An maintaining quality assurance across infections. Aboriginal health remains an Approach To…” lecture, on lung biopsy multiple disciplines, and this is the focus enormous public health issue for all for non-neoplastic lesions. The combined of later sessions in the program. Australians, and speakers from research Anatomic and Paediatric Pathology Haematology has a program that institutes in the Northern Territory, and the seminar will feature Dr Adrian Charles encompasses updates on malignant UK, will discuss their personal experience from Perth, and Prof Yee Khong and Dr haematological disorders with reviews of and research. Microbiology impinges Nicholas Manton from Adelaide. The some practical day-to-day issues of upon all parts of pathology, so we have Anatomical Pathology stream will also assessing haemostasis and managing designed the program around the needs include one of a number of cross- alloimmunisation in pregnancy. Overseas of all pathologists, trainees, and clinicians discipline sessions this year, in joint speaker Dr Wendy Erber opens the from a wide variety of subspecialties. presentations with Genetics and with Oral Update with Acute Leukaemia; sub- Oral Pathology is a specialised area of Pathology. classification and markers of prognosis, Anatomical Pathology, dealing with the Chemical Pathology The program will local speakers follow with topics on mouth, teeth, and jaws. The Oral include a joint session with individualizing therapies for childhood Pathology program commences with a Microbiologists to update attendees on leukemia. There will be a combined review of the Oral Pathology Quality the latest advances in all aspects of viral session with Immunopathology on Assurance Program module, followed by a hepatitis, including a lecture on blood lymphoma. series of case reports. There will be a joint tests for liver fibrosis, as well as drug Immunopathology has a range of Oral Pathology and Anatomical Pathology toxicity of the liver. There will also be highlights, including some of the top plenary session featuring Dr Jocelyn updates from working parties on cardiac Australian B cell biologists discuss the Shand, an Oral and Maxillofacial Surgeon markers, serum urate, creatinine and application of recent advances in B cell who will talk about surgical eGFR, as well as from the Australian biology to clinical practice. There are also management of head Pathology Lipid Interest Group. A whole talks on clinical application of some the and neck pathology. This session is devoted to the Chemical newer autoantibodies including antibodies presentation will enable Pathology of pregnancy, and experts on against water channels and nucleosomes pathologists to better PSA and vitamin D will be bringing the and a joint session with haematology on understand the current thinking in their areas of expertise. lymphoma diagnosis. In addition a treatment of Forensic Pathology will include how to session has been devoted to newer the various distinguish real injuries from post-mortem aspects of allergy epidemiology and conditions and decomposition artefacts, presenting diagnosis. In all a varied but very they report in evidence in court, pros and cons of the interesting program. patients. expert witness by two eminent lawyers, sudden death due to alcohol, the problem of drowning, sudden death in schizophrenia, the toxicology of the new anti-psychotics and the documentation of sexual assault. Last but not least… Genetics The genetic code acts as a resource for building and maintaining the Network and Relax at human body, and also dictates the body's Pathology Update response to a variety of external challenges, such as infection. For this As well as an important professional event, Pathology Update 2008 has a fun reason, genetics is pervasive and has and relaxing social program that gives attendees the chance to meet with other relevance in every discipline of pathology. local and international colleagues in a relaxed and informal environment. The The genetic program in Pathology Update Update will kick-off with the Welcome Cocktail Party, ‘Jive at Five’, on Friday 2008 is closely integrated with other March 14 with a special cocktail. The Industry dinner of the year is always one disciplines, including anatomical that’s not to be missed – at Doltone House, nestled on the upper deck of the pathology (genetics of tumours), historic Finger Wharf at the newly restored Jones Bay Wharf, Pyrmont Point. haematology (genetics of leukaemia), and PATHWAY_41

2008 Conference Calendar Trust BD Vacutainer Family of products you can rely on ® MARCH 2008 SEPTEMBER 2008 5 25 Accuracy Is Our 13th Ottawa International Conference College of American Pathologists First Priority on Clinical Competence 5 - 8 March 25-28 September 2008 …because it’s not San Diego just a test, it’s a patient. Melbourne, Australia http://www.cap.org 14 OCTOBER 2008 Pathology Update 14 - 16 March 6 Sydney, Australia The 19th International Symposium www.rcpa.edu.au/pathologyupdate on the Forensic Sciences 6 - 9 October 17 Melbourne, Australia Focus Cytology Tutorial for www.anzfss2008.org.au Pathologists 17 - 19 March 16 Sydney, Australia American Society of Clinical Pathology Joanne.clarke@symbionhealth.com October 16-19 2008 MAY 2008 Baltimore MD, USA http://www.ascp.org 30 Cytopathology Course Singapore 29 30 May - 1 June The National Forum on Safety and Quality in Health Care Singapore www.med.nus.edu.sg/path/teach/cytopath2008.htm 29 - 31 October Adelaide, Australia JUNE 2008 www.achs.org.au/nationalfiorum08 Quality test results demand quality specimen collection. The BD Vacutainer® brand of 22 products provides a total system American Academy of Oral for specimen collection needs. We Maxillofacial Pathology back our products with clinical 22 - 26 June expertise, educational materials, California, USA and training programs to help you www.iaop.com obtain the best results possible. JULY 2008 BD…over 100 years of quality Pathology Update 2009 and service you can trust. in conjunction with XXV WASPalm 20 13-15 March 2009 - Sydney Australia World Summit of Antivirals - WSA 2008 MARCH 2009 20 July 2008 to 26 July 2008 Kunming, China www.bitlifesciences.com/wsa2008 13 4 Research Park Drive Macquarie University Research Park The XXV WASPaLM Congress in North Ryde NSW 2113 conjunction with Pathology Update Toll Free Phone 1800 656 100 13 - 15 March BD, BD Logo and all other trademarks Sydney, Australia are property of Becton, Dickinson and www.rcpa.edu.au/pathologyupdate Company. © 2008 BD. APAS005 02/08 42_PATHWAY

PathWay_Issue#12_2

by Pammy98

Accessibility

Upload Details

Usage Rights

Statistics