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  2. 2. 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: 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: Foreign correspondence: Wisdom in the Solomons 35 PathWay Email: Australian expertise is behind the setting up of the Solomon 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 PATHWAY_1
  3. 3. 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 pathol- ogy 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 Ph: +612 8356 5814
  4. 4. 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
  5. 5. 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
  6. 6. 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® Symbion Health Ltd ABN 56 004 073 410
  7. 7. 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
  8. 8. 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
  10. 10. 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
  11. 11. 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
  12. 12. “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 PATHWAY_11
  13. 13. 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
  14. 14. 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
  15. 15. “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
  16. 16. 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
  17. 17. 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
  18. 18. “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 >
  19. 19. “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
  20. 20. 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
  21. 21. testing testing THE PCR OF
  22. 22. 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 >
  23. 23. 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