redefining diagnosis, disease
and drug therapy
A REVOLUTIONARY DISCOVERY
IGNORANCE IS NOT BLISS
Autumn 2008 | Issue #15
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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
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
Dr David Roche
New Zealand Representative, RCPA
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.
ADVERTISING SALES DIRECTOR
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
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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
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.
Foreign correspondence: Wisdom in the Solomons 35
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IMAGES OF IRAN
From the CEO 4
Welcome from RCPA CEO Dr Debra
Under the microscope 6
News + views
6minutes news 30
Interesting news from around the
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
Travel: Images of Iran 46
Judy Myers finds a country rich in history, culture, colour and
Conference calendar 42
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.
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
Racing to unravel the mystery of AIDS: Who discovered AIDS? Dr
George Biro looks at one of the great feuds of our time
from the CEO
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
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
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
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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
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.
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.
Australian innovation GPs ordering
advances genetic more path
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.
A perfect fit
GENETICS CAN PREDICT A PERSON’S RESPONSE TO A DRUG EVEN BEFORE THEY’VE
TAKEN IT. PETER LAVELLE LOOKS INTO THIS BRAVE NEW WORLD.
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
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
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
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.
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
“We are still unravelling the
genetic differences that
underlie the variation in
response from person to
person. So there are plenty
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
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
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.
“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.
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
PHOTO CREDIT: ELIZABETH ADAMS
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
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
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.”
“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
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
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.
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
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,”
“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
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
“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
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
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.
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.
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.”