 Dr
Ricky Johnstone
Dr Ricky Johnstone is a cancer researcher who is interested in dissecting
the molecular events underpinning cancer cell death by chemotherapeutic-drugs,
determining how tumors become multidrug resistant and identifying and
characterising new drugs designed to circumvent chemotherapeutic drug
resistance. He is currently a Wellcome Trust Senior International Fellow
and a Group Leader in the Cancer Immunology Program at the Peter MacCallum
Cancer Centre. Dr Johnstone performed postgraduate studies at the University and
Melbourne and later at the Austin Research Institute under the guidance
of Professor Ian McKenzie where he characterised molecular and biochemical
activities of the complement regulatory protein CD46. He was awarded
his PhD in 1993 and received a C.J. Martin Postdoctoral Scholarship
from the National Health and Medical Research Council of Australia
(NHMRC) to perform postdoctoral studies at Harvard University in Boston
USA. In the laboratory of Professor Yang Shi, Dr Johnstone cloned and
characterised Par-4, a novel protein capable of binding to and regulating
the transcription and growth regulatory activities of the tumor suppressor
protein WT1. Dr Johnstone returned to Australia in 1996 to work with Drs Joe Trapani
and Mark Smyth at the Austin Research Institute. He was awarded an
NHMRC R.D. Wright Fellowship and made the seminal finding that the
drug efflux protein, P-glycoprotein (P-gp) encoded by the MDR1 gene,
can inhibit the activation of caspases. He discovered that P-gp can
protect tumor cells by both actively effluxing the chemotherapeutic
drugs out of the cell and, by inhibiting caspase activation. These
findings challenged the existing dogma regarding the role of P-gp in
mediating multidrug resistance, and established a paradigm for the
dual function of P-gp in inhibiting chemotherapeutic drug action. Dr
Johnstone’s search for compounds that could overcome the apoptotic
regulatory effects of P-gp lead to his current work with histone deacetylase
inhibitors (HDACi), novel chemotherapeutic drugs that regulate gene
transcription through chromatin remodelling. Dr Johnstone has made
key discoveries defining novel molecular mechanisms of action of structurally
diverse HDACi and with clinical colleagues at the peter MacCallum Cancer
Centre has initiated clinical trials with two HDACi for the treatment
of T cell lymphoma. During the course of his Pfizer Australia Research Fellowship, Dr Johnstone will use genetically modified mice as models of human
cancer to functionally dissect the apoptotic proteins and pathways
necessary for the therapeutic effects of HDACi, alone and in combination
with novel small molecule chemotherapeutics. It follows that a detailed
understanding of how anticancer agents induce cell death, and how defects
in death pathways promote resistance, will revolutionize the way chemotherapeutic
drugs are designed and used, moving from “trial and error” to
a more rational strategy that may be tailored to each cancer patient. |
 Associate
Professor David Mackey
Associate Professor David Mackey is an ophthalmologist, whose main
field of work lies in understanding the genetics of hereditary eye
diseases. In particular he is interested in the prevalent eye disease
Glaucoma. Dr Mackey is currently working in the Hereditary Eye Disease
Clinics of the Royal Hobart Hospital and the Royal Victorian Eye and
Ear Hospital. In addition he co-ordinates the Glaucoma Inheritance
Study in Tasmania and the Twins Eye Study.
Dr Mackey completed his basic medical studies in Tasmania before
specialising in Ophthalmology at the Royal Victorian Eye and Ear Hospital
in Melbourne. His research career began at the Murdoch Institute at
the Royal Children’s Hospital while studying with the University
of Melbourne Department of Ophthalmology. This was followed by fellowships
with the Johns Hopkins Centre for Hereditary Eye Diseases in Baltimore,
and Moorfields Eye Hospital and the Great Ormond St Hospital in London.
Dr Mackey completed his MD thesis on the hereditary eye disease Leber’s
Hereditary Optic Neuropathy (LHON). LHON is associated with sudden
vision loss primarily in young males, and through Dr Mackey’s
work a causative gene in the mitochondrial DNA was identified. Dr Mackey
led an international consortium that pooled data from over 11,000 family
members of LHON pedigrees, from 6 European countries, as well as Australia.
Specifically this team investigated LHON causative mutations, as well
as a controversial collection of other possible LHON associated mutations.
This work established that just 3 mutations account for 95% of all
LHON pedigrees, and has subsequently allowed predictive genetic testing
for many at risk people. The polymorphisms (non disease causing DNA
changes) are an important tool in population evolutionary research.
Dr Mackey, working with Professor Neil Howell in Texas, found that
in large pedigrees the polymorphisms were changing at a rate much faster
than that used by evolutionary biologists. This discovery sparked heated
scientific debate about ‘resetting the mitochondrial DNA evolutionary
clock’ and the time since various races of man shared a common
ancestor. Since this work, Dr Mackey has been involved in the identification
of several eye disease genes, such as the retinal dystrophies, retinitis
pigmentosa and Malattia Leventinese, and locations of genes for megalocornea,
keratoconus, and strabismus.
Upon returning to Tasmania in the 1990’s, Dr Mackey realised
the unique advantages of an island population in genetic research into
common eye diseases such as glaucoma. Glaucoma is the second commonest
cause of blindness in Australia and half the people who have it do
not realise until they have actually lost a large amount of their sight.
Dr Mackey set up the Glaucoma Inheritance Study in Tasmania (GIST),
the largest population study of this eye disease in the world. To date
over 2,000 people with glaucoma, (and several thousand relatives) have
been seen by the study. Over the past decade the GIST researchers have
collected DNA from almost every family in Tasmania known to have glaucoma.
Dr. Mackey was part of a multinational collaboration with the University
of Iowa that identified the first glaucoma gene Myocilin, a finding
that was published in Science in 1997. Extensive work with the GIST
team has established the frequency of different mutations in the Myocilin
gene, as well as their associated clinical features. The GIST work
highlighted that glaucoma is in fact caused by concurrent alterations
in many different interacting genes. Consequently this has made further
identification of glaucoma genes through conventional family studies
alone very difficult. Thus to break the bottleneck in glaucoma genetics
research, Dr Mackey established the Twins Eye Study. This new study
will clarify the heritability of various glaucoma measurements in the
normal population. With the aid of the Australian Twin Registry over
400 sets of twins have been seen to date. However, many more are required
before the precise ‘blindness causing’ genes can be identified.
During the course of his Pfizer Australia Research Fellowship,
Dr Mackey will continue work into the genetics of glaucoma, expanding
the clinical collection of glaucoma families in the Glaucoma Inheritance
Study in Tasmania as well the recruitment of twins in the Twins Eye
Study. Clinical parameters are now being reassigned and genetic data
(previously collected and new) will be analysed with the re-characterise
the phenotypes within pedigrees.
Through the collaboration with other laboratories new genes responsible
for glaucoma will be identified. Identification of such genes will
allow DNA testing to detect those people at risk of developing the
blinding disease. Blindness from glaucoma can be prevented through
early identification and treatment. As such, twin genetic work is vital
for the development of successful strategies to treat and eradicate
glaucoma blindness in Australia and throughout the world. The ability
to translate the results of such state of the art scientific research
will also help ensure Australia maintains its current internationally
competitive edge in this burgeoning field.
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