1. Islet transplants for treatment of type 1 diabetes – 2007-current
Ten patients with type 1 diabetes have received a total of 18 transplants of insulin-producing islets isolated by a team from SVI, through the Australian Islet Transplantation Program (ITP). Many of these patients are now insulin independent and no longer suffer severe hypoglycaemic episodes. This new type of transplant surgery to help people with a severe form of type 1 (juvenile) diabetes is carried out at St. Vincent’s Hospital, Melbourne in collaboration with SVI. Initially funded by the Juvenile Diabetes Research Foundation (JDRF) and the Australian Department of Health and Ageing, and now through a Nationally Funded Centre, the ITP aims to take islet transplantation from an experimental procedure to a real clinical option for Australians with type 1 diabetes. The ITP is a consortium involving St. Vincent’s and Austin Health in Melbourne, Westmead Hospital in Sydney and the Queen Elizabeth Hospital in Adelaide.
2. Structure of the GMCSF receptor – (published in Cell in 2008)
A team of scientists led by SVI’s Professor Michael Parker and Professor Angel Lopez of the Centre for Cancer Biology, Adelaide have unravelled the structure of a cell signalling receptor, called the GMCSF receptor, which is involved in control of the blood system. When damaged, the receptor is responsible for diseases such as leukaemia. The discovery helps to explain, for the first time, how the receptor is activated and will form the springboard for the development of new treatments.
Using leading edge technology that allows scientists to view minute parts of cells, the scientists have developed the first 3D image of the receptor’s structure and will use the unique knowledge it provides to find drugs to modify its action and control diseases such as leukaemia and asthma.
3. Role of copper and APP in Alzheimer’s disease – 2002
Professor Michael Parker and his group pioneered studies into the structure of amyloid precursor protein; a fragment of this protein is thought to cause Alzheimer’s disease. This work has lead to detailed insights into the function of the protein and is being used to develop novel drugs that will inhibit the breakdown of the protein that causes release of the toxic fragment with the potential to prevent Alzheimer’s disease. In collaboration with Professor Colin Masters, Mental Health Institute and Melbourne University.
4. Bacterial pore forming protein structures – 1998-current
Protein toxins are produced by a variety of living organisms, particularly bacteria, certain insects, poisonous reptiles and stinging marine invertebrates. As offensive weapons these toxins can aid digestion or degeneration of the host whilst as defensive weapons they can protect by killing invaders. Of the more than 300 protein toxins characterised to date, at least a third act by punching holes or pores in cell walls causing cells to die.
Professor Michael Parker and his lab have been world leaders in visualising the three-dimensional structures of pore-forming toxins from bacteria that cause devastating diseases including pneumonia, meningitis and gangrene. The structures have revealed the detailed mechanism behind how these toxins work and in doing so provided new insights into how other related toxins work such as diphtheria and anthrax toxins.
5. AMPK and obesity – 1994
AMPK is an enzyme that regulates energy metabolism in response to diet
and exercise and is thought to mediate their health benefits. In the
brain AMPK controls appetite whereas in other tissues it increases
energy production and reduces energy expenditure in response to demand.
Because of its central role in energy metabolism AMPK has become a
pharmaceutical drug target for the treatment of a number of age onset diseases that include obesity, type 2 diabetes, cardiovascular disease
and cancer. Professor Bruce Kemp and his group, in collaboration with Dr Lee Witters at
Dartmouth Medical College New Hampshire, the were first to identify AMPK in 1994 and this paved the way for a new era in metabolism research.
6. Osteoclast regulation and biology in arthritis, osteoporosis and bone cancer - 1988-current
Osteoclasts are the only cells that are able to break-down
bone in the continuing cycle of bone building and bone breakdown. Their production and activity needs to be very tightly regulated. Professor Jack Martin and his team have discovered a number of the locally produced factors in other bone cells that control osteoclasts, and this has led to much greater understanding of diseases such as osteoporosis, rheumatoid arthritis
and the spread of cancer to bone.
7. Twitchin kinase and autoregulation – (published in Nature in 1994 and 1996)
The human genome codes for over 500 protein kinases that are regulatory enzymes controlling all of the body’s functions. One
important subfamily of protein kinases is regulated by the
calcium-binding protein calmodulin and these enzymes are turned off in
the absence of calcium. These protein kinases have important functions in the control of blood vessel contraction and memory.
Professor Kemp showed that these enzymes are turned off because a part of their structure binds in the catalytic site and in collaboration with Dr Jörg Heierhorst, Professor Bostjan Kobe and Professor Michael Parker solved
the structure of twitchin kinase, a member of the calmodulin-regulated protein kinase subfamily that proved the mechanism of autoregulation. Their subsequent work showed this concept of regulation extends to other proteins such as enzymes and transport proteins.
8. Angiotensin and bradykinin: insights into the treatment and prevention of heart disease - 1994
The hormone angiotensin regulates blood pressure by controlling blood vessels, and by controlling the water and salt balance of the body. In Western societies with high salt content diets, even normal levels of angiotensin can cause high blood pressure, heart disease and stroke. The drugs most commonly used to treat these diseases either block angiotensin production or block its effects, and together form the most frequently prescribed drug group in Australia. These drugs also lead to increased bradykinin levels, a hormone that decreases blood pressure and protects against heart disease.
9. Three dimensional structure of human Chorionic Gonadotropin hCG - 1994
Dr Neil Isaacs, together with Professor Frank Morgan, a former Director of SVI, and their groups determined the three-dimensional structure of human chorionic gonadotropin in 1994. This hormone is made by the embryo soon after conception and later made by the placenta. The hormone plays an essential role in the early stages of pregnancy. Early pregnancy testing is often based on detecting hCG in urine or blood. Knowledge of the structure of hCG has helped in the understanding of the structure and function of a number of other hormones essential for reproduction that are related to hCG.
10. Role of PTHrP in foetal development – 1988
When Professor Jack Martin and his team discovered PTHrP it was thought that it was present in the circulation only in cancer, where its excess causes complications. The research team
then discovered that it also circulates in the blood of the foetus during pregnancy and promotes the transfer of calcium from mother to foetus to
provide calcium for the foetal skeleton.
11. Role of PTHrP in breast cancer - 1988
Professor Jack Martin and his research group were interested in discovering why patients with certain cancers so commonly
developed a high blood calcium level, causing nausea, vomiting,
dehydration and often ending in coma. They discovered parathyroid
hormone-related protein (PTHrP) in the 1980s and went on to purify, clone and synthesise it. They showed that PTHrP is the cause of high blood calcium levels in most patients and also that PTHrP produced by certain cancers, especially of the breast, helps those cancers to establish as secondary growths in bone.
12. The Sequenator – 1967 (Australia’s second most highly cited paper)
Proteins are the essential building blocks of the body and all diseases involve a change in protein behaviour. Knowledge of a protein’s structure enables the development of ways to block or promote its action in the prevention or treatment of disease. SVI’s first Director, Pehr Edman was a pioneer in the study of protein structure and developed a set of reactions that could be used to identify all the amino acids found on a protein.
His work began to be recognised internationally but the manual, test tube method he used could only determine 10 amino acids at the rate of one per day. Edman and one of SVI’s staff members, Geoff Begg, recognised the enormous potential of automation and together, hand-built a machine to carry out the process. Known as the Sequenator, the machine could determine the sequence of 60 amino acids at the rate of one amino acid per hour. This enabled structurally based functional studies to be carried out on biologically important proteins in many areas from haematology and immunology to endocrinology.
American instrument makers Beckman marketed a commercial version of the sequanator based on Edman's design, called the Sequencer, which became widely used in laboratories throughout the world. Use of this machine and Edman's method of determining amino acid structure dominated the field of structural biochemistry until the 1990s when it was replaced by mass spectrometry and DNA sequencing.