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01/08/10
Walter and Eliza Hall Institute researchers have made a discovery that has upended scientists’ understanding of programmed cell death and its role in tumour formation.
Programmed cell death, also called apoptosis, is an important process in human biology as it removes unwanted and damaged cells from our bodies. This process protects us against cancer development and autoimmune disease.
The research team’s discovery, led by Professor Andreas Strasser from the institute’s Molecular Genetics of Cancer division, has implications for the understanding of how cancers develop and will inform the ongoing development of a new class of anti-cancer drugs called BH3 mimetics.
“Until now everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumour development,” Professor Strasser said. “That’s certainly still true but we discovered that, in certain settings, the opposite holds: the body’s natural cell-suicide program can fuel tumour development.”
The research team’s experiments revealed that repeated cycles of cellular depletion and tissue regeneration, by activating stem cells, could promote tumour development.
In situations where the DNA in many cells is damaged, such as when the body is repeatedly exposed to low doses of radiation, there are repeated cycles of cell death in the body’s tissues. “Attempts by the body’s stem cells to repopulate the depleted tissue can then actually drive the tumour development,” Professor Strasser said. “That’s because the radiation, while killing many cells within a tissue, will create mutations in some of the surviving stem cells. When such abnormal (mutated) stem cells repopulate the tissue, they will divide many times and this can promote the development of tumours.”
The research, done in collaboration with Dr Ewa Michalak, Dr Cassandra Vandenberg, Mr Alex Delbridge, Dr Li Wu, Dr Clare Scott and Professor Jerry Adams, is published in today’s issue of the international journal Genes and Development.
Crucial to the team’s research was an understanding of what happens to mice exposed to radiation when a gene called Puma is missing. “If normal mice (which have the Puma gene) are given a low dose of radiation it destroys around 80 per cent of the white blood cells,” Professor Strasser said. “That does not kill the mouse but it does mean the stem cells in the bone marrow have to work extra hard to replenish the blood system. This can lead to the formation of tumours of white blood cells, called leukaemias, if the stem cells doing the repopulating have cancer-causing mutations.
“The surprise was that mice that don’t carry the Puma gene are protected from this type of tumour development. Puma is essential for the death of cells that have damaged DNA. If mice don’t have the Puma gene when they receive low doses of radiation the white blood cells are not destroyed, so you don’t force mutated stem cells to become activated (and divide) to replenish the blood system.”
Professor Strasser said the research suggested that the risk of cancer was increased in people who experienced cycles of tissue destruction followed by tissue re-population by stem cells. “Such cycles may account for the liver cancers frequently associated with viral (hepatitis C) infection or alcohol-related liver damage.” The research also helps explain the so-called secondary cancers that sometimes arise in patients who were cured of their primary cancer by chemotherapeutic drugs that cause DNA damage.”
The findings will also inform the ongoing development of a new class of anti-cancer drugs called BH3 mimetics. These drugs are designed to kill cancer cells. “Chronic exposure to such drugs could lead to the death of large numbers of normal cells that would then need to be replaced,” Professor Strasser said. “In certain circumstances this could promote the development of secondary cancers, particularly if patients are receiving treatments such as chemotherapy or gamma-radiation that can lead to cancer-causing mutations in stem cells.”
The research was supported by the National Health and Medical Research Council, the Leukemia and Lymphoma Society, the National Institutes of Health (US), the Juvenile Diabetes Research Foundation, Cancer Council Victoria and the Victorian Government.
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22/07/10
Walter and Eliza Hall Institute scientists have identified the three protein fragments that make gluten - the main protein in wheat, rye and barley – toxic to people with coeliac disease.
Their discovery opens the way for a new generation of diagnostics, treatments, prevention strategies and food tests for the 200,000 Australians with coeliac disease.
When people with coeliac disease eat products containing gluten their body’s immune response is switched on and the lining of the small intestine is damaged, hampering their ability to absorb nutrients. The disease is currently treated by permanently removing gluten from the patient’s diet.
Dr Bob Anderson, head of the Walter and Eliza Hall Institute’s coeliac disease research laboratory, said it had been 60 years since gluten was discovered to be the environmental cause of coeliac disease.
“In the years since, the holy grail in coeliac disease research has been to identify the toxic peptide components of gluten; and that’s what we’ve done,” Dr Anderson said.
The research, done in collaboration with Dr Jason Tye-Din, Dr James Dromey, Dr Stuart Mannering, Dr Jessica Stewart and Dr Tim Beissbarth from the institute as well as Professor Jamie Rossjohn at Monash University and Professor Jim McCluskey at the University of Melbourne, is published in today’s issue of the international journal Science Translational Medicine. Find out more and download the full text paper.
The study was started by Professor Anderson nine years ago and has involved researchers in Australia and the UK as well as more than 200 coeliac disease patients.
The patients, recruited through the Coeliac Society of Victoria and the Coeliac Clinic at John Radcliffe Hospital, UK, ate bread, rye muffins or boiled barley. Six days later, blood samples were taken to measure the strength of the patients’ immune responses to 2700 different gluten fragments. The responses identified 90 fragments as causing some level of immune reaction, but three gluten fragments (peptides) were revealed as being particularly toxic.
“These three components account for the majority of the immune response to gluten that is observed in people with coeliac disease,” Dr Anderson said.
This knowledge has already been used by Melbourne-based biotech company, Nexpep Pty Ltd, to develop a ‘peptide-based’ immunotherapy that aims to desensitise people with coeliac disease to the toxic effects of gluten. Nexpep’s Phase 1 trials of the therapy were completed in June and final results are expected in coming months.
The immunotherapy works by exposing people with coeliac disease to small amounts of the three toxic peptides and is based upon the same principles as desensitisation for allergies.
Dr Anderson said although coeliac disease could be managed with a gluten-free diet, compliance with the diet is often challenging and nearly half the people on the diet still have residual damage to their small intestine. “Consequently, the immunotherapy and three other drugs are under development to help people with coeliac disease.”
The research was supported by the National Health and Medical Research Council, Coeliac UK, the Coeliac Research Fund, Nexpep Pty Ltd, BTG International and the Victorian Government.
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Penny Fannin
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10/06/10
Walter and Eliza Hall Institute scientist Dr Mark McKenzie has this week been commended in the Victorian Government’s Premier’s Award for Public Health and Medical Research.
Dr McKenzie, a Leukaemia Foundation postdoctoral fellow in the institute’s Molecular Medicine division, received the commendation for his investigations into how insulin-producing cells are destroyed, resulting in diabetes.
His findings have implications for the development of treatments for the more than 1.2 million Australians with type 1 or type 2 diabetes.
Dr McKenzie received his commendation for work he undertook at St Vincent’s Institute for Medical Research, where he focused on developing a better understanding of how insulin-producing cells are destroyed and identifying key molecules implicated in the process.
“There is an urgent need to identify new ways of treating diabetes, and particularly treatments that prevent the death of insulin producing cells, the initial cause of type 1 diabetes,” Dr McKenzie said.
His research has showed that members of the Bcl2 protein family are responsible for controlling cell death in both type 1 and type 2 diabetes.
Dr McKenzie discovered that one of these family members, called Bid, is important in cell death in type 1 diabetes while other members, such as Bim, Puma and Bax, are critical for cell death in type 2 diabetes.
These findings have implications for the development of drugs or other therapies that treat diabetes by preventing the death of insulin-producing cells.
Dr McKenzie’s research at the Walter and Eliza Hall Institute is applying the insights he gained into cell death and diabetes to finding ways of killing cancer cells.
He is using a new technology known as RNA interference to inhibit genes that are abundant in leukaemia and lymphoma cells. “I want to determine whether inhibiting these genes can kill the cancer cells without having undesirable effects on normal tissue,” Dr McKenzie said. “If this is the case it should be possible to develop a new generation of drugs for treating blood cancers that have greater potency and fewer side effects.”
Dr McKenzie was presented with his commendation on Monday by the Victorian Premier, Mr John Brumby. Two other commendations were awarded, to Dr Radwa Badawy and Dr Benjamin Howden; the winner was Dr Julia Archbold from Monash University.
For further information
Penny Fannin
Strategic Communications Manager
Ph: +61 3 9345 2345
Mob: 0417 125 700
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