Institute for Molecular Bioscience
Institute for Molecular Bioscience
News Article | May 22, 2017
A new gene behind a rare form of inherited childhood kidney disease has been identified by a global research team. University of Queensland researchers were part of the team that made the discovery that will improve genetic testing and could provide clues for future treatments for autosomal recessive polycystic kidney disease (ARPKD). UQ Institute for Molecular Bioscience researcher Associate Professor Carol Wicking, a lead author of the study, said it had previously been difficult to determine the underlying cause of all cases of ARPKD. "It was thought that errors in a gene called PKHD1 were solely to blame for this rare form of kidney disease," Associate Professor Wicking said. "But there was always a subset of patients who appeared to have the disease, even though they possessed a normal version of that gene. "The aim of this study was to find other genetic culprits that could be responsible for this devastating condition." ARPKD causes enlarged kidneys, liver problems and high blood pressure, and often leads to renal failure in the 70 per cent of patients who survive the first weeks of life. Using a technique called whole exome sequencing to analyse all of a patient's genes simultaneously, researchers in Germany and the US found errors in a gene called DZIP1L in four families with ARPKD. Associate Professor Wicking and colleagues in Australia, Singapore and Germany used laboratory-based models to confirm that errors in this gene did indeed cause kidney defects, and began to explore and understand why. "The gene DZIP1L appears to be related to the function of cilia, which are small antenna-like extensions that project from almost all cells of the body, including those in the kidney, and play an important role in controlling vital cellular functions," Associate Professor Wicking said. "This gene makes a protein that acts at the base of the cilium, which, when faulty, causes a domino effect that leads to problems in cilia and, in turn, a malfunctioning kidney. "ARPKD has a more complex cause than originally thought, and our work to understand this rare disease may eventually help us to better manage both rare and more common forms of polycystic kidney disease." Many patients with a rare disease wait years for a genetic diagnosis and often endure multiple misdiagnoses. Rare Voices Australia Executive Director Nicole Millis said this exciting discovery provided much-needed answers for patients. "These findings highlight how new genomic technologies are helping to find answers for patients with rare diseases, giving them more certainty about their condition. "Having a genetic diagnosis also gives patients and their families a chance to connect with other people living with a similar rare disease and build vital support networks," Ms Millis said. The research, published in Nature Genetics (DOI: 10.1038/ng.3871), was funded by the Australian National Health and Medical Research Council, The University of Queensland, the German Research Fund, DFG Collaborative Research Centre KIDGEM 1140, the German Federal Ministry of Education and Research, the US National Institutes of Health, and the Agency for Science, Technology and Research of Singapore.
News Article | May 1, 2017
The brain has its own inbuilt processes for mopping up damaging cellular waste -- and these processes may provide protection from stroke and dementia. University of Queensland scientists discovered a new type of lymphatic brain "scavenger" cell by studying tropical freshwater zebrafish -- which share many of the same cell types and organs as humans. Lead researcher Associate Professor Ben Hogan from UQ's Institute for Molecular Bioscience said the fundamental discovery would help scientists understand how the brain forms and functions. "It is rare to discover a cell type in the brain that we didn't know about previously, and particularly a cell type that we didn't expect to be there," he said. "The brain is the only organ without a known lymphatic system, so the fact that these cells are lymphatic in nature and surround the brain makes this finding quite a surprise. "These cells appear to be the zebrafish version of cells described in humans called "mato" or lipid laden cells, which clear fats and lipids from the system but were not known to be lymphatic in nature. "When wastes such as excess fats leak out of the bloodstream, it is the job of the lymphatic system to clean them out to avoid damaging our organs." Dr Hogan said the study focused on the presence and development of "scavenger" cells in zebrafish, however there was good reason to believe that equivalent cells surrounded and protected the human brain from a build-up of cellular waste. "Zebrafish are naturally transparent, which means we can use advanced light microscopes to see directly into the zebrafish brain," Dr Hogan said. "Examining the zebrafish brain up close allowed us to find these cells and see how they form and function in detail. "Normally, lymphatic endothelial cells will group together to form lymphatic vessels to carry fluid, but impressively, in the adult zebrafish brain these cells exist individually, independent of vessels and collect waste that enter the brain from the bloodstream. "Our focus now is to investigate how these cells function in humans and see if we can control them with existing drugs to promote brain health, and improve our understanding of neurological diseases such as stroke and dementia." The study was published today in Nature Neuroscience (DOI: 10.1038/nn.4558) and involved researchers from UQ's Institute for Molecular Bioscience, The University of Melbourne, Monash University and Japan's National Cerebral and Cardiovascular Centre. The National Health and Medical Research Council and UQ funded the research.
News Article | May 2, 2017
The researchers - from the University of Queensland (UQ) in Australia - report the discovery of the new type of lymphatic cell in the journal Nature Neuroscience. They found the cell in freshwater zebrafish, which provide a useful model for studying human biology because many of their cells and organs are similar to ours. Another advantage of using zebrafish is that they are transparent, and the researchers were able to use advanced light microscopes to see what was happening in their brains. Senior author Ben Hogan, an associate professor in the Institute for Molecular Bioscience at UQ, says, "It is rare to discover a cell type in the brain that we didn't know about previously, and particularly a cell type that we didn't expect to be there." The lymphatic system has three main functions: it is part of the immune system; it returns fluid from tissues to the blood; and it absorbs fat-soluble nutrients and fats from the digestive tract and carries them to the bloodstream. The lymphatic system comprises: a fluid called lymph that is similar to blood plasma; vessels that carry lymph; and organs - such as the lymph nodes, tonsils, thymus, and spleen. It is similar to the cardiovascular system in that it carries fluid through a network of vessels that permeates nearly every type of tissue in the body. However, whereas the cardiovascular system has a pump - that is, the heart - to move blood through the vessels, the lymphatic system relies on contraction of smooth muscle in its vessel walls, together with movement of skeletal muscle and breathing to push the lymph along. For a long time, it was thought that the brain did not have any lymphatic vessels, but a recent landmark discovery showed that it does and that the reason it took so long to find them is because they are "very well hidden." Now, in the new study, the UQ researchers make another surprising discovery in finding that the brain may also contain isolated lymphatic cells that help to clean up waste that leaks from the bloodstream. Prof. Hogan says that "the cells appear to be [the] zebrafish version of cells described in humans called 'mato' or lipid-laden cells." He adds that in humans, mato cells "clear fats and lipids from the system but were not known to be lymphatic in nature." When excess fats and other waste leaks from the bloodstream into surrounding tissue, the lymphatic system clears it away to prevent it damaging organs, Prof. Hogan explains. Using the advanced light microscopes, the researchers were able to closely examine the zebrafish brain, see the cells, and observe in detail how they develop and work. Prof. Hogan says that normally, lymphatic cells develop into lymphatic vessels that carry the lymph fluid. Consequently, they were surprised to find that "in the adult zebrafish brain these cells exist individually, independent of vessels and collect waste that enter the brain from the bloodstream." He concludes: The following video from UQ summarizes the study's findings. Learn how Parkinson's disease may begin in the gut.
News Article | March 21, 2017
Australian scientists have made an amazing discovery with the potential to revolutionize stroke treatment. A team of researchers from the University of Queensland and Monash University isolated a protein in the venom of the infamous funnel-web spider that can considerably reduce brain damage due to cerebrovascular accidents, even when administered eight hours after apoplexy. This isn't the first time researchers pointed out tremendous health benefits can be reaped from the toxins of different venomous spiders. Last year, the University of Queensland published two other studies on the therapeutic properties of spider venom, one detailing how the green velvet tarantula can help with chronic pain, the other suggesting tarantula venom can ease the discomfort of irritable bowel syndrome. "We believe that we have, for the first time, found a way to minimize the effects of brain damage after a stroke," explained lead researcher Professor Glenn King in a university press release. Funnel-web spiders are among the world's deadliest arachnids, with extremely toxic venom that is potent enough to kill a human within 15 minutes. Since the venom is designed to specifically target the prey's nervous system, King, from the Institute for Molecular Bioscience at the University of Queensland, wondered if it could be harnessed to reverse brain damage after a life-threatening event. His team travelled to Fraser Island to investigate this hypothesis and brought back three Darling Downs funnel-web spiders (Hadronyche infensa) to be tested in the lab. After engaging the spiders to make them release their toxin - by applying electric charges to their fangs and gathering the venom with a pipette, a process also known as "milking" - the scientists studied its chemical composition and found a harmless compound with the potential to save lives. DNA sequencing of the venom revealed a molecule called Hi1a, which closely resembled another chemical known for its protective effects on brain cells. This prompted the team to synthesize the molecule and observe its properties, which proved to be even more effective than the compound that initially served as comparison. Lab tests confirmed the molecule can halter neuron loss after a stroke by blocking ion channels in brain cells. These channels are activated by the acid produced in the brain when it no longer receives oxygen and are responsible for most of the cell damage that occurs during a cerebrovascular accident. A single dose of the Hi1a molecule was shown to reduce neuron damage by 80 percent when administered to rats two hours after an induced stroke. The compound retains its protective properties even for a longer period, as researchers found it can restore neurological and motor functions by nearly 65 percent when dispensed eight hours after the stroke. "Hi1a even provides some protection to the core brain region most affected by oxygen deprivation, which is generally considered unrecoverable due to the rapid cell death caused by stroke," said King. The researchers detailed their findings in the journal Proceedings of the National Academy of Sciences. They are hoping to commence human trials of the Hi1a molecule in the next couple of years, pending further research. In 85 percent of stroke cases, the damage is produced by a blockage in cerebral blood vessels, while the rest of cerebrovascular accidents are caused by hemorrhaging ruptured vessels. Hi1a had shown incredible results in the first type of stroke, and now researchers plan to determine whether the molecule is equally effective in the second type of cerebrovascular accidents. Cerebrovascular accidents are the second largest cause of death worldwide after heart attacks, and claim the lives of nearly 6 million people every year. Current treatments rely either on clot-busting drugs when the stroke is caused by a blood clot, or endovascular thrombectomy, a surgical procedure that removes the clot from the brain. With no available medication to protect stroke victims against neuron damage, the newly discovered molecule could greatly improve treatment plans, offering a safe and reliable alternative. If future tests prove Hi1a can be also administered in cases of brain hemorrhage, the compound could reduce the number of fatalities and restore brain functions for stroke survivors. "The drug could be given in the ambulance to most stroke patients before hospital arrival, maximizing the number of neurons that can be saved," said King. According to Kate Holmes, from the Stroke Association, the treatments currently available require more urgency and must be administered in half the time as the Hi1a molecule, making the compound particularly beneficial for "people who are unable to arrive at hospital quickly." "We welcome any treatment that has the potential to reduce the damage caused by stroke," said Holmes. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.
News Article | February 20, 2017
Researchers at The University of Queensland's Australian Institute for Bioengineering and Nanotechnology (AIBN) have designed a virus-like nanoparticle (VNP) that delivers drugs directly to the cells where they are needed. The lead author of a paper on the topic, Dr Frank Sainsbury, said the VNP was made from the structural proteins that formed the virus's protective shell. "Viruses have evolved to contain and protect bioactive molecules," Dr Sainsbury said. "They've also evolved smart ways to get into cells and deliver these bioactive molecules. "The VNP is an empty shell. It looks like a virus but it's not infectious. This makes it safe to use as a targeted drug delivery system." With infectious viral genes removed, empty shells can be loaded with small molecules or proteins resulting in a stable, well-protected therapeutic package. The outside of the shell then determines where the package will go. The ability to send drugs directly to their target is a critical goal in the development of safe, effective therapeutics. Currently many drugs, including anti-cancer chemotherapies, must be administered at high doses in order to have a therapeutic effect. This can lead to harsh side effects because drugs can damage healthy cells as well as intended targets. Dr Sainsbury and his colleagues developed a VNP using the Bluetongue virus, which normally infects cows, sheep and other ruminants. They picked the virus because of its stable shell, made of hundreds of proteins that are known to bind to a molecule found in high levels around many cancer cells. Dr Sainsbury teamed up with Dr Michael Landsberg at UQ's School of Chemistry and Molecular Biosciences and researchers at the Institute for Molecular Bioscience and the UK's John Innes Centre. They were able to demonstrate that the porous VNPs could be filled with small molecules for drug delivery and it also was possible to design VNPs to contain larger molecules, such as therapeutic proteins. Importantly, the researchers showed VNPs were able to bind to breast cancer cells, and then be absorbed. Dr Sainsbury said the next step was to load the VNPs with anti-cancer drugs and see if they could kill cancer cells without harming healthy cells. Although VNPs are highly complex and difficult to synthesise, Dr Sainsbury said they could be easily produced in the leaves of Nicotiana benthamiana, a wild relative of tobacco. By providing plant cells with genetic instructions for making VNPs, the plant was able to assemble virus protein shells without any permanent change to the plant's own genetic code. Dr Sainsbury said one day greenhouses may be able to produce large amounts of the nanoparticles within days. "This research unlocks a myriad of potential applications in therapeutic delivery," Dr Sainsbury said. Because the nanoparticles they have designed are highly stable, the AIBN research team is exploring other biotechnology applications. Explore further: Plant-made virus shells could deliver drugs directly to cancer cells
News Article | April 13, 2016
School of Biomedical Sciences researcher Dr Richard Clark said marine snail venom was a well-known and promising source of new pain drugs, but substantial hurdles had restrained progress. "Translating the venom's toxins into a viable drug has proved difficult," Dr Clark said. "But now we've been able to identify a core component of one of these conotoxins (toxins from cone snail venom) during laboratory tests. "We think this will make it much easier to translate the active ingredient into a useful drug." Dr Clark said a sea snail used its venom to immobilise prey and protect itself. "The venom's analgesic properties have been well researched," he said. "In this study, we've been able to shrink a particular conotoxin to its minimum necessary components for the pain relief properties to continue to work. "Using a laboratory rat model, we used the modified conotoxin to successfully treat pain generated in the colon, similar to that experienced by humans with irritable bowel syndrome. "Although the conotoxin has been modified, its pain relief properties remained as effective as the full-size model. "Simplifying the conotoxin will make a drug much faster and cheaper to develop." Dr Clark said further research was under way to improve the modified conotoxin's stability and to test its ability to treat other types of pain. The research, published in Angewandte Chemie International Edition, was undertaken in collaboration with Professor David Craik at UQ's Institute for Molecular Bioscience, Professor David Adams at the Royal Melbourne Institute of Technology and Associate Professor Stuart Brierley at the University of Adelaide. Explore further: Cone snails and plants used to develop oral drug for pain More information: Bodil B. Carstens et al. Structure-Activity Studies of Cysteine-Rich α-Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABA Receptor Activation Reveal a Minimal Functional Motif , Angewandte Chemie International Edition (2016). DOI: 10.1002/anie.201600297
News Article | February 22, 2017
IMB Centre for Superbug Solutions Deputy Director Associate Professor Lachlan Coin said arming clinicians with this information could help them prescribe the most effective antibiotic for their patient. "Antibiotic resistance is a global challenge that threatens our ability to treat common infections," he said. "Sequencing a bacterial genome using standard techniques resulted in a genome splitting into hundreds of fragments which was impossible to piece together. "In particular, pathogenicity islands—which are crucial to identifying antibiotic resistance—usually split across multiple pieces. "For the past two years, we have used cutting-edge Oxford Nanopore Technologies sequencing devices to sequence bacterial genomes and understand how antibiotic resistance develops. "Because this technology is so new, we needed to develop a powerful method that could help us make the most of its results and really understand the genetic drivers of antibiotic resistance," Associate Professor Coin said. IMB Postdoctoral Researcher Dr Minh Duc Cao said the team developed a new method for analysis of sequencing data on the fly, which allowed them to quickly and accurately piece together complete genomes. "With our method, we can reconstruct an entire bacterial genome shortly after you switch on the machine and put in the DNA sample. "The speed is key as we're interested in predicting antibiotic resistance in real time on clinical samples, because when it comes to diagnosing and treating infections, every minute counts," he said. Associate Professor Coin said the method could be applied to help unravel the genomic causes of other diseases. "We would like to work towards finding new ways to apply this approach to help unravel other diseases, particularly cancer. "Cancer genomes are about 1000 times larger than bacterial genomes, so the powerful combination of this leading technology and our improved method holds enormous potential for rapid assembly of personalised tumour genomes," Associate Professor Coin said. The research was published in Nature Communications and was funded by The University of Queensland, National Health and Medical Research Council and the Australian Research Council. The University of Queensland's Institute for Molecular Bioscience Centre for Superbug Solutions will host the Solutions for Drug-Resistant Infections conference in Brisbane from 3-5 April 2017. The conference will bring international experts and advocates in the field to network and discuss new ways to solve the global challenge of drug-resistant infections. More information: Minh Duc Cao et al. Scaffolding and completing genome assemblies in real-time with nanopore sequencing, Nature Communications (2017). DOI: 10.1038/ncomms14515
News Article | February 8, 2017
Australian researchers are a step closer to understanding immune sensitivities to well-known, and commonly prescribed, medications. Many drugs are successfully used to treat diseases, but can also have harmful side effects. While it has been known that some drugs can unpredictably impact on the functioning of the immune system, our understanding of this process has been unclear. The team investigated what drugs might activate a specialised type of immune cell, the MAIT cell (Mucosal associated invariant T cell). They found that some drugs prevented the MAIT cells from detecting infections (their main role in our immune system), while other drugs activated the immune system, which may be undesirable. The results, published in Nature Immunology overnight, may lead to a much better understanding of, and an explanation for, immune reactions by some people to certain kinds of drugs. The findings may also offer a way to control the actions of MAIT cells in certain illnesses for more positive patient outcomes. The multidisciplinary team of researchers are part of the ARC Centre of Excellence in Advanced Molecular Imaging, and stem from Monash University, The University of Melbourne and The University of Queensland. Access to national research infrastructure, including the Australian synchrotron, was instrumental to the success of this Australian research team. Dr Andrew Keller from Monash University's Biomedicine Discovery Institute said that T cells are an integral part of the body's immune system. "They protect the body by 'checking' other cells for signs of infection and activating the immune system when they detect an invader," he said. "This arrangement is dependent on both the T cells knowing what they're looking for, and the other cells in the body giving them useful information." PhD student Weijun Xu from The University of Queensland's Institute for Molecular Bioscience used computer modelling to predict chemical structures, drugs and drug-like molecules that might impact on MAIT cell function. Such small compounds included salicylates, non-steroidal anti-inflammatory drugs like diclofenac, and drug metabolites. University of Melbourne Dr Sidonia Eckle from the Peter Doherty Institute for Infection and Immunity said the implications point to possible links between known drug hypersensitivities and MAIT cells. "A greater understanding of the interaction between MAIT cells and other host cells will hopefully allow us to better predict and avoid therapeutics that influence and cause harm," she said. "It also offers the tantalising prospect of future therapies that manipulate MAIT cell behaviour, for example, by enhancing or suppressing immune responses to achieve beneficial clinical outcome." Article: Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells, Andrew N Keller, Sidonia B G Eckle, Weijun Xu, Ligong Liu, Victoria A Hughes, Jeffrey Y W Mak, Bronwyn S Meehan, Troi Pediongco, Richard W Birkinshaw, Zhenjun Chen, Huimeng Wang, Criselle D'Souza, Lars Kjer-Nielsen, Nicholas A Gherardin, Dale I Godfrey, Lyudmila Kostenko, Alexandra J Corbett, Anthony W Purcell, David P Fairlie, James McCluskey & Jamie Rossjohn, Nature Immunology, doi:10.1038/ni.3679, published online 6 February 2017.
News Article | January 20, 2016
While the phenomenon sounds like the stuff of horror films, it is common practice for these "butterflies of the ocean", a new University of Queensland-led study published today in PLOS One has found. Dr Karen Cheney of UQ's School of Biological Sciences said the multi-disciplinary study examined five closely-related nudibranchs (sea slugs) collected from the Great Barrier Reef and from South East Queensland, Australia. "These carnivorous creatures are well-known to scuba divers for their beautiful colours and intricate patterns," she said. "Science has known that many sea slugs obtain toxins from what they are eating, such as sponges, but in our study we found they selected only one toxin to store a particularly toxic compound called Latrunculin A. "Toxicity tests demonstrated that even the smallest amounts of the compound killed brine shrimp." "Further tests conducted at the Institute for Molecular Bioscience demonstrated that this compound was more toxic to cancer cell lines than other compounds found in sea slugs." Dr Cheney said sea slugs used chemical defences and bright colours to warn potential predators away, similar to poison dart frogs and brightly coloured butterflies which signalled they were toxic by their colours. "However, we still are learning if colour patterns are related to the strength of their chemical defences," she said. "We are investigating whether the most brightly coloured sea slugs are the most toxic, and also whether cryptic sea slugs that blend in with their environment also contain strong toxic defences." She said while fish recognised visual signals such as bright colours, the presence of the same toxic compound in the closely related sea slugs suggested that something else was at play. It was possible that other predators, such as crabs, might use other ways of detecting the toxicity of their prey. One future research avenue would be to explore how these creatures were able to eat their prey and transport toxic chemicals without causing internal damage. The study tapped into the expertise of co-author Professor Mary Garson of UQ's School of Chemistry and Molecular Biosciences, who has been researching chemicals stored by marine animals for the past 20 years. "One interesting study aspect is the potency of the compound which five different sea slug species chose to store," Professor Garson said. "This is a well-studied compound which kills cells. In this study we've uncovered a new use for it in an ecological context." Natural products play an invaluable role as a starting point in the drug discovery process. "The role this chosen toxin plays in the natural environment potentially could be transferred in the medical field to guide research into treatments for cancer research or neurodegenerative disease," Professor Garson said. Professor Garson said a good analogy for sea slugs, because of their bright colours, was the "butterflies of the ocean". Explore further: Traumatic mating may offer fitness benefits for female sea slugs
News Article | February 22, 2017
Researchers from The University of Queensland’s Institute for Molecular Bioscience (IMB) have developed a faster and more accurate method for assembling genomes which could help clinicians rapidly identify antibiotic-resistant infections. IMB Centre for Superbug Solutions Deputy Director Associate Professor Lachlan Coin says arming clinicians with this information could help them prescribe the most effective antibiotic for their patient. “Antibiotic resistance is a global challenge that threatens our ability to treat common infections,” he says. “Sequencing a bacterial genome using standard techniques resulted in a genome splitting into hundreds of fragments which was impossible to piece together. “In particular, pathogenicity islands — which are crucial to identifying antibiotic resistance — usually split across multiple pieces. “For the past two years, we have used cutting-edge Oxford Nanopore Technologies sequencing devices to sequence bacterial genomes and understand how antibiotic resistance develops. “Because this technology is so new, we needed to develop a powerful method that could help us make the most of its results and really understand the genetic drivers of antibiotic resistance,” Coin says. IMB Postdoctoral Researcher Dr. Minh Duc Cao says the team developed a new method for analysis of sequencing data on the fly, which allowed them to quickly and accurately piece together complete genomes. “With our method, we can reconstruct an entire bacterial genome shortly after you switch on the machine and put in the DNA sample. “The speed is key as we’re interested in predicting antibiotic resistance in real time on clinical samples, because when it comes to diagnosing and treating infections, every minute counts,” he says. Coin says the method could be applied to help unravel the genomic causes of other diseases. “We would like to work towards finding new ways to apply this approach to help unravel other diseases, particularly cancer. “Cancer genomes are about 1000 times larger than bacterial genomes, so the powerful combination of this leading technology and our improved method holds enormous potential for rapid assembly of personalized tumor genomes,” Coin says. The research was published in Nature Communications and was funded by The University of Queensland, National Health and Medical Research Council, and the Australian Research Council.