News Article | May 8, 2017
An international study led by researchers at Monash University' Biomedicine Discovery Institute (BDI) has shone light on the way the Hepatitis C Virus (HCV) hijacks the communication systems in the host cells it infects, uncovering potential new therapeutic targets for the disease. HCV affects about two per cent of the world's population. Infection can lead to chronic hepatitis, which can progress to liver cirrhosis and carcinoma. Importantly, the approach used by the scientists - which led to the identification of a drug-like molecule that stopped the virus from replicating within cells - may have broader application to other infectious diseases. This is because all intracellular pathogens rely on their host cell signalling system to replicate. The study, published in Nature Communications today, focused on protein kinases, enzymes that are key regulators of cellular processes. It built on previous ground-breaking work on malaria published in 2011 by author Monash Professor Christian Doerig, and others, who found that if host cell protein kinases were prevented from working it would kill malaria parasites. The Monash BDI researchers worked in collaboration with Canadian-based company Kinexus, and used an antibody microarray to simultaneously investigate hundreds of factors involved in cell signalling that were modulated by HCV replication, including human protein kinases. "This antibody microarray allowed us to find a number of new cell signalling pathways that were activated or suppressed by an HCV infection," Professor Doerig said. First author Dr Reza Haqshenas said the researchers then used gene silencing technology to determine whether the genes' cell factors identified using the antibody microarray were indeed important for HCV replication and therefore potential targets for anti-HCV compounds. They were then able to use a compound recently discovered by Harvard University investigator Professor Nathanael Gray to block the activity of one of the kinases important in HCV replication, MAP4K2. "Nathanael sent us his new molecule, and we put it in our host cells, infected them with HCV and found that while the cells were fine, they didn't support virus replication anymore," Dr Reza Haqshenas said. Professor Doerig said the study provided a compelling "proof of concept." "The platform we have established can be adopted to identify new anti-infective compounds against any pathogen including, viruses, bacteria and parasites, that invade mammalian cells," he said. "Importantly, fighting a pathogen by hitting an enzyme from the host cell is likely to slow the emergence of drug resistance, because the pathogen cannot easily escape through the selection of target mutations," Professor Doerig said. The researchers will now extend their work in studies on the Zika virus and toxoplasmosis. The study, which included Monash BDI Professor Roger Daly, was carried out in collaboration with the Peter MacCallum Cancer Centre (Associate Professor Kaylene Simpson) and the Garvan Institute (bioinformatician Dr Jianmin Wu), Associate Professor Hans Netter, and the French National Institute of Health and Medical Research INSERM (Professor Thomas Baumert). It was supported with funding from the Australian Centre for HIV and Hepatitis Virology Research (ACH2). Read the full paper (DOI: 10.1038/NCOMMS15158 - active once embargo lifts), titled Signalome-wide assessment of host cell response to Hepatitis C virus, published today in Nature Communications. Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery
News Article | March 22, 2017
Laboratory Design (LD): How did you get into your field? David Keenan (DK): In an un-conventional way. I studied Zoology at University in the U.K., after which I joined a wine company that sent me to Edinburgh. After a couple of years, I realized I wanted to get back into science and found myself at the Medical Research Council’s Human Genetics Unit in Edinburgh working in a lab looking into the genetic disorders of muscle disease. The lab was successful and my boss was recruited to Sydney. He invited me to join him, so I left the U.K. to move to Australia, where I took on the role of setting up the lab and aquarium at the Victor Chang Cardiac Research Institute in Sydney. I thoroughly enjoyed this and it led to my next job, at the Garvan Institute. Over time I became responsible for planning and delivering larger and larger research buildings. My last project was the Victorian Comprehensive Cancer Center, a large $1 billion Public Private Partnership mixed health and research facility in Melbourne. I’ve now found my way to HDR. LD: What’s the most surprising thing you’ve learned in your career? DK: How close many door frames are to the height of a ULT-80 freezer, or how wide a double door is for a pallet movement/large piece of equipment. It is important to consider the items moving through any given door and, in particular, the full travel path for some large items to ensure usefulness and flexibility of the space. LD: What’s a common mistake made by those working on designing/constructing a laboratory? DK: The movement of materials and people through a lab is often not considered fully or in all situations. I’ve seen ramps in places where heavy loads are moved, or a single elevator at one end of a building that might often be on exclusive use. Then there are the issues of moving biological materials through non-lab environments to get from point A to B: Do you wear gloves or not, gowns or not; double-bag or not; are you traversing where people might eat/drink; and so on. These are all issues to be carefully considered in planning out how the spaces will be used. LD: What do you consider the highlight of your career? DK: It’s a tough pick but the Kinghorn Cancer Centre is a beautiful facility that is planned to be both functionally simple and, in my opinion, ‘elegant.’ The Victorian Comprehensive Cancer Centre is a close second for the sheer scale and challenge—everything about it was big! LD: If you could give just one piece of advice to others in your field, what would it be? LD: Can you describe a funny or exciting moment in your career? DK: A very exciting AND scary moment in my career had to be when we unveiled the Richard Long (U.K. Turner Prize-winning artist) artwork in the Kinghorn Cancer Centre. The artwork is a chalk mix on painted concrete that is eight stories high: spectacular in both scale and impact. There was a heart-stopping moment when a leak appeared during a freak torrential storm immediately after occupancy. Water tracked to just above the piece and began to run down the middle of the artwork … thankfully we repaired the leak immediately and the art wasn’t damaged but it was a scary time! LD: Is there anything else you’d like to share with the readers of Laboratory Design? DK: Don’t take yourself too seriously.
Clark I.A.,Australian National University |
Vissel B.,Garvan Institute
British Journal of Pharmacology | Year: 2015
This review concerns how the primary inflammation preceding the generation of certain key damage-associated molecular patterns (DAMPs) arises in Alzheimer's disease (AD). In doing so, it places soluble amyloid β (Aβ), a protein hitherto considered as a primary initiator of AD, in a novel perspective. We note here that increased soluble Aβ is one of the proinflammatory cytokine-induced DAMPs recognized by at least one of the toll-like receptors on and in various cell types. Moreover, Aβ is best regarded as belonging to a class of DAMPs, as do the S100 proteins and HMBG1, that further exacerbate production of these same proinflammatory cytokines, which are already enhanced, and induces them further. Moreover, variation in levels of other DAMPs of this same class in AD may explain why normal elderly patients can exhibit high Aβ plaque levels, and why removing Aβ or its plaque does not retard disease progression. It may also explain why mouse transgenic models, having been designed to generate high Aβ, can be treated successfully by this approach. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd.
News Article | November 17, 2016
SAN DIEGO, Nov. 17, 2016 (GLOBE NEWSWIRE) -- MOgene, LC, a full service, global genomics service provider, and BioNano Genomics, Inc., the leader in physical genome mapping, today announced the adoption of an Irys® System at MOgene’s Bio Research & Development Growth (BRDG) Park facility at the Danforth Plant Science Center in St. Louis. By adding BioNano’s Next-Generation Mapping (NGM) to its suite of genomics solutions, MOgene will be able to address the needs of customers who are increasingly seeking to reveal true genome structure as a critical component in their research. MOgene’s existing service offerings in genomics include short read sequencing from Illumina and long read sequencing from PacBio. The Irys® System introduces optical mapping to their repertoire, to reveal ultra long-range genomic information enabling two unique capabilities. First, by combining sequencing data and BioNano mapping data, MOgene will be able to create reference-quality genome assemblies for the abundance of non-model organisms for which no reference exists or organisms where the existing assemblies would benefit from improvement or diversification. Additionally, Irys® can be used as a stand-alone tool to screen genomes to reveal structural variations (SVs) ranging from 1 kilobase pair to megabase pairs in size. BioNano’s sensitivity to SVs in this size range is unparalleled in genomics, enabling MOgene to differentiate its offerings. Shaukat Rangwala, Senior Vice President of MOgene LC, commented, “Our customers will find the incorporation of next-generation mapping to our portfolio of innovative genomic service offerings to be incredibly valuable. BioNano’s NGM with the Irys® System enables us to offer better genomic solutions and match the sequencing needs of academic and commercial researchers. Both as a standalone technology and as a complement to the long-range sequencing techniques developed by PacBio, NGM using the Irys® System collectively addresses the diverse needs of our customers who would like to generate complete genome assemblies or want to have a more complete view of structural variations present in the genome.” Erik Holmlin, Ph.D., CEO of BioNano Genomics, commented, “Genomic service providers such as MOgene are leading the way to provide researchers with the latest available solutions in genomics, allowing them to achieve more comprehensive and complete genome analyses. MOgene’s adoption of the Irys® System is a clear indication that NGM is becoming essential among the suite of tools used for genome analysis, and we look forward to supporting MOgene as they provide data and insights discovered using NGM to researchers worldwide.” The Irys® System provides a comprehensive view of the whole genome via single molecule imaging, facilitating high resolution de novo mapping without the guidance of a reference genome and generates valuable insights about the biology of the genome based on information about the order, orientation, arrangement, and interaction of genomic components. The Irys® System uses IrysPrep® Reagents to extract and label long DNA molecules and the IrysView® and IrysSolve® software to provide powerful de novo assemblies and analysis of the genome. MOgene, a Limited Liability Company has been in operations since February 2004. The company has established solid reputation as a global genomics service provider to academic, government and industrial research groups and institutions. MOgene offers nucleic acid isolation, library preparation, microarrays, Real-Time PCR, NextGen sequencing, Next-Generation Mapping, sequence capture and bioinformatics. MOgene is also CLIA certified. www.mogene.com BioNano Genomics, Inc., the leader in next-generation mapping (NGM), provides customers with genome analysis tools that advance human, plant and animal genomics and accelerate the development of clinical diagnostics. The Company’s Irys® System uses NanoChannel arrays integrated within the IrysChip® to image DNA at the single-molecule level with average single-molecule lengths of about 350,000 base pairs, which leads the genomics industry. The long-range genomic information obtained with the Irys System helps decipher complex DNA involving repeats, which are the primary cause of inaccurate and incomplete genome assembly. On its own, next-generation mapping with the Irys System enables detection of structural variants, many of which have been shown to be associated with human disease as well as complex traits in plants and animals. As a companion to next-generation sequencing (NGS), next-generation mapping with the Irys System integrates with sequence assemblies to create contiguous hybrid scaffolds that reveal the highly informative native structure of the chromosome. Only BioNano Genomics provides long-range genomic information with the cost-efficiency and throughput to keep up with advances in next-generation sequencing. The Irys System has been adopted by a growing number of leading institutions around the world, including: National Cancer Institute (NCI), National Institutes of Health (NIH), Wellcome Trust Sanger Institute, BGI, Garvan Institute, Salk Institute, Mount Sinai and Washington University. Investors in the Company include Domain Associates, Legend Capital, Novartis Venture Fund and Monashee Investment Management. For more information, please visit www.BioNanoGenomics.com. Notes: BioNano Genomics is a trademark of BioNano Genomics, Inc. Any other names of actual companies, organizations, entities, products or services may be the trademarks of their respective owners.
News Article | February 15, 2017
SAN DIEGO, Feb. 15, 2017 (GLOBE NEWSWIRE) -- Bionano Genomics, a company focused on genome structure analysis, today highlighted study results that demonstrate the translational and clinical significance of next-generation mapping (NGM) to improve serious human disease research by precisely detecting large structural variations (SVs) often missed by other technologies such as sequencing. Research is being presented at the Advances in Genome Biology and Technology (AGBT) General Meeting this week. Erik Holmlin, Ph.D., CEO of Bionano, commented, “Large genomic rearrangements are increasingly understood as drivers of serious human health conditions. Sequencing solutions based on short reads do not capture these SVs with sufficient sensitivity and specificity to enable comprehensive studies of their biological and clinical significance and even long read sequencing does not overcome these limitations. Results of these four studies demonstrate the ability of Bionano's next-generation mapping to accurately detect large SVs, many of which have critical clinical implications with the potential to meaningfully improve patient outcomes. We look forward to sharing these results with researchers at AGBT this week.” Key findings from four of the studies being presented include: Poster #814: Detecting a novel range of large somatic genomic rearrangements in human cancer using the Bionano Optical mapper Vanessa Hayes, Ph.D., Lab Head of Human Comparative and Prostate Cancer Genomics, Garvan Institute of Medical Research, and her team demonstrate NGM as a complimentary tool to next-generation sequencing (NGS) due to NGM’s ability to examine megabase length DNA molecules outside the detection range of NGS. Using optical mapping with Bionano’s Irys® System, the researchers generated complete human genome maps from tumor-normal pairs of both primary and metastatic prostate cancer from five prostate cancer patients, and identified a novel set of large SVs within prostate cancer, of which almost 90% were undetectable using NGS alone. Use of NGS and NGM methods allowed for verification of up to 95% of the large SVs identified through NGM. Most importantly, the researchers identified a target mutation of drug metabolism in the NGM results that was completely missed by NGS. This finding could have guided patient treatment, illustrating the significant need to accurately and comprehensively detect large SVs that have clinical implications in serious human health conditions, including cancer. Poster #516: Potential for improved molecular diagnosis of FSHD through D4Z4 array quantitation using Bionano technology Jonathan Pevsner, Ph.D., Research Scientist, Kennedy Krieger Institute and primary faculty appointment at Johns Hopkins University School of Medicine, and his team used NGM with Saphyr to determine the genomic architecture of specific regions of chromosomes associated with Facioscapulohumeral muscular dystrophy (FSHD), the third most common hereditary form of muscle disease for which genetic testing, while sensitive and specific, is also complex, laborious, and specialized. 95% cases of FSHD have a defect in FSHD1 gene that is associated with contraction of a 3.3 kilobase D4Z4 repeat in the subtelomeric region of chromosome 4q35. The researchers assembled D4Z4 genome maps from normal individuals and FSHD patients, and demonstrated that NGM correctly distinguished between the pathogenic and the non-pathogenic allele, correctly determined the number of D4Z4 repeats on chromosome 4 while at the same time distinguishing it from the non-relevant but highly similar repeat on chromosome 10. Whole-genome sequencing and 10X-Genomics sequencing failed to resolve this locus or to distinguish the chromosome 4 and 10 repeats. Han Cao, Ph.D., Founder and Chief Scientific Officer at Bionano Genomics, presents the results of collaborators at the University of California, San Francisco (UCSF), Drexel University, and Chinese University of Hong Kong. The team examined the sensitivity of detection and localization of SVs in human populations. Researchers constructed genome optical maps using Irys for 146 unrelated individuals from 26 human populations with long DNA molecules (>150 kb) using native DNA without amplification and then de novo assembled the map without the use of the NGS-generated human reference genome assembly. The NGM-generated optical maps showed clear specific SV patterns among different ethnic groups and individuals in the population, with patterns most pronounced in complex regions of the genome where large (>50 kb) inversions and tandem duplications are mixed together in the same loci. The study demonstrates the power of long single-molecule NGM in resolving complex SVs in the human genome beyond the ability of NGS. Furthermore, it explains the need to create specific reference genomes for a wide range of ethnically diverse populations to allow for precision medicine initiatives reflecting the correct genomic structure of each patient. Poster #1116: Efficient de novo structural variation analysis and annotation using next-generation mapping (NGM) with the Bionano Irys System Andy Wing Chun Pang, Ph.D., Senior Scientist at Bionano Genomics, and the Bionano team demonstrate the significance of NGM using Irys to discover de novo SV mutations that are associated with genetic disease and can be missed by NGS and microarray. Blood samples were obtained from a quintet family with all three children displaying developmental delay, and for each individual, DNA molecules larger than 150 kbp were extracted and assembled de novo, creating megabases-long optical maps. The process from sample collection to SV-discovery took only one week. In each sample, researchers detected more than 3,500 insertions and deletions of lengths more than 500 bp, and discovered five to seven de novo SVs in the affected children, one of which was shared among all three and possibly associated with developmental delay. The study suggests that Irys may replace conventional approaches for rapid discovery of functionally-relevant variants, and overall, significantly improves deeper understanding of genomes. Learn more by visiting Bionano’s Saphyr Room # 213 at AGBT and visiting www.bionanogenomics.com/AGBT2017. Bionano Genomics, Inc. provides the Irys and Saphyr systems for next-generation mapping (NGM), which is the leading solution in physical genome mapping. NGM offers customers whole genome analysis tools that reveal true genome structure and enabling researchers to capture what’s missing in their data to advance human, plant and animal genomic research. NGM uses NanoChannel arrays to image DNA at the single-molecule level with average single-molecule lengths of about 350,000 base pairs, which leads the genomics industry. The long-range genomic information obtained with NGM detects and deciphers structural variations (SVs), which are large, complex DNA segments involving repeats that are often missed by sequencing technologies and which are a leading cause of inaccurate and incomplete genome assembly. As a stand-alone tool, NGM enables the accurate detection of SVs, many of which have been shown to be associated with human disease as well as complex traits in plants and animals. As a complementary tool to next-generation sequencing (NGS), NGM integrates with sequence assemblies to create contiguous hybrid scaffolds for reference-quality genome assemblies that reveal the highly informative native structure of the chromosome. NGM also provides the additional ability to verify, correct and improve a NGS-generated genome assembly. Only Bionano provides long-range genomic information with the cost-efficiency and high throughput to keep up with advances in NGS. NGM has been adopted by a growing number of leading institutions around the world, including: National Cancer Institute (NCI), National Institutes of Health (NIH), Wellcome Trust Sanger Institute, BGI, Garvan Institute, Salk Institute, Mount Sinai and Washington University. Investors in the Company include Domain Associates, Legend Capital, Novartis Venture Fund and Monashee Investment Management. For more information, please visit www.BionanoGenomics.com. Notes: Bionano Genomics is a trademark of Bionano Genomics, Inc. Any other names of actual companies, organizations, entities, products or services may be the trademarks of their respective owners.
Ryugo D.,Garvan Institute
Cell and Tissue Research | Year: 2015
Data from our laboratory show that the auditory brain is highly malleable by experience. We establish a base of knowledge that describes the normal structure and workings at the initial stages of the central auditory system. This research is expanded to include the associated pathology in the auditory brain stem created by hearing loss. Utilizing the congenitally deaf white cat, we demonstrate the way that cells, synapses, and circuits are pathologically affected by sound deprivation. We further show that the restoration of auditory nerve activity via electrical stimulation through cochlear implants serves to correct key features of brain pathology caused by hearing loss. The data suggest that rigorous training with cochlear implants and/or hearing aids offers the promise of heretofore unattained benefits. © 2014, Springer-Verlag Berlin Heidelberg.
Lee H.J.,Garvan Institute |
Ormandy C.J.,Garvan Institute
Molecular and Cellular Endocrinology | Year: 2012
Progesterone and prolactin remodel mammary morphology during pregnancy by acting on the mammary epithelial cell hierarchy. The roles of each hormone in mammary development have been well studied, but evidence of signalling cross-talk between progesterone and prolactin is still emerging. Factors such as receptor activator of NFkB ligand (RANKL) may integrate signals from both hormones to orchestrate their joint actions on the epithelial cell hierarchy. Common targets of progesterone and prolactin signalling are also likely to integrate their pro-proliferative actions in breast cancer. Therefore, a thorough understanding of the interplay between progesterone and prolactin in mammary development may reveal therapeutic targets for breast cancer. This review summarises our understanding of Pg and PRL action in mammary gland development before focusing on molecular mechanisms of signalling cross-talk and the implications for breast cancer. © 2011 Elsevier Ireland Ltd.
Clark I.A.,Australian National University |
Alleva L.M.,Australian National University |
Vissel B.,Garvan Institute
Pharmacology and Therapeutics | Year: 2010
Certain cytokines, the prototype being the highly pleiotropic TNF, have many homeostatic physiological roles, are involved in innate immunity, and cause inflammation when in excess. These cytokines have long been accepted to have central roles in the pathogenesis of systemic or local non-cerebral disease states, whether acute or chronic, and whether or not caused by infectious agents. Over the last decade they have also been appreciated to be broadly important in brain physiology. As in other organs, excessive levels in brain are harmful, and its physiological complexity leads to correspondingly complex dysfunction. This review summarizes the burgeoning literature on this topic, and how the functions of these molecules, particularly TNF, are influencing the outlook of researchers on the pathophysiology of these diseases. Basic brain physiology is thus informing knowledge of the brain dysfunction that characterizes such apparently diverse states as Alzheimer's disease, trauma (mostly, but not only, to the brain), Parkinson's disease, and severe systemic infectious states, including malaria, sepsis, viral diseases and major depression. The implication is that the anti-cytokine therapies now in use, typically directed at TNF, warrant testing in these diseases in circumstances in which the therapeutic agent enters the cerebrospinal fluid. Routinely administering such drugs to patients exhibiting the neurological changes discussed in this review would simply add another organ system to what is already a very successful strategy in the treament of inflammatory disease at other sites, such as joints, skin and gut. Clearly, the most relevant research is focussed on Alzheimer's disease, but the principles may also apply to other encephalopathies. © 2010 Elsevier Inc.
Clark I.A.,Australian National University |
Vissel B.,Garvan Institute
Neural Plasticity | Year: 2015
Tumor necrosis factor (TNF) is an ancient and widespread cytokine required in small amounts for much physiological function. Higher concentrations are central to innate immunity, but if unchecked this cytokine orchestrates much chronic and acute disease, both infectious and noninfectious. While being a major proinflammatory cytokine, it also controls homeostasis and plasticity in physiological circumstances. For the last decade or so these principles have been shown to apply to the central nervous system as well as the rest of the body. Nevertheless, whereas this approach has been a major success in treating noncerebral disease, its investigation and potential widespread adoption in chronic neurological conditions has inexplicably stalled since the first open trial almost a decade ago. While neuroscience is closely involved with this approach, clinical neurology appears to be reticent in engaging with what it offers patients. Unfortunately, the basic biology of TNF and its relevance to disease is largely outside the traditions of neurology. The purpose of this review is to facilitate lowering communication barriers between the traditional anatomically based medical specialties through recognition of shared disease mechanisms and thus advance the prospects of a large group of patients with neurodegenerative conditions for whom at present little can be done. © 2015 Ian A. Clark and Bryce Vissel.
News Article | November 19, 2015
Scientists have long speculated about the nature of the dark proteome, the area of proteins that are completely unknown, but a recent study by CSIRO has mapped the boundaries of these dark regions, bringing us one step closer to discovering the complete structure and function of all proteins. The work, led by Dr Sean O'Donoghue, a data visualisation scientist with CSIRO and the Garvan Institute, has been published today in the prestigious Proceedings of the National Academy of Sciences journal. As knowledge of three-dimensional protein structures continues to expand, we can identify regions within each protein that are different to any region where structure has been determined experimentally, coined the 'dark proteome'. "These dark regions are unlike any known structure, so they cannot be predicted," Dr O'Donoghue said. "Identifying these areas is very exciting as we now have a map to focus our research efforts." "Our map defines the boundaries right at the edge of protein knowledge." The research has yielded some surprising results, including that nearly half of the proteome in eukaryotes is dark and has unexpected features, including an association with secretory tissues, disulfide bonding, low evolutionary conservation, and very few known interactions with other proteins. This work will help future research shed light on the remaining dark proteome, revealing molecular processes of life that are currently unknown. It may also provide insight into protein based illnesses like cancer, type 2 diabetes, and many neurodegenerative diseases, such as Parkinson's disease and Alzheimer's. Protein molecules compose many of the major elements of our body, and dark proteins—those with completely unknown structure—are abundant in skin and hair, and glands that make saliva, semen, and milk. "The dark proteome undoubtedly plays a key role in human health, as well as many other areas of life science," Dr O'Donoghue said. "We believe that studying the dark proteome will clarify future research directions, as studies of dark matter have done in physics." The discovery was made using Aquaria, CSIRO's free web based tool that uses data from the Protein Data Bank to create 3D structural models for 546,000 protein sequences. Explore further: Powerful tool promises to change the way scientists view proteins More information: N. Perdigao et al. Unexpected features of the dark proteome, Proceedings of the National Academy of Sciences (2015). DOI: 10.1073/pnas.1508380112