May 28, 2010
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A Map to Better Beer? The key signaling protein-protein interactions in yeast have been mapped. Mass spectrometry was used to discover the global network between protein kinases and phosphatases to generate the “kinome” map, which contains 1844 interactions. Since yeasts are model organisms with similar signaling pathways as in human cells, this information is relevant for human disease research and drug design. The data set in this study was so large that the research team created software to store and analyze the data (ProHits) and perform statistical analysis (SAINT). Dr. Mike Tyers (Samuel Luenefeld Research Institute) is the lead author of the project described in Science magazine. The entire data set is available at the yeastkinome.org resource website.
Shhhh… Improving Gene Silencing: Micro RNAs (miRNA) control gene expression by interfering with specific RNA transcripts and this requires the Argonaute proteins (AGOs) to perform this function. Researchers isolated the specific key region in AGO and solved the crystal structure of this segment. From this, they discovered that there are intricate and specific molecular interactions between the miRNA and AGO that can dictate specificity. As RNA interference techniques are gaining traction in the therapeutic arena, this discovery may lead to modifications to enhance the effectiveness of these therapies. Dr. Bhushan Nagar led the McGill University research team and published the findings in Nature or check out this video podcast.
E. coli Survival Switch: The AceK protein in some bacteria acts as a switch responding to stressful environmental cues, allowing the bacteria to bypass the energy-producing Krebs cycle and go into a conservation mode. Bacteria such as E. coli and Salmonella can survive in low-nutrient environments such as water. Therefore, the discovery of how AceK works provides a potential target to prevent bacterial contamination in drinking water by inhibiting the ability of the bacteria to go into survival mode. Dr. Zongchao Jia and postdoctoral fellow Dr. Jimin Zheng at Queen’s University solved the structure of the protein that led to understanding the unique properties of the enzyme in having both phosphorylation and de-phosphorylation activities on the same protein. This breakthrough is described in the latest edition of Nature.
Little Buggers All Over Us: The Human Microbiome Jumpstart Reference Strains Consortium is trying to catalog all the microbes in the human body. We are covered by millions and millions of these little critters – as many as 10x more microbes than the number of cells in our body, but they’re not necessarily bad for us. They actually play important roles in protecting against infection, aid with digestion, developing our immune system and keeping us healthy. So far, 178 genomes have been sequenced with the goal to sequence around 900 genomes. The NIH initiated the project and Dr. Michael Surette and his team at the University of Calgary is a major contributor to the study. The first phase of this initiative is published in Science.
Genomic Modifications in Stem Cells: To further understand stem cells and embryonic development, scientists took a closer look at how the structural organization of genomic DNA (chromatin and histones) plays a role in determining what tissue they become. They identified and compared specific modifications across the genome that either activates or represses gene expression in different stem cells. The value of this information is that it suggests differential regulatory mechanisms controlling development and depends on the specific stem cell lineage. The safety of regenerative medicine lies in these types of studies in basic stem cell biology. Developmental biologist Dr. Janet Rossant at The Hospital for Sick Children led the study, which appears in the Proceedings of the National Academy of Sciences. Also, congratulations to Dr. Rossant as a recent recipient of the 2010 Premier’s Summit Award for Medical Research.
Improving Alzheimer Immunotherapy: Delivering antibodies against amyloid-beta peptide (Abeta) directly into the brain is more effective than systemic delivery in reducing amyloid plaques, as demonstrated in a mouse model. In this novel approach, transcranial focused ultrasound (FUS) was applied to improve permeability of the blood brain barrier without the need for high doses of the antibody. The researchers administered the therapeutic antibody intravenously along with a contrast agent to follow the progress via MRI imaging. Using this MRI guided FUS method, they could see the contrast agent enter the brain within minutes and amyloid pathology was improved in the mouse model after four days. Drs. Kullervo Hynynen and Isabelle Aubert at Sunnybrook Research Institute published their study on-line in PLoS One.
April 30, 2010
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Maybe these primary research projects will lead to the next great “Dendreon” story…
Mirror-rorriM Movement Disorder: Defects in the proper connections between the left and right sides of the brain can lead to involuntary movements where one side of the body follows or mirrors the movement of the other side. A study of two families affected by inherited cases of mirror movements led to the identification of mutations in the DCC gene (Deleted in Colorectal Carcinoma). DCC is a receptor for netrin-1, which is a factor that is important for guiding neural axons across the midline to make the proper left-right connections. This is a key finding in understanding the complexities of how our brains are wired. Dr. Guy Rouleau (Université de Montréal) and Dr. Frédéric Charron (Institut de recherches cliniques de Montréal) collaborated on the study and is published in the prestigious Science journal.
Improving RNA Therapeutics: RNA interference based therapeutics is gaining traction in the biotech world (eg. Tekmira, Alnylam, MDRNA). Enhancing the potency of siRNA is the focus of this research study published in Nucleic Acids Research journal. The technology uses a combination of DNA and RNA analogs to increase the stability of the siRNA agent against nucleases and helps them to evade immune responses that often limit their effectiveness. Dr. Masad Damha led his group at McGill University.
Also in Montreal, Drs. François Major and Gerardo Ferbeyre (Université de Montréal) announced the launch of the first ribonucleic acid (RNA) engineering laboratory in Canada. They are using bioinformatics and biochemistry to come up with designer microRNAs that can control the behaviour of RNAs to control or cure cancers.
New Tumour Suppressor: A recent study demonstrates the tumour suppressor properties of the Cdh11 gene. The first hint of this function arose from studies showing a frequent loss Cdh11 in retinoblastoma cancers. Using a series of animal models to determine the role of Cdh11, Dr. Brenda Gallie’s team (Ontario Cancer Institute) demonstrated the tumour suppressor properties of Cdh11 through a mechanism promoting cell death or apoptosis. The full text article appears online in PLoS Genetics.
Lung Cancer Drug Target: CXCR4 may be the next therapeutic target for treating lung cancer. Its overexpression in about 10% of lung cancers is associated with poor patient outcome (2.7 vs. 6.1 months survival), likely due to CXCR4’s support for the rapid growth and metastasis of tumours. On the brighter side, anti-CXCR4 drugs, which are already in existence for the treatment of HIV/AIDS, may be “fast tracked” for testing in lung cancer patients. Dr. Gwyn Bebb, from the University of Calgary, presented her data recently at the 2nd European Lung Cancer Conference.
November 13, 2009
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No bad luck here in unraveling new genetic and proteomic links in disease…
Gene Variants Linked to Hearing Loss: A genetic link to hearing loss in children who are being treated with the chemotherapy drug, cisplatin, has been identified. Cisplatin is a widely used anti-cancer drug but one of the harmful side effects is hearing loss experienced by over 60% of young cancer patients. In the study by Dr. Michael Hayden’s team (Child & Family Research Institute, Vancouver), they analyzed 220 drug metabolism genes and found variants in two particular genes that are associated to hearing loss in children – one gene is called TPMT (thiopurine methyltransferase) and the other is COMT (catechol-O-methyltransferase). With this information, doctors can perform genetic tests to determine the patient’s susceptibility to developing hearing loss and seek alternative treatment if necessary. Further studies investigating how these enzymes contribute to cisplatin-induced hearing loss could lead to drugs to counteract these effects while receiving the benefits of cisplatin therapy. The study appears in this week’s Nature Genetics.
The Missing Links in 5q- Syndrome: In patients with 5q- syndrome, a portion of chromosome 5 is deleted and the result is abnormal function of bone marrow cells leading to severe anemia. We now know what is missing in this region of chromosome 5 that have key roles in maintaining the integrity of bone marrow cells. In the investigation reported in Nature Medicine, Dr. Aly Karsan at the University of British Columbia and BC Cancer Agency discovered that two microRNAs (miRNAs), miR-145 and miR-146a, are lost in 5q- syndrome. MicroRNAs are short, single-stranded RNA that act to down regulate expression of specific target genes. The targets of miR-145 and miR-146a are two proteins called TIRAP and TRAF6, which play important roles in immune signalling but should be turned off in hematopoietic stem/progenitor cells during blood cell development. In support of their hypothesis, the researchers demonstrated in mice that forced expression of TRAF6 results in a condition that is similar to human 5q- syndrome.
Cancer Genes Now Linked: Researchers at Queen’s University studying C. elegans worms identified a connection between two genes involved in cancer. PTEN is a tumour suppressor and loss of function mutations are known to be involved in a number of cancers. Eph receptor signalling is required in developmental pathways and its expression level is elevated in some cancers. New evidence now connects PTEN and Eph receptors in development and cancer. The research led by Dr. Ian Chin-Sang’s team demonstrated an inverse relationship where Eph receptors can phosphorylate and downregulate PTEN. Conversely, PTEN activity can modulate Eph receptor signaling. If there is an imbalance in this relationship, then the (negative) effects may be amplified quickly. The study report appears in the current issue of Developmental Cell.
Determining Thryoid Hormone Receptor Complexes in Yeast: This is a neat genetic array assay using yeast as a simple model system to unravel co-regulators in thyroid hormone receptor (TR) activity. A yeast strain expressing TR was systematically crossed with each of 384 yeast strains bearing deletions of known genes. From this unbiased assay, researchers identified four genes that are deemed essential for thyroid hormone function and are also conserved in humans. Dr. Paul Walfish (Toronto Mount Sinai Hospital) and his team focused on one of these genes, CCR4. They validated its role in thyroid hormone receptor action by performing a series of CCR4 expression and deletion analyses in cultured human cells and proved its association with TR in response to thyroid hormone. Details of their findings appear in the early online edition of The Proceedings of the National Academy of Sciences.
FGFR3 Phosphorylation Network in Disease: An emerging field in proteomic studies is large-scale phospho-proteomic analyses using mass spectrometry to map signalling pathways. This technique was applied to define the FGFR3 phosphorylation network in multiple myeloma and other cancers. The researchers also demonstrated in their work the ability to quantitatively detect the upregulation or downregulation of over 60 phosphorylation sites on proteins that either responded to growth factor stimulation or inhibition by the pharmacologic drug PD173074. One could apply this general method for pharmacodynamic monitoring of any drug inhibitor to fully understand its implications in the cell. Dr. Michael Moran’s research team at the Hospital for Sick Children and University of Toronto published their report in this week’s Proceedings of the National Academy of Sciences.
February 25, 2009
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The question this week: a shot in the arm or a kick in the teeth?
A shot in the arm for:
- Fewer shots in the arm! (har)
- British Columbia is the first jurisdiction in North America to offer a children’s vaccine called Infanrix-hexa™, which contains six immunizations in one, resulting in three fewer needles in the overall B.C. infant vaccine schedule, and
- With the discovery of a constant region of flu virus protein hemagglutinin, a universal flu vaccine may be possible (no more yearly shots);
- The Naval Surface Warfare Center in White Oak, a suburb of Washington, where the FDA is spending $1.15 billion to consolidate its offices and labs and to anchor a new biotech hub;
- Pine Island, near Rochester, Minnesota, which could soon be the home to a new biotech research, development and manufacturing park with the help of up to $900 million in funding reportedly pledged by Steve Burrill. Funding announcements also from Maryland and Pittsburgh;
- Sustainable agriculture, when the White House announced its nominee for second-in-command at USDA: Kathleen Merrigan of Tufts University, who had been a top choice of the Cornucopia Institute to run USDA’s National Organic Program;
- The National Science Foundation, from the stimulus (a $3 billion boost) and the budget (a 6.7% increase, to $6.49 billion);
- Multiple Sclerosis, with Merck, Novartis, Teva, Biogen Idec and Sanofi Aventis all planning to release new oral therapeutics between now and 2012;
- Conflict of interest disclosure, with a new editorial in PLoS Medicine;
- Deterrence, with the arrest of four animal-rights extremists;
- Organ failure biomarkers,
- with the discovery of liver toxicity-associated MicroRNAs, and
- with the injection by Pfizer Canada of $1 million to the PROOF Centre to fund research into vital organ failure biomarkers; and
A kick in the teeth for: