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Category Archives: Friday Science Review

Friday Science Review: February 19, 2010

Hunks and pigs highlight this week’s research wrap-up…

HUNKs Stop Cancer Metastasis: Researchers screening tumour cells found that expression of the enzyme HUNK (Hormonally Up-regulated Neu-associated Kinase) is significantly lower in cancers.  When they reconstituted HUNK into metastatic cancer cells, it decreased their metastastic potential when tested in mouse cancer models.  Its actions block the association of PP2A and cofilin-1 and prevent the formation of actin filaments, which are key skeletal proteins involved in the cell migration process.  Dr. Tak Mak led the research team at the Campbell Family Institute for Breast Cancer Research and published the study in the Proceedings of the National Academy of Sciences.

Malaria Research Gets Genomic Help: A genome-wide study on the parasite Plasmodium falciparum should help researchers in the hunt for new drugs against malaria.  The genome of 189 malaria samples from around the world were decoded and analyzed to try to identify key genes that are responsible for the parasite’s propensity to evolve and become resistant to currently available drug treatments.  These data are invaluable for the design of future therapeutic approaches.  An international team was co-led by Dr. Philip Awadalla at the Université de Montréal and reports their work in the current issue of Nature Genetics.

Genetic Clues to Diabetes: Using a genome-wide association approach, 13 SNPs concentrated in 4 genetic regions were identified to be strongly correlated with glycemic control in type 1 diabetes.  For example, SORCS1 is strongly associated with hypoglycemia (low blood glucose) and BNC2 is correlated with eye and kidney complications.  This study is a first for suggesting that there may be a genetic contribution to the individual’s ability to control blood glucose levels.  The Hospital for Sick Children’s Dr. Andrew Paterson led the study, which appears in the journal Diabetes.

Porky Pig to the Rescue: Scientists revealed a significant advantage to transplanting porcine pancreatic islet cells as a therapeutic for diabetes.  In contrast to using human islet cells, porcine derived cells do not result in the formation of islet amyloids, which allows them to continue functioning properly for the long term.  They attribute this porcine advantage to differences in the sequences of islet amyloid polypeptide (IAPP).  Dr. Bruce Verchere’s team at the University of British Columbia describes their work in the Proceedings of the National Academy of Sciences.

In (un)related news, Guelph University’s genetically engineered pigs or “Enviropigs” were given the OK by Environment Canada as being non-toxic to the environment.  Now they await Health Canada’s nod before they appear in your local supermarket.

Stem Cells Don’t Mind DNA Damage: Canadian scientists have discovered that stem cells intentionally damage their own DNA in order to regulate development… continue reading the rest of the story here at the Stem Cell Network Blog.

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Friday Science Review: February 12, 2010

New Discovery for Neonatal Diabetes: Researchers uncovered an important role for the Rfx6 gene.  Its integrity is required for normal development of the islets of Langerhans cells in the pancreas that produces important hormones including insulin.  Genetic mutations found in Rfx6 are the cause of severe neonatal diabetes where there are no insulin producing islets of Langerhans cells.  To prove the critical role of Rfx6 in directing the differentiation of early pancreatic cells, researchers disrupted the gene in mice and observed the development of an identical disorder as displayed in humans.   Identifying the gene is a key piece of the puzzle and will lead to new avenues to find treatments for all types of diabetes.  Dr. Constantin Polychronakos and his team at McGill University collaborated with researchers from UCSF and report their study in the on-line edition of Nature.

Controlling Stem Cell Fate: A genome-wide screen identified the PCL2 (polycomb-like 2) gene as a key decision maker in determining the fate of stem cells.  This is an important area of research because stem cell based therapies in regenerative medicine are on the rise but more thorough understanding of stem cell control is necessary for safety reasons.  In the absence of PCL2, stem cells can no longer differentiate into specialized cells regardless of adding stimulating factors to try to push it to differentiate.  Once they re-introduced PCL2 into the stem cells, they were able to drive differentiation again.  By mapping the network of genes that PCL2 regulates, they can trace the steps in the path of a stem cell in becoming one of the many cell types in our body.  University of Toronto scientist, Dr. William Stanford and his team describe their research in the journal Cell Stem Cell.

Stem Cell Prediction: This is a neat study.  Researchers generated an algorithm to predict the future of a stem cell – whether it divides and self-renew as stem cells or produce alternate cell types.  They recorded video of retinal progenitor cells under the microscope to ‘observe’ the cell’s characteristic dynamic behaviour and movements just prior to dividing.  This information was computed to generate a predictive algorithm that was tested to be (amazingly!) 99% accurate in identifying cells that will self-renew as stem cells and 87% correct in predicting a differentiation cell fate.  This may lead to new tools to help scientists isolate pure populations of stem cells for their future studies.  Dr. Michel Cayouette’s group at the Institut de Recherches Cliniques de Montréal presents their work in this week’s edition of Nature Methods.

Genomics of Flesh-eating Disease: The genomic sequences of Streptococcus bacterial strains from past epidemics in Ontario were determined in a study involving Canadian and US researchers.  They identified and compared single nucleotide polymorphisms (SNPs) between the strains and found that they were different by an average of only 49 SNPs.  Each strain, however, also contained unique sequences that could be used for tracking purposes in future outbreaks.  Some genes were highly variable, which is information that they can use to try to understand the bacterial virulence factors at play in gaining an advantage over the infected person.  These comparative pathogenomic studies are invaluable for microbial epidemiology research and for shedding light on new potential targets for antibiotic drugs.  Drs. Donald Low and Allison McGeer at Mount Sinai Hospital participated in the research that is reported in this week’s edition of the Proceedings of The National Academy of Sciences.

Friday Science Review: February 5, 2010

Several neurological related stories this week and quantum biology?

Glial Cells – They’ll turn against you: An unusual molecule can turn glial cells, which normally surround neurons, into killer cells that attack the neurons they are suppose to protect.  Researchers made the surprising discovery of proNGF’s role while trying to figure out its function in the eye.  They found that it can activate glial cells to turn against retinal neurons and potentially cause vision impairment or loss.  Some of the molecular details were also worked out and they describe the significance of TNFalpha and p75NTR proteins in this cell death process.  These results shed light on potential routes for therapeutic targets to prevent certain cases of vision loss.  The study, published in the early on-line edition of the Proceedings of the National Academy of Sciences, is a collaboration involving Dr. Adriana Di Polo at Université de Montreal and Dr. Philip Barker at the Montreal Neurological Institute.

Unexpected Heart Failure and Treatment: Researchers studying mouse models for neuronal diseases, such as Alzheimer’s, noticed progressive abnormalities in the rodent’s heart function.  The mice had slower heart rates (as expected) but they also had difficulty pumping blood and researchers soon realized that they may have stumbled upon a possible mechanism of human heart failure.  The genetic modification in these mice resulted in decreased levels of the neurotransmitter, acetylcholine.  In contrast to previous reports on heart failure, this is the first study suggesting that slower heart rates may lead to cardiac dysfunction.  Furthermore, the administration of the drug Pyridostigmine, which increases acetylcholine levels and is approved for treating muscle weakness, corrected the cardiac dysfunction.  The research team of Drs. Marco Prado and Vania Prado at the Robarts Research Institute at The University of Western Ontario describe their findings in the latest edition of Molecular and Cellular Biology.

Early Stages of Huntington’s: Insight into the cellular mechanisms in the brain that causes Huntington’s disease is described in this article appearing in the journal Neuron.  Using mouse models expressing the gene mutations causing the disease, scientists discovered increased numbers of NMDA receptors surrounding the synaptic connections between neurons.  The increased NMDA receptor activity also diminishes survival signals leading to brain cell death.  In other words, the neurons become confused and triggers cell death (excitotoxicity).  Although it is not known why the receptors accumulate outside of the neuron, a therapeutic drug is already available (for Alzheimer’s) to treat the early stages of the disease.  Memantine can control the abnormal NMDA receptor signaling specifically outside the synapses and not disrupt the normal activity within the synapse, thereby reducing side effects.  Clinical trials are underway.  Dr. Lynn Raymond at the University of British Columbia led the research team.

Algae + Quantum Biology?: It appears that algae, a very simple organism, figured out quantum mechanics nearly two billion years ago.  During the process of photosynthesis, antenna proteins in the light-harvesting complexes absorb light and transmit the energy between molecules to proteins in the reaction centre.  Researchers at the University of Toronto decided to study this energy transfer and discovered quantum mechanics at play in this photosynthetic process.  This is just a bit beyond the scope of our blog but you can read Drs. Greg Scholes and Paul Brumer’s commentary here or enrich yourself with the detailed study here in the journal Nature.

Friday Science Review: January 29, 2010

A productive week of international collaborations leading to new drugs or targets…

Genetic Map of Yeast: A large-scale, genome-wide interaction map of yeast genes was constructed in an international study.  The extensive network of genetic interactions lays out a functional map of the cell where similar biological processes can be grouped together. Yeast has been studied in the past and present because their molecular signaling is similar to human cells and is easy to manipulate.  The detailed “genetic atlas” in this project, a first for any organism, provides important information to better understand genetic functions in relation to diseases.  Their technique also allowed the scientists to map interactions between genes and chemicals, which will aid in choosing drug targets by predicting the extent of the interaction with other genes and how it may affect the cell.  The multi-national project was led by University of Toronto researchers Drs. Brenda Andrews and Charles Boone.  Details of the yeast map study appear in the prestigious journal, Science.

Mutations in Lymphomas: The identity of new mutations associated with specific types of lymphomas is described in this latest Nature Genetics article.  Sequencing of genes involved in the NF-kappaB signalling pathway led to the identification of recurrent mutations affecting the EZH2 histone methyltransferase enzyme.  The oncogene is the second member of this enzyme group found to be mutated in different types of cancer.  Mutations were found in over 21% of a lymphoma subtype, affecting amino acid Tyrosine 641 that renders the enzyme with lower activity.  Dr. Marco Marra at the Michael Smith Genome Sciences Centre (BC Cancer Agency) conducted the sequencing project.

Stopping Alzheimer’s Disease: Inhibition of ACAT1, an enzyme directly involved in cholesterol metabolism, significantly decreases the accumulation of amyloid plaques when tested in a mouse model of Alzheimer.  To gain deeper knowledge of how this works, researchers deleted the ACAT1 gene in mice predisposed to develop Alzheimer’s disease.  The brains of these mice had fewer amyloid plaques with improved cognitive function.  The key finding is that without ACAT1 function, cholesterol accumulates in a subcellular compartment of the cell where it is converted and no longer available to be involved in amyloid plaque formation.  These data supports the use of ACAT1 inhibitors in the battle against Alzheimer’s disease and lends insight into future improvement.  Dr. Nabil Seidah at the Institut de Recherches Cliniques de Montréal collaborated with researchers in the U.S. and published the study in the Proceedings of the National Academy of Sciences.

New Treatment to Stop Malaria: Two enzymes important to the survival of Plasmodium falciparum, the parasite causing malaria, have been discovered in an international collaboration aimed at stopping the drug-resistant parasite.  Malaria parasites invade red blood cells and digest the proteins for fuel to grow and divide until they burst out of the red blood cell and repeat the process again.  The discovery of the parasitic enzymes, PfA-M1 and PfA-M17, which are keys to the digestive process in red blood cells, was the first step in designing therapeutic drugs.  Building three-dimensional structures of the enzymes was the next step in determining how best to target and inhibit the enzyme.  The study suggests that blocking PfA-M1 and Pfa-M17 would prevent the parasite from feasting on the red blood cell and represents a new wave of promising anti-malarial drugs.  McGill University’s Dr. John Dalton led the international research project and is reported in this week’s The Proceedings of the National Academy of Sciences.

Vitamin D fights Crohn’s Disease: Vitamin D deficiency in individuals may contribute to the development of Crohn’s disease, as suggested in this new research report.  Mismanagement of intestinal bacteria triggers an inflammatory response that develops into the autoimmune disorder.  The action of Vitamin D, as the study suggests, is to directly promote the expression of NOD2, which signals to the body of a microbial invasion.  NOD2 then activates NF-kappaB to induce expression of DEFB2 (defensin beta2), an anti-microbial peptide.  To further support Vitamin D’s role, both DEFB2 and NOD2 have been linked to Crohn’s disease in earlier studies.  This is significant to the management of the disease because Vitamin D deficiency is easy to test for through a simple blood test and Vitamin D supplements (and sunlight!) are readily available.  Dr. John White and his team at McGill University and the Université de Montréal published their study in the Journal of Biological Chemistry.

Friday Science Review: January 22, 2010

Some really exciting research in this week’s review…

Special (RNAi) Delivery: One of the obstacles for RNAi based therapeutics is the difficulty in getting the RNAi into the cells efficiently to invoke a positive response.  Vancouver based Tekmira Pharmaceuticals (TSX: TKM.TO), in partnership with Alnylam Pharmaceuticals (Nasdaq: ALNY) and researchers at the University of British Columbia, Drs. Pieter Cullis and Marco Ciufolini, developed a new and improved RNAi delivery method that is 10X better than their standard delivery platform.  Using their knowledge of lipid structure and how specific features influences delivery into cells, they used a rational design approach to develop a new cationic lipid, DLin-KC2-DMA (KC2), that is used with their current SNALP system (stable nucleic acid-lipid particles) to achieve the remarkable results.  Details of the study are reported in this week’s issue of Nature Biotechnology.

Resolving Stem Cell Populations: The differentiation of stem cells is a complex multi-step process that is not fully understood.   With each step, the potential of that stem cell becomes more and more restricted.  Researchers performed a series of intricate detailed studies on cell populations to resolve distinct Intermediate Term Reconstituting Hematopoietic Stem Cells or ITRC (versus long- and short-term populations).  The significance of this key finding is that researchers who are interested in harnessing the potential of long-term reconstituting hematopoietic stem cells can more accurately study a pure population of true, self-renewing stem cells with homogeneous characteristics.  Prior to this new “intermediate-term” identification, the majority of “long-term” cells were actually comprised of intermediate-term cells.  Dr. Norman Iscove and his team at the University Health Network describe their work in the latest issue of Cell Stem Cell.

Fishing for New Drugs: A high-throughput behavioural monitoring system to observe the response of Zebrafish to neuroactive chemical compounds should help expedite the discovery of new drugs for neurological disorders.  Researchers setup a video system and applied “behavioural barcodes” that they say can track the effects of 14,000 chemicals on zebrafish behaviour.  The capacity of this large-scale screen is unique and the use of zebrafish is quite informative because they are transparent, genetically tractable, and more similar to humans than you might think.  In this platform, response to two strong light pulses after exposure to chemicals is monitored and the observations are translated into barcodes that make data analysis of this magnitude a lot more manageable.  Drs. Jennifer Bryan and Rick White at UBC collaborated with Harvard researchers and published their study in Nature Chemical Biology.

Intrinsic Stimulator of Muscle Regeneration: A new subpopulation of cells in muscle tissue that contribute to muscle injury repair has been identified.  The surprise is that these cells, called fibro/adipogenic progenitors (FAPs), are derived from a different developmental lineage as muscle cells.  These fat-lineage cells, which are resident in muscle tissue, are ‘activated’ in response to muscle damage but they do not become muscle cells.  Instead, they release factors that promote and enhance muscle progenitors in the myogenesis repair process.  The conundrum, however, is that too much of these FAPs can lead to fibrosis and contribute to muscle disorders.  The study, reported in Nature Cell Biology, was led by Dr. Fabio Rossi at the University of British Columbia.

Pharmacoviral Therapy for Gliomas: Oncolytic viruses (VSVs) are used in the treatment against malignant gliomas but are limited in efficacy due to the viral induced IFN (interferon) response – one of our body’s natural defense mechanism.  Knowledge of the molecular mechanisms involving the mTOR pathway in IFN production led researchers to investigate the use of rapamycin, an mTOR inhibitor, in conjunction with the VSVs.  This “pharmacoviral” combinatorial approach was very successful when tested in rats with malignant gliomas and represents a potentially new therapeutic strategy.  Dr. Nahum Sonenberg and his team at McGill University are experts in the mTOR pathway and describe their work in the Proceedings of the National Academy of Sciences.

Friday Science Review: January 15, 2010

A little sunflower power to brighten up a quiet week…

Understanding Cancer Therapy Resistance: A molecular contribution to resistance to cancer treatments is from the cellular protein Clusterin (CLU).   This cell survival protein is targeted by the antisense based OGX-011, one of OncoGenex Pharmaceutical’s leading compounds currently in phase 2 trials for prostate, lung and breast cancers.  In this recent research project, the mechanism of clusterin mediated treatment resistance was investigated by Dr. Martin Gleave’s team at the University of British Columbia.  They found that CLU enhances the degradation of two proteins, COMMD and I-kappaB, which in turn leads to an increase in the transcriptional activity of NF-kappaB to support cell survival.  These findings surely provide additional potential drug targets for Dr. Gleave, who is the founder of OncoGenex and currently serves as the Chief Scientific Officer.  The study is reported in Molecular Cancer Research.

Sunflower Genome: This is an award announcement to fund the $10.5M (USD) “Genomics of Sunflower” Project.  The contributions are from a ‘cross-border’ consortium including Genome Canada, Genome BC, the US Departments of Energy and Agriculture, and France’s INRA (National Institute for Agricultural Research).  An international team including University of British Columbia researchers and led by Dr. Loren Rieseberg will generate the reference genome that is approximately 3.5 billion bases long for the sunflower family, which includes 24,000 different species.  This agri-biotech project will support the future of the sunflower industry (its seed industry alone is worth $14B) by trying to identify genes that are responsible for agriculturally important traits such as seed-oil content, flowering, seed-dormancy, and wood producing-capacity as well as adapt to today’s changing environment and consumer tastes.

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Friday Science Review: January 8, 2010

I am starting the new year and decade by recognizing the accomplishments of two distinguished scientists…

Two outstanding Canadian scientists were recognized for their valuable contributions to the global research community.

Dr. Andras Nagy’s innovative technique to reprogram mature body cells into stem cells – called induced pluripotent stem cells or iPS cells – was named Method of the Year by the prestigious journal Nature Methods.  Earlier in the year, Dr. Nagy was selected as one of Scientific American magazine’s top 10 – Guiding Science for Humanity.

Dr. Tony Pawson was honoured as one of ten “Nation Builders of the Decade” by the Globe and Mail.  His breakthrough research over the past decade and beyond has propelled our understanding of the intricate communication that goes on within a cell and between cells.  Dr. Pawson was also awarded the Kyoto Prize this year.

Bypassing PTEN Mutants in Cancer Cells: The discovery of a novel link between the proteins PTEN and PKR may lead to new approaches forncer treatments.  Dr. Antonis Koromilas’ research at McGill University identified that the tumour suppressor function of PTEN requires it to activate the PKR-eIF2alpha pathway, which applies an inhibitory control on protein synthesis.  In a cancer cell where PTEN is mutated, PKR also loses its ability to control protein synthesis and the cell continues growing into a tumour.  The significance of this is that they can now try to bypass the PTEN mutation and find alternate ways to activate PKR and regain control of cell growth.  The research is reported in the journal Science Signaling.

Distinguishing Sister Chromatids: In studying cell division, scientists have long desired to follow the fate of sister chromatids – the identical chromosome copies that is distributed to each cell during the process of cell division.  Researchers used the CO-FISH (chromosome orientation fluorescence in situ hybridization) technique with unidirectional probes.  When they observed the process in different cell types, they found that the chromatids segregated randomly in some cell types but not in others.  The non-randomness may be a mechanism to direct cells to be slightly different from its sister cell and is one of many layers of complexity in developing higher organisms.  The solution to this biological phenomenon by Dr. Peter Lansdorp at the BC Cancer Agency deserves the recognition in the prestigious journal Nature.

Prognostic Marker for Bone Cancer Survival: Genetic deletion mutations in a specific chromosome region called osteo3q13.31 may be predictive of a poor prognosis for osteosarcoma patients.  The copy number alteration (CNA) marker was identified in subsets (80%) of osteosarcoma patients where their bone cancers appeared to be more difficult to treat.  With this genetic marker, patients may be screened to identify candidates who should be treated more aggressively from the onset of diagnosis.  Furthermore, the osteo3q13.31 region contains 3 genes that were not previously associated with the disease and requires further investigation that may lead to additional therapeutic options.  The study was conducted by Dr. David Malkin’s team at The Hospital for Sick Children and is published in Cancer Research.

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Friday Science Review: December 18, 2009

Advancing Cell Research with Proteomic Tools: Advances in technology – particularly in proteomics – are allowing scientists to perform research in more complex systems, a complexity that more closely reflects the situation inside the body.  In the latest trend, researchers can label two different populations of cells with different modified amino acids and use mass spectrometry to distinguish proteins derived from one population versus the other.  This strategy was recently applied to study the EphB2 receptor protein, which plays an important role in a cell’s communication with an adjacent cell expressing ephrin-B1 protein.  Differential labeling allowed the researchers to determine the unique (and similar) molecular signaling network in each cell population as they coordinate their self-organizational activity.  It’s a powerful tool that can be adapted to investigate various systems that cannot be studied in isolation.  The research was performed in Dr. Anthony Pawson’s group at the Samuel Lunenfeld Research Institute and is published in the journal Science.

New Member in the Protein Synthesis Club: After decades of studying and trying to fully understand the mRNA translational machinery for protein synthesis, new components in this complex process continue to be discovered.  The latest is a protein called DHX29, a helicase enzyme that helps to untangle the nucleic acid during the initiation phase of translation.  Down-regulating the enzyme holds up protein synthesis and presents a possible target point to block cancer cells from growing.  Indeed, when the researchers blocked DHX29 in cancer cells, tumour growth was significantly reduced.  Dr. Nahum Sonenberg was the lead author of the study reported in the early online edition of the Proceedings of the National Academy of Sciences.

PS.  Congratulations to Dr. Sonenberg in becoming the 2009 Researcher of the Year for Biomedical and Clinical Research presented by CIHR.

Low Oxygen Response in Cancer Cells:  Within a large tumour, there may be areas of hypoxic microenvironments – regions that are under low oxygen conditions.  Cells in this environment undergo a stress response to try to adapt by carrying out a process called autophagy.  The consequence of this is that the cancer cells ‘get tough’ and subsequently become resistant to radiation therapy.  This recent study investigated one of the possible cell adaptation methods through activation of the unfolded protein response (UPR) pathway.  Induction of two key proteins, MAP1LC3B and PERK, were required for autophagy.  They also demonstrated that inhibition of autophagy resulted in the cells becoming sensitive to hypoxia and irradiation.  Thus, the molecular players involved in autophagy may be good therapeutic targets.  Dr. Bradly Wouters at the Ontario Cancer Institute led the research and reports the findings in the Journal of Clinical Investigation.

Teasing out the Role of E2f Transcription Factors: Members of the E2f family of transcription factors are key regulators that commit cells through the cell division process.  Information in the literature is somewhat perplexing regarding whether they are essential for this process and different studies will support one argument or the other.  New research settles this debate – at least for the E2f1-3 isoform.  Through a series of expression and deletion studies and looking at the different molecular players involved, it was concluded that E2fs are not absolutely required for normal cell division.  The surprise finding is that E2f1-3 is necessary for cell survival in development and its function switches from ‘activator’ in progenitor cells to ‘repressor’ mode in differentiating cells.  The research was conducted at Toronto Western Research Institute by Dr. Rod Bremner’s team and appears in this week’s Nature journal.  The story is corroborated in another similar study in the same issue.

Possible Risk for Diabetes or Heart Disease: A large genome-wide study revealed an association between a polymorphism in the ARL15 gene (ADP-ribosylation factor-like 15) with lower levels adiponectin.  Adiponectin is a fat cell protein and its circulating level is inversely associated with type 2 diabetes and coronary heart disease.  Accordingly, the polymorphism is also associated to some degree with higher risk of heart disease, diabetes and other metabolic related traits.  Surely this requires a more in depth molecular study but this is a good example of how you can sift through large amounts of data from various genome-wide studies and fish out an important finding.  Dr. Brent Richards, now at McGill University, is the corresponding author of the study published in PLoS Genetics.

Genetic Mutation in Intellectual Disability: Approximately 50% of intellectual disability cases are not related to other syndromes.  In these cases, an explanation for the intellectual disability may lie in the gene called TRAPPC9, where a mutation in the gene causes a truncated form of the protein and renders it inactive.  The research team led by Dr. John Vincent at the Centre for Addiction and Mental Health used microarrays to screen a family that had seven members with non-syndromic intellectual disability to map the TRAPPC9 gene.  Additional families with mutations affecting the same gene validated the importance of TRAPPC9, which encodes proteins involved in the NF-κB signaling pathway.  With this new knowledge, researchers can screen patients or family members to track the mutation and also dig deeper into the mechanisms in the brain that affects cognitive development.  The study appears in the American Journal of Human Genetics.

Friday Science Review: December 11, 2009

WOW!  A busy week in the bioscience world…

Pull Down Your ‘SOCS’ and Grow Some Nerves: A long standing question is how to get mature neurons, which stop growing at around the age of two, to start growing again after sustaining nerve damage.  The answer may lie in a protein called SOCS3 (suppressor of cytokine signaling 3).  SOCS3 controls neuronal growth in adults but when it is absent (in a knockout mouse model), axons can regenerate after nerve injury.  This process may be enhanced by supplying a cocktail of neurotrophic growth factors that the researchers also identified in their study.  This is a very important discovery that will push regenerative medicine to new therapeutic strategies.  Dr. Patrice Smith started the research as a postdoctoral fellow at Harvard University and now runs her own lab at Carleton University.  The study is published in the latest edition of Neuron.  There is also an inspirational story about Dr. Smith in the Globe and Mail.

Protecting your Brain after a Stroke: Following a stroke, neurons are at risk of permanent damage caused by overactivation of NMDARs (N-methyl-D-aspartate glutamate receptors).  A key molecular step leading to this excitotoxic neuronal death was discovered in this recent study.  The trauma causes degradation of Insig-1 (insulin-induced gene-1), which triggers the activation of the transcription factor SREBP-1 (sterol regulatory element binding protein-1).  However, when they blocked the activation of SREBP-1 they were successful in reducing the neuronal damage.  This is a promising target for generating therapeutic drugs aimed at minimizing the detrimental effects of strokes and brain trauma.  The research team was guided by Dr. Yu Tian Wang at the University of British Columbia and the study is reported in the latest Nature Medicine.

Breakthrough in Children’s Brain Cancer Research: A rare pediatric brain tumour called Central Nervous System-Primitive Neuroectodermal Tumours (CNS-PNET) offers a very poor prognosis for young patients.  In this gene expression study, a cluster of microRNAs called C19MC was found to be amplified in the diseased tissue in about 25% of the patients. This cluster acts as an oncogene that enhances cell growth and affects differentiation of neural stem cells.   The new discovery will advance opportunities to study this rare pediatric cancer and possibly use C19MC as a diagnostic marker and/or therapeutic target.  The international study was led by Dr. Annie Huang at SickKids Hospital and is reported in the current issue of Cancer Cell.

Genomics Study on Pathogenic Factors: In a large scale study of bacterial genomes, it was proven broadly across microbial species that many of the bacterial virulence factors are contained within genomic islands or clusters of genes.  The virulence factors are proteins that have more “offensive” functions such as toxins that help the bacteria invade the host.  Another significant outcome of this research is the discovery of potentially new pathogen-associated genes that are present pre-dominantly in pathogenic bacteria but less frequently in the non-pathogenic bacteria.  These factors require a closer look as they may represent novel targets for anti-microbial drug development, a critical area of research to combat the increasing prevalence of drug resistant bacteria.   Dr. Fiona Brinkman’s team at Simon Fraser University conducted the research and is detailed in PLoS One.

Dabigatran vs. Warfarin (round 2): Following up on a study that I mentioned here earlier this year, new research further supports the use of Dabigatran over Warfarin.  Patients with a common clotting disorder called venous thromboembolism (VTE) can benefit from Dabigatran as an equally effective and safe blood thinning treatment but without the complications associated with using Warfarin, which requires frequent visits to the clinic for blood monitoring and dosage adjustments.  The study was conducted by Dr. Sam Schulman at McMaster University and appears in this week’s The New England Journal of Medicine.

Research on Congenital Myopathy in Mice:  University of Toronto scientists have generated a mouse model to study a specific type of skeletal muscle disorder.  The mice express a mutant form of the RyR1 protein (type 1 ryanodine receptor/Ca2+ release channel), which causes a severe form of central core disease (CCD). Symptoms in mice that mimic the human condition include progressive congenital myopathy, respiratory stress, skeletal muscle weakness and impaired mobility.  Their study offers insight and future potential to unravel the mechanism behind the disorder.  Dr. David MacLennan’s research is published in The Proceedings of the National Academy of Sciences.

Here is a list of many more important research reports this week from across the country:

Cofactor-activated phosphorylation is required for inhibition of cortical neuron differentiation by Groucho/TLE1. (Dr. Stefano Stifani, McGill University)

Dlx5 Is a cell autonomous regulator of chondrocyte hypertrophy in mice and functionally substitutes for Dlx6 during endochondral ossification. (Dr. Andrew Bendall, University of Guelph)

Pluripotent transcription factors possess distinct roles in normal versus transformed human stem cells. (Dr. Mickie Bhatia, McMaster University)

Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. (Dr. Tak Mak, The Campbell Family Institute for Breast Cancer Research and University of Toronto).

A novel enediynyl peptide inhibitor of furin that blocks processing of proPDGF-A, B and proVEGF-C. (Dr. Amik Basak, University of Ottawa)

The specificity of the FOXL2 c.402C>G Somatic mutation: a survey of solid tumors. (Dr. David Huntsman, University of British Columbia)

Nuclear function of Smad7 promotes myogenesis. (Dr. John McDermott, York University)

Asf1-like structure of the conserved Yaf9 YEATS domain and role in H2A.Z deposition and acetylation. (Dr. Michael Kobor, University of British Columbia)

Friday Science Review: December 4, 2009

Universal Cancer Signalling Pathway: This is an interesting new twist on cancer signalling that may make scientists rethink how to tackle the disease.  It is thought that there is no single cure for cancer as the hetergenous disease may arise from mutations in a number of different pathways.  In this report, however, researchers demonstrate that many of the cancers converge on HIF-2a, part of the oxygen-sensing system that is required for tumours to grow.  By inhibiting HIF-2a, they could attenuate the growth of a diverse number of aggressive cancers including glioblastomas, colorectal tumours, and non-small cell lung carcinomas.  This universal cancer axis converging on HIF-2a could turn out to be a silver-bullet for cancer therapy.   Dr. Stephen Lee at the University of Ottawa led the team and describes the research in the online edition of the Proceedings of the National Academy of Sciences.

SKP’ing Stem Cells: A special type of cell called SKPs (skin-derived precursors) may be the elusive adult dermal stem cell involved in regenerating skin, wound-healing, and keeping hair healthy and growing.  In the study, researchers characterized the specialized population of cells and determined that SKPs can self-renew, maintain their ability to transform into other cells types, and regenerate hair follicles or other dermal cell types when grafted.  These properties are suggestive that SKPs are indeed THE dermal stem cells and may have important future applications such as in hair restoration and wound-healing.  Dr. Jeffrey Biernaskie completed the research in the lab of Dr. Freda Miller at Sickkids Hospital and recently started his own group at the University of Calgary.  The report appears in this latest edition of Cell Stem Cell.

Comparative Genomics Links Autism and Schizophrenia: A new study comparing the genomes of autistic patients and schizophrenic patients proved the connection between the two disorders that were previously thought to share behavioural similarities.  Both illnesses are associated with anomalies in the same region of the genome but differ substantially in the nature of the genetic changes.  Part of the genomic region is missing in autistic patients whereas extra copies of the genome are present in schizophrenic patients.  The affected genes appear to control head size and brain growth with overdevelopment of the brain in autistic patients and underdevelopment in schizophrenics.  By knowing that the two disorders are genetically linked, research on one disorder immediately provides clues for the other and will aid in advancing treatment options for both.  The study was conducted by Dr. Bernard Crespi’s group at Simon Fraser University and is reported in the Proceedings of the National Academy of Sciences.

Signalling Links in Neurological Disorders: Perturbations in either Dopamine or BDNF (brain-derived nerutrophic factor) pathways are implicated in neurological disorders.  Researchers have now defined the molecular relationship linking the two pathways to similar disorders.  The calcium signalling cascade is the key intermediate between dopamine receptor activation and BDNF production leading to neuronal growth.  With this new understanding of the pathways associated with schizophrenia, depression, and drug addiction, additional molecular targets are available for potential therapeutic intervention.  The study was led by Dr. Susan George at the Centre for Addiction and Mental Health (Toronto) and is reported in the early online edition of the Proceedings of the National Academy of Sciences.

Small Molecule Pathway Database: SMPDB (www.smpdb.ca) is an interactive, visual database containing more than 350 small-molecule pathways found in humans.  It is designed to support drug discovery research and pathway elucidation by employing clinical metabolomics, transcriptomics, proteomics and systems biology information.  The pathways describe relevant organs, organelles, subcellular compartments, protein cofactors, protein locations, metabolite locations, chemical structures and protein quaternary structures.  SMPBP is a very useful tool that was put together by Dr. David Wishart’s group at the University of Alberta and is described in detail in Nucleic Acids Research.

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Friday Science Review: November 27, 2009

Two quick reviews on studies addressing Alzheimer’s and lung damage therapy…

An ‘- omics’ Study of Lipids in Alzheimer’s Disease: Clues to the underlying molecular mechanisms of amyloid plaque proteins causing Alzheimer’s disease were revealed using a lipidomic method (think broad ‘-omics’ type profiling of lipids).  In diseased tissue, accumulation of certain isoforms or types of lipids is associated with hyperphosphorylation of the tau protein, which destabilizes neuronal cells and leads to neuronal cell death.  The researchers also demonstrated that pharmacological modulation of lipid metabolism has positive effects in protecting the integrity of the neurons and may be a strategy to prevent further decline in patients suffering from the disease.  Dr. Steffany Bennett and her research team at the University of Ottawa published the study in the Proceedings of the National Academy of Sciences.

Stem Cell Therapy for Lung Damage:  Premature newborns often suffer lung damage that leads to chronic lung disease.  However, new research using mesenchymal stem cells injected into the lungs shows promise in stimulating lung repair.  The study by Dr. Bernard Thébaud and his team at the University of Alberta in Edmonton used newborn rats as the subjects to test their hypothesis.  What is surprising is that it does not appear that the stem cells establish themselves in place of the damaged cells.  Instead, they act protectively to allow the lung to repair themselves and this may involve the release of factors from the stem cells to stimulate the regeneration process.  This strategy holds a lot of promise and hopefully the same is true in humans.  The study is a first on stem cell therapy in newborn lungs and is reported in the American Journal of Respiratory and Critical Care Medicine.

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Friday Science Review: November 20, 2009

Intestinal disease genomics and how hedgehogs cause arthritis…

Genetic Clues to ‘Belly Aches’ in Children: The largest genomic investigation into early onset inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis involved the efforts of an international research team.  In total, genetic information from 3,400 children with IBD and 12,000 healthy children were compared.  This study resulted in the identification of five genetic regions associated with susceptibility to pediatric and adolescent IBD.  The team is now taking a closer look at these regions to try to identify the specific proteins that may explain why or how the disease develops.  Another question that they would like to address is why some individuals develop IBD early whereas others develop it later in life.  Two Toronto researchers, Dr. Anne Griffiths (Sickkids) and Dr. Mark Silverberg (Mount Sinai Hospital), contributed their expertise to the study, which appears in this week’s issue of Nature Genetics.

Colon Cancer Susceptibility Genes: In another intestinal disease research project, scientists noticed that different strains of mice exhibited different levels of resistance or susceptibility to colon cancer induced by a chemical carcinogen.  Using genetic studies, the determining factor was mapped to a specific region in chromosome 3 that they designated as colon cancer susceptibility locus 3 (Ccs3).  Within this region are about 94 known genes and they have identified a subset that are expressed at high levels in the colon.  What is also interesting is that Ccs3 in mice is homologous to regions in human chromosome 1 and 4, which also contain genes known to be associated with inflammatory bowel disease and colorectal cancer.  This mouse model will be a very useful tool for future studies on the pathogenesis of colon cancer.  Dr. Philippe Gros led the research team at McGill University and published the study in the journal Oncogene.

Hedgehogs are Key to Osteoarthritis: An unexpected discovery may hold the key to solving painful osteoarthritic disease.  Elevated expression or activity of a group of proteins called Hedgehog resulted in the development of osteoarthritis in mice.  In simple terms, the balance of this signalling pathway in chondrocyte cells determines whether they go on to make cartilage or bone.  In the animal model of osteoarthritis, Hedgehog levels are high and there is less cartilage being produced from the chrondrocytes.  Obviously, Hedgehog becomes an immediate pharmacologic target for the treatment or prevention of osteoarthritis.  You may find it strange that this study on a disease primarily affecting adults is from The Hospital for Sick Children but it just shows that research is full of surprises and you never know where it may take you!  Dr. Benjamin Alman and his research team reported their study in the online edition of Nature Medicine.

Pathway Signalling Antibody Production: A key signalling pathway required for the efficient production of antibodies was identified recently and verified using knockout mice.  A receptor on T cells called ICOS (Inducible Costimulator) is required for their conversion into a specialized type of T cell called Tfh cells (follicular B helper T cells).  As the name implies, their role is to help B cells make the right antibodies to the target.  Dr. Woong-Kyung Suh’s team at Institut de recherches cliniques de Montréal discovered that ICOS activates an enzyme called phosphoinositide 3-kinase (PI3K), which eventually leads to the release of factors that trigger the formation of Tfh cells.  With this knowledge, researchers may find ways to tweak the system to suppress (in autoimmune disease) or enhance (in infectious disease) antibody production as required.  The study is reported in the Proceedings of the National Academy of Sciences.

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Friday (the 13th) Science Review: November 13, 2009

No bad luck here in unraveling new genetic and proteomic links in disease…

Gene Variants Linked to Hearing LossA 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.

Friday Science Review: November 6, 2009

Just two stories this week – a cancer pathway and innovative dipsticks…

New Relationship between Tumour Suppressor Genes: Knocking out genes in mice believed to play a tumour inhibiting role would intuitively result in rapid cancer development.  However, it was a surprise to McGill researchers that mice lacking the tumour suppressors 4E-BP1 and 4E-BP2 were refractory to cancer growth.  When they deleted another well known tumour suppressor, p53, then they observed enhanced tumour growth more aggressive than knocking out p53 alone.  These results demonstrate for the first time a cooperative effect between 4E-BPs and p53 and highlight the advantages of indentifying individual molecular profiles to predict responsiveness to therapeutic strategies.  Dr. Nahum Sonenberg, who led the research team at McGill University remarks “this is another fine example how basic research, which intends to provide answers to fundamental questions about molecular mechanisms of cell proliferation, leads to unexpected findings that advance our ability to understand and cure human disease.”  The study appears in this week’s issue of Cancer Cell.

Bioactive Paper Sensors: A simple and rapid method to detect pesticides or toxins in food using innovative test strips was recently developed at McMaster University.  These “dipsticks” can sense the presence of small amounts of pesticides in food and within five minutes, a colour change indicates the level of the contaminant.  Future applications of this technology, with a few tweaks,  include detecting for the presence of food borne bacteria such as E.coli, Listeria, or Salmonella.  The practicality, ease of use without the need for large equipment, and the ability to get almost immediate results are huge advantages of the dipsticks to provide rapid screening and could play a role in curbing future outbreaks.  Dr. John Brennan’s team describes their research in the latest issue of Analytical Chemistry.

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Friday Science Review: October 30, 2009

Regenerative medicine and Cross-border awards…

Gene Therapy Saves Donor Lungs: A technique using gene therapy on donor lungs before transplantation may be used to repair and save damaged lungs, making them potentially suitable for transplantation into patients.  The procedure involves first preserving the lungs at normal body temperature in a protective chamber called the Toronto XVIVO Lung Perfusion System, which continuously pumps a solution of oxygen, proteins and nutrients.  Next, adenovirus gene therapy is used to introduce the IL-10 cytokine gene into the lungs.  IL-10 helps to decrease inflammation, which would lead to improved health and function of the donor lungs and better outcome for the patient.

Dr. Shaf Keshavjee, the project leader at the McEwen Centre for Regenerative Medicine, describes the rationale:

“It’s as if gene therapy turbocharges each individual cell to manufacture many more proteins in its own IL-10 factory.”

“This protein down-regulates or decreases the inflammatory potential of cells injured before and during the transplant process. It also has the capacity to turn down the recipient’s immune system which rejects the transplanted organ.”

The research study is reported in this week’s issue of Science, Translational Medicine.

A Platform to Test Cardiac Cell Therapy:  A model system for evaluating stem cell transplant in cardiac cell therapy to repair damaged heart tissue is described in this study by Drs. Peter Zandstra and Milica Radisic’s team at the University of Toronto.  Using their engineered heart tissue (EHT) as the analytical platform, they applied stem-cell derived cardiac cells and measured molecular and electrophysiological parameters of the EHT.  The system was verified as a predictive strategy to interrogate different cell transplantation conditions for the capacity to survive and functionally integrate into heart tissue.  This tool should help researchers accelerate development of cardiac cell therapy strategies and it can also provide mechanistic insight into the challenges of a successful transplant.  On a personalized medicine theme, an advantage of the system is that the EHTs are customizable and can be derived from individuals for patient specific testing prior to the actual treatment.  The study appears in this week’s edition of the Proceedings of the National Academy of Sciences.

“Cross-border” Cancer Stem Cell Therapy Award: The Collaborative Partnership Program between the California Institute for Regenerative Medicine (CIRM) and the Cancer Stem Cell Consortium (CSCC) in Canada have awarded two internationally recognized Canadian researchers with support to lead their respective cancer stem cell based therapy projects.

One project will develop agents to directly target leukemic stem cells that are resistant to current therapies.  This will be co-led by Dr. John Dick, Princess Margaret Hospital and Dr. Dennis Carson, University of California San Diego.

The other project will develop small molecules targeting cancer-initiating cells within solid tumor cancers and will be co-led by Dr. Tak Mak, Princess Margaret Hospital and Dr. Dennis Slamon, University of California, Los Angeles.

The awards offer each project up to $40 million (USD) over four years, with funding for the Canadian investigators contributed by Genome Canada and Canadian Institutes of Health Research through the CSCC and funding for the Californian investigators contributed by CIRM.

Congratulations to Drs. John Dick and Tak Mak!

Top 10The Scientist magazine ranked Dalhousie University in Halifax and the University of Toronto in the top 10 best places to work in academia outside of the U.S. Based on a web survey of scientists regarding job satisfaction, pay, research resources and relationships with their peers and management, Dalhousie ranked 5th and U of T came in at 10th place.  It is very nice to see Canadian institutions and our great research environment recognized by peers around the world.

Friday Science Review: October 23, 2009

A lucky find and two very different genomics projects…

Connective Tissue Disorder Linked to Defects in Ltbp4:  A McGill University researcher collaborating on two independent projects, one from Washington University School of Medicine and the other from New York University School of Medicine, made the coincidental link between the two after realizing that the tissue defects were identicalDr. Elaine Davis, an electron microscopy expert at McGill, analyzed tissue from children born with abnormally developed lungs, gastrointestinal and urinary systems, skin, skull, bones and muscles.  The underlying cause is a connective tissue disorder called cutis laxa that also causes skin to hang loosely from the body.  At the same time, Dr. Davis was analyzing tissue taken from Ltbp4 gene knockout mice from New York University when she realized that the connective tissue defects in the human and mouse samples were identical.  This connection was confirmed when they sequenced the Ltbp4 gene in human patients and discovered recessive mutations.  With this discovery, they now have a molecular target to understand the disease and to design therapeutic strategies.  The study is reported in The American Journal of Human Genetics.

A Deep-sea Microbe Genome: The microbe, SUP05, lives in the deep ocean “dead zone” where oxygenated water is minimal. It survives by using other compounds instead of oxygen, such as nitrates, sulphates and metals.  A recent surge in population suggests an expanding low-oxygen ocean ecosystem and is an indicator of global climate change.  University of British Columbia professor Dr. Steve Hallam and his research group analyzed the entire genome of SUP05 and identified a number of genes mediating carbon assimilation, sulfur oxidation, and nitrate respiration.  This study provides the first insight into the metabolism of these microbes and their effects on nutrients and gases in the deep-ocean ecosystem and will also lead to further understanding of their ecological and biogeochemical role.  The report appears in this week’s edition of Science.

Allelic Expression Genomic Map: Illumina genomics technology was used in this study to map global allelic expression differences associated with cis-acting variants.  Cis-acting elements can affect gene expression and variations due to single nucleotide polymorphisms (SNPs) explain a large percentage of the phenotypic differences in the population.  It is very informative to have this global map of the cis-acting variants and helps researchers identify variants associated with diseases.  To demonstrate this, they finely mapped cis-regulatory SNPs in a region in chromosome 8 associated with lupus.  The study was performed by Dr. Tomi Pastinen and his Genome Quebec team at McGill University and the report was published in Nature Genetics.

DNA Repair Suppresses c-Myc Lymphoma:  Overexpression of c-Myc in B cells is associated with lymphomas but requires secondary mutation events for the disease to develop.  In this study, immunologist Dr. Alberto Martin and his research team at the University of Toronto identified that the DNA repair protein, Msh2, plays an important role in mitigating c-Myc associated cancer.   To demonstrate this, they generated mice that overexpress c-Myc but with Msh2 mutations such that they are deficient in DNA mismatch repair.  These mice rapidly develop B cell lymphomas, which suggests that Msh2-dependent DNA repair actively suppresses c-Myc associated oncogenesis.  The report appears in the early edition of The Proceedings of the National Academy of Sciences.

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Friday Science Review: October 16, 2009

A mixed bag of research reports but nonetheless important and significant…

How MS Drug Works: Glatiramir Acetate (COPAXONE®, Teva Pharmaceuticals) is used for the treatment of patients with Multiple Sclerosis, however, it is not clear how this drug works.  In this new study, researchers demonstrate that glatiramir acetate can regulate the formation of myelin, the protective sheath around nerve fibers that is compromised in MS patients.  Glatiramir acetate induces the formation of helper immune cells that produce nerve promoting molecules, which in turn stimulate the myelin repair process. The study was led by Dr. V. Wee Yong at the University of Calgary and appears in this week’s issue of The Proceedings of the National Academy of Sciences.

New Target to Fight Diabetes: In genetic knockouts of the Lkb1 gene specifically in beta cells, the insulin producing units in the pancreas, the knockout mice exhibited an increased number of beta cells that were also larger than normal with greater amounts of insulin.  When they challenged the knockout mice with a high-fat diet to try to induce diabetes, the mice responded and kept blood glucose levels down.  Lkb1 is a tumor suppressor gene that was also known to be involved in energy metabolism but it was unclear whether the Lkb1 protein was associated with diabetes.  Dr. Robert Screaton’s group at the Children’s Hospital of Eastern Ontario Research Institute answered this question in a report appearing in this week’s Cell Metabolism.  Also noteworthy is that a research team from Israel published a similar study leading to the same conclusions.  With these surprising and dramatic results, Lkb1 may represent another therapeutic avenue to treat or prevent diabetes.

Sialyltransferase Crystal Structure Solved: Many important proteins, lipids or sugars are modified by the addition of sialic acid and these steps are essential for a number of processes including cell recognition, cell adhesion and immunogenicity.  The key enzyme responsible for catalyzing this reaction is a set of related sialyltransferases (ST).  In a Nature Structural and Molecular Biology report published this week, Dr. Natalie Strynadka (University of British Columbia) describes solving the crystal structure of ST and provides the first detailed understanding of the enzyme.  Without getting into any molecular jargon, suffice it to say that the structural data brings insight into how the enzyme works and how it achieves specificity, which is useful knowledge for developing prospective inhibitors.

Power of Pheromones: Researchers removed the pheromone-producing cells in fruit flies (male or female) and found that these flies were extremely attractive to normal male fruit flies and also flies of other related species.  This contradicts the notion that these chemical signals simply attract one individual to another.  Instead, they are part of a complex signaling system used by the flies to recognize and distinguish sexes and species.  Other unusual behaviour by male fruit flies without pheromones included trying to copulate with each other’s heads.  Dr. Joel Levine and his team at the University of Toronto (Mississauga) describe their research in detail in this week’s edition of Nature.

Beta-globin Switch: A proteomics screen was used to identify the enzyme G9a as the interacting partner of NF-E2, which act together to control expression of the beta-globin genes in red blood cell development.  This study provides a clearer understanding of the molecular determinants controlling embryonic expression of beta-globin where G9a acts as a repressor and its transition to adult beta-globin expression where G9a promotes expression.  The research team at the Ottawa Hospital Research Institute was lead by Dr. Marjorie Brand and the study appears in the early online edition of the Proceedings of the National Academy of Sciences.

Friday Science Review: October 9, 2009

Breast cancer, genomics and two cover stories in prestigious journals…

Cancer Evolution and Progression:  Scientists at the BC Cancer Agency have sequenced and compared the entire cancer genome of a metastatic tumour versus the primary breast tumour that originated nine years earlier.  They used next generation DNA sequencing technology to reveal 32 mutations in the metastatic cancer but surprisingly only five of these were present in the original tumour.  Six mutations were present at lower frequencies in the primary tumour, 19 were not detected and 2 were undetermined.  These differences may provide clues about how cancer becomes resistant to therapy or how a tumour switches to aggressive metastasis that spreads to other sites in the body.  The study demonstrated that cancers evolve and that there may be significant heterogeneity within the tumours.  These findings emphasize the importance of ongoing research efforts to sequence all cancer genomes and buttress arguments in favour of personalized medicine.

The study was lead by Dr. Samuel Aparicio at the BC Cancer Agency and appears as the cover story in the latest edition of Nature.

Honey, I shrunk the lab: The “lab-on-a-chip” concept has been in use for a number of years but Dr. Aaron Wheeler’s Microfluidics Laboratory at the University of Toronto has designed a new module for use in breast cancer detection and care.  The hand-held sized device can extract and quantify estrogen in a very small sample size – as little as a 1 microliter sample of tissue or blood – by using electrical charges to move liquids around in a precise manner over a microchip.  Current methods require a much larger sample, about the size of a penny, which is often impractical to obtain.  Since elevated estrogen levels are associated with breast cancer risk and pathogenesis, this new device could be used at point-of-care to screen at-risk patients or to monitor therapies and provide results within minutes instead of days.

Dr. Wheeler collaborated with Dr. Robert Casper (University of Toronto and Samuel Lunenfeld Research Institute) on this project, which garnered the inaugural cover story in the new journal, Science Translational Medicine.

Genome Map Upgrade: Researchers have generated a comprehensive structural map of the human genome in identifying and marking regions that are duplicated or deleted, the so-called copy number variation (CNV).  Genetic variation is what makes us different and certain areas of the genome reflect these differences whereas other genetic regions show very little variation and are likely essential function genes.  It also provides important clues to understanding evolution and provides the foundation for future research in developing personalized medicine.   The international study was co-lead by Dr. Stephen Scherer at The Centre for Applied Genomics (Hospital for Sick Children, Toronto) and provides the following comments:

“The scale of this current project is 100 times the scale of all others.”

“Previous work in this field would be like a paper fold-up map; this advancement is like a GPS that takes you where you need to go. It allows you to navigate the landscape of the genome, from its peaks where there is vast genetic variation, to its valleys devoid of it.”

“Variation is indeed the spice of life and we now know that nature buffers this variation by using CNVs. We are harnessing this knowledge to fight disease.”

Dr. Scherer is also involved in maintaining the Database of Genomic Variants, which provides researchers around the world access to a curated catalog of CNVs.  Details of the research report appear in the advanced on-line edition of Nature.

Congratulations to McGill University alumni Jack Szostak and Willard Boyle for winning the 2009 Nobel Prize in their respective disciplines.

Dr. Jack Szostak started at McGill when he was 15 years old and graduated in 1972, specializing in cell biology.  This was the start of a brilliant research career where he co-discovered how telomeres and telomerase protects chromosomes from losing genetic material during cell division.  He shares the 2009 Nobel Prize for Medicine.

Dr. Willard Boyle completed his BSc (1947), MSc (1948) and PhD (1950) from McGill.   He shares the Nobel Prize for Physics for the 1969 co-invention of the charged-couple device (CCD) that is used in today’s digital photography technology.

Friday Science Review: October 2, 2009

Prostate cancer and H1N1 updates…

Nanotechnology is Coming:  A research study by a group of University of Toronto engineers, nanoscientists, and pharmaceutical specialists has garnered a lot of media attention this week describing the use of nanomaterials in microchip technology to create a highly sensitive biosensor.  In the more technical report published in Nature Nantotechnology this week, they describe a special nanostructuring technique arranged in an array architechture to expand the dynamic range and sensitivity of the system for nucleic acid and protein biodetection.  The microchip is small, fast, and super sensitive.

In an earlier publication in ACS Nano, they applied their nanotechnology to detect prostate cancer biomarkers.  They demonstrated the accuracy, sensitivity and speed of the non-invasive test, which they are trying to package into a small hand-held device that can readily conduct testing at the point-of-care.  Of course, the application of this technology goes far beyond prostate cancer and can be adapted to detect other cancer biomarkers, HIV and other diseases.   Nanomaterial, nanotechnology, nanomedicine – these are hot words that you will hear about more frequently in the near future.

The research was lead by University of Toronto scientists, Drs. Shana Kelley and Ted Sargent.  A spinoff company based on the molecular diagnostic platform, tentatively called GenEplex, is in the works with the support of the Ontario Institute for Cancer Research’s Intellectual Property Development and Commercialization Program.  Also, the Ontario Genomics Institute is funding a microRNA application of the technology to the tune of almost $1 million.

In other prostate cancer research news:

Targeting IGF-1R:  Researchers targeted the Insulin-like growth factor-1 receptor (IGF-1R) with antisense technology to suppress IGF-1R expression in prostate cancer cells.  They found that by inhibiting IGF-1R signaling activity, the cancer cells grew more slowly but also increased their rate of cell death.  This is the first preclinical proof-of-principal that antisense therapy targeting IGF-1R in prostate cancer may be a viable treatment route and warrants further investigation.

The study was conducted by Dr. Michael Cox at the Vancouver Prostate Centre and published in this week’s editon of The Prostate.

Fatty Acids Promote Prostate Cancer: The hormone androgen, and its androgen receptor partner, have been shown to contribute to prostate cancer progression.  In this research report, researchers at the University of British Columibia suggest that elevated fatty acid (arachadonic acid) levels in the tumors may lead to increased activation of steroid hormone synthesis and contribute to the progression of the cancer.  Therefore, they recommended that fatty acid pathways should also be targeted as part of a therapeutic approach to treating prostate cancer.

Dr. Colleen Nelson led the research team at the Vancouver Prostate Centre and published the report also in this week’s edition of The Prostate.

H1N1 Update: Following last week’s “seasonal flu vs. swine flu” vaccination story, the Public Health Agency of Canada reviewed their own data and soon declared their position on the yet unpublished study saying that “there is no link between having a seasonal flu shot and developing a severe bout of pandemic flu.”  More to follow on this as the controversial study should become public next week.

In other H1N1 news:

Big Pharma gets Immunity: As increasing H1N1 cases emerge and Health Canada is being encouraged to expedite the approval of H1N1 vaccines, the Public Health Agency of Canada is following other countries in stating that they will protect GlaxoSmithKline, the maker of the vaccine, from any lawsuits arising from potential side effects.

Surgical Masks are Adequate: Healthcare workers should be encouraged by a study comparing standard surgical masks versus N95 respirator in protecting against flu viruses (swine included).  In the randomized controlled study, conducted by flu expert Dr. Mark Loeb at McMaster University, 446 nurses from eight hospitals in Ontario were equally distributed to wear either sugical masks or fit-tested N95s.  The results showed that there was an insignificant difference (23.6%, surgical mask vs. 22.9%, N95) in the number who contract the ‘flu’ during the course of the season.  However, this study is sure to raise more debate within the healthcare community as unpublished work in China found that N95 masks can cut the risk of catching the flu virus by 75% while surgical masks offer no protective effect.  Dr. Loeb’s study is published in the early edition of JAMA.   A commentary on this issue is also provided by the U.S. Centers for Disease Control and Prevention.

Benefits of Handwashing? And if you are not confused enough about how to avoid catching the virus, consider this article in CMAJ questioning the benefits, due to lack of scientific evidence, of hand washing in preventiing the transmission of influenza viruses.

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Friday Science Review: September 25, 2009

A quiet week for journal publications but there were a few significant research related activities…

Canadian Stem Cell Charter: At the recent World Stem Cell Summit in Baltimore, Canada stepped up and demonstrated why we are one of the leaders in stem cell research.  This time it was not a lab discovery but the Canadian Stem Cell Foundation’s launch of a charter outlining ethical principals and a code of conduct to guide stem cell research in a responsible and ethical way.

The Stem Cell Charter upholds the following principles:
• Responsibility to maintain the highest level of scientific quality, safety and ethical probity
• Protection of citizens from harm and the safeguarding of the public trust and values
• Intellectual Freedom to exchange ideas in the spirit of international collaboration
• Transparency through the disclosure of results and of possible conflicts of interest
• Integrity in the promotion and advancement of stem cell research and therapy for the betterment
of the welfare of all human beings

Bartha Knoppers, a bioethicist at McGill University’s Centre of Genomics and Policy, authored the charter in collaboration with a working group of scientists, patients, ethicists and laypeople.  She describes the purpose of the charter:

“There have been a lot of spurious claims in this area, people doing the first of this or the first of that, and it not being true,”

“It’s a wake-up call to scientists to remind them that if they want to work in this field, they have to do so under a scientific code of conduct and it’s to reassure the public that this is not the Wild West.”

“We’d like to keep it a credible science,”

“We’d like to keep it a science that merits public investment and public funding.”

Signing on (www.stemcellcharter.org) and adhering to the charter is one way of doing just that.  It is also a way for the public to show their support for stem cell research and to make their voices heard.

By the way, September 23rd was Stem Cell Awareness Day!

The Michael J. Fox Foundation for Parkinson’s Research (MJFF): This was mentioned in yesterday’s post on this blog.  Michael J. Fox announced the charity status of the Canadian arm of his MJFF for Parkinson’s Research in association with The McEwen Centre for Regenerative Medicine (MCRM) and Toronto Western Hospital (TWH).  I just want to emphasize the significance from a research perspective.  He is an advocate for stem cell based therapy and his Foundation promotes and emphasizes the sharing of scientific information to facilitate quicker results – “We don’t just fund research.  We fund results.”

Flu shot increases risk of H1N1 virus:  An unpublished Canadian study is garnering attention by suggesting that a seasonal flu shot may actually increase an individual’s chances of catching the H1N1 virus.  The report is still under peer-review and the details are not available but it was enough for Ontario to modify its flu vaccination program this season.  Younger people will not be offered the seasonal flu vaccine until they receive the H1N1 vaccine, which will not be available until mid-November.  Other provinces are also considering making some changes to their programs.

The CDC and WHO are looking into this controversial study but are taking a cautious stance, refraining from acting too quickly:

“The reason why this may be different in Canada and in this particular study than in other places of the world is not yet identified. It may be a study bias, it may be that something is real,”

“None of the other countries have been able to find anything like that”

This enhancing effect would be unusual for flu viruses but not completely new from a biological perspective.

Dr. Danuta Skowronski of the British Columbia Centre for Disease Control and Dr. Gaston De Serres of Laval University led the research study.

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Friday Science Review: September 18, 2009

Some “brainy” research this week…

brainy

Curiosity Driven <=> Intelligence: There is new evidence that “fostering curiosity should also foster intelligence and vice versa.”  Researchers have discovered what they believe is the region of the brain, the dentate gyrus in the hippocampus, that is responsible for generating curiosity.  They also identified that the interaction between the neuronal calcium sensor-1 protein (NCS-1) with the dopamine type-2 receptors (D2R) is what triggers the curiosity-like behaviour.  In the investigation lead by  Dr. John Roder at the Samuel Lunenfeld Research Institute, they modestly overexpressed NCS-1 in the dentate gyrus region of mice and observed an exploratory type behaviour, interpreted as curiosity driven.  Researchers also noted improvements in intelligence as demonstrated by the performance of the mice in spatial memory tests.  Conversely, these phenotypes were reversed when the mice were treated with a drug that inhibits NCS-1 from binding to D2R.  This study appears in the latest edition of Neuron.  So go ahead and let your mind go free…

Dream on: Here’s how you can enjoy your nice dream twice as long – have your doctor perform deep brain stimulations (DBS) on you!  When scientists specifically stimulated an area of the brain responsible for the deep REM (rapid eye movement) sleep in parkinsonian patients undergoing a surgical procedure, they observed an extended period of brain wave activity consistent with REM sleep.  This is the “dreaming sleep” that we enjoy and provides the refreshing recharge we all need.  Sleep specialist Dr. Brian Murray was the lead investigator in the study conducted at Sunnybrook Health Sciences Centre and published in Annals of Neurology “This finding is significant for patients as it confirms, in principle, that we can selectively adjust different stages of sleep and this may make a big difference to sleep quality as well as other affected neurological functions and brain health.” Now we just need a longer day to accommodate the extra sleep!

Helping the vision impaired to seeevSpex, is an innovative sunglass-type device that can help those who are nearly blind to see via a digital image captured on a high resolution camera and played on a small LCD screen projected onto the user’s eyes.  The key feature is that the image is first processed and customized to the user before it is presented to the part of the vision that is most functional, maximizing “vision.”  The device includes features such as zoom and recording capabilities that can be played back instantly in case the viewer missed something.  Many people with different types of visual impairments will be able to benefit greatly from this technology.

evSpex was developed by eSight Corp in Ottawa with help from Dr. Réjean Munger, a senior scientist at the Ottawa Hospital Research Institute.

Friday Science Review: September 11, 2009

Two great medical discoveries…

Stayin’ Alive:  During a stroke, for example, neurons deprived of oxygen undergo cell death.  In a recent discovery lead by Dr. Michael Tymianski’s team at the Krembil Neuroscience Centre at Toronto Western Hospital, the protein TRPM7 was found to play a critical role in mediating this detrimental effect.   After suppressing TRPM7 expression in a localized region of a rat’s brain, they simulated a stroke by cutting off blood flow to the brain for 15 minutes.  The subsequent analysis revealed a complete lack of tissue damage compared to rat brains expressing TRPM7.  The resistance to death by cells lacking TRPM7 even preserved the brain’s cognitive function and memory performance following the ‘stroke’.  This may have tremendous implications for preventing further cell damage following ischemia in any tissue and is not necessarily limited to the brain, although it is yet to be tested elsewhere in the body

Details of the discovery are reported in the latest edition of Nature Neuroscience.

Insulin Resistance Gene Discovery: An international effort led by Dr. Robert Sladek and Dr. Constantin Polychronakos at McGill University performed a genome-wide comparison and identified a single nucleotide variation in the genetic region near the IRS1 gene that is associated with insulin resistance and hyperinsulinemia.

Dr. Sladek explains it best:

“It’s a single-nucleotide polymorphism (SNP, pronounced ‘snip’), a single letter change in your DNA,” said Sladek. “What’s interesting about this particular SNP is that it’s not linked genetically to the IRS1 gene in any way; it’s about half-a-million base-pairs away, in the middle of a genetic desert with no known genes nearby. In genetic terms, it’s halfway from Montreal to Halifax. And yet we can see that it causes a 40-per-cent reduction in the IRS1 gene, and even more important, a 40-per-cent reduction in its activity. Which means that even if insulin is present, it won’t work.”

IRS1 is known to be the key signalling protein involved in the cell’s initial response to insulin.  This recently discovered variant allele affects the level of IRS1 protein expressed and reduces the capacity of the cells to respond to insulin. Unlike other diabetes risk genes that affect insulin production in the body, this is the first that is known to suppress insulin stimulation in the cells.

The research article appears in the early online edition of Nature Genetics.

Friday Science Review: September 4, 2009

Potential future therapeutic options…

Dabigatran versus Warfarin: Dabigatran (PRADAX®, Boehringer-Ingelheim) was compared with warfarin (a commonly used anti-coagulant) in a large scale study for the treatment of patients with atrial fibrillations.  The trial demonstrated that the group of patients taking the higher dose of Dabigatran had significantly reduced risk of stroke compared to patients on warfarin but with similar risk of hemorrhaging.  With a lower dose of Dabigatran, they achieved protection from strokes that was similar to that afforded patients using warfarin but with a significantly reduced risk of major bleeding.  Dabigatran is the first alternative therapy option to warfarin treatment showing efficacy and improved safety to patients.  The global study was headquartered out of Hamilton at McMaster University and Hamilton Health Science Centre and appears in this week’s The New England Journal of Medicine.

Drug combo for Bell Palsy: Combinatorial therapy may be a better treatment method to improve the facial paralysis symptom of Bell Palsy patients. In the study lead by Dr. John de Almeida at Sunnybrook Health Science Centre, they compared the standard treatment with corticosteroids alone versus corticosteroids supplemented with antiviral drugs.  It is thought that a herpes infection is likely the cause of the disorder.  As the patients appeared to have experienced a slight incremental benefit from the combo therapy, the researchers will continue their study to provide a definitive answer.  The report was published in the current issue of the Journal of the American Medical Association (JAMA).

Key finds from studying protein structure:

  • The RAF family of proteins is an integral component of the RAS signaling module involved in cell growth, differentiation and survival.  This new structural study on BRAF revealed that its catalytic function is regulated by a “side-to-side” dimerization mode.  Interestingly, a mutation found in oncogenic versions of BRAF is located in this dimerization interface and promotes aberrant activation.  Surely, the side-to-side dimer interface of BRAF will be a potential target for therapeutic intervention against BRAF-dependent tumorigenesis.  This exciting research was lead by a collaborative effort between Dr. Frank Sicheri at the Samuel Lunenfeld Research Institute in Toronto and Dr. Marc Therrien at Université de Montréal and published in the early edition of Nature.
  • New insight into how bacteria can steal iron from its host was revealed through structural studies of the bacteria’s transferrin receptor.  The bacterial transferrin receptor binds to the host’s iron containing transferrin protein, extracts the iron and transports it across the membrane.  When they mutated a critical residue at the interface of this interaction, binding was completely abolished.  Perhaps these results from Dr. Anthony Schryvers’ research team at the University of Calgary will lead to future directions for antimicrobial therapeutics.  The study was published in the recent edition of Molecular Cell.

Nervous system development in today’s issue of Cell…

  • Researchers revealed how the neural-specific SR-related protein of 100 kDa (nSR100) is responsible for facilitating alternative transcript splicing specifically in the nervous system.  nSR100 is required for neural cell differentiation and contributes to the greater complexity of the vertebrate nervous system.  The research was lead by Dr. Benjamin Blencowe at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research.

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Friday Science Review: August 28, 2009

A Montreal flavour this week…

Critical link between EGFR and Src oncogenes: On the heels of last week’s Friday Science Review post on Stat3 in breast cancer, Dr. William Muller’s research team at McGill University has published another significant find linking well known oncogenes, Src and EGFR/ErbB2.  Among their results, they demonstrated how Src can interact with some mutant EGFR receptors (identified in lung cancers) but not with wild type EGFR.  When a Src inhibitor was applied to cells expressing mutant EGFR, it attenuated the cancer-inducing potential of these EGFR mutants.  This suggests that Src is an important enzyme in the EGFR mutant signaling pathway and may present an alternate pathway to combat cancer cell resistance to EGFR inhibitors.

Details of this study are described in this week’s Molecular and Cellular Biology.

MET oncogene in breast cancer: Next door to the Muller Lab at the new Goodman Cancer Centre in Montreal is Dr. Morag Park and her research team who recently generated a mouse model to mimic and study the Met oncogene in breast cancer.  The results were a complex cancer phenotype where gene expression and histological profiles demonstrated similarities to aggressive human breast cancers expressing Met.  Whereas prior to their study, Met was only correlated with poor outcome in breast cancer patients, this mouse model provides the specific link and identifies clinical cases where anti-Met therapy may be beneficial.

You can read more about it here in Proceedings of the National Academy of Sciences.

Key proteins in Natural Killer Cells: Also this week, Dr. André Veillette’s lab at the Institut de recherches cliniques de Montréal (IRCM) generated new insight into how Natural Killer Cells combat cancers of the blood, such as leukemias and lymphomas, or virus-infected blood cells.  As part of our immune system, the defense function of Natural Killer Cells requires three small proteins named SAP, EAT-2 and ERT that are unique to immune cells.  The proteins relay information from the cell surface SLAM family receptors to direct immune activities.  These data may eventually lead to pharmacological methods to increase the activity of Natural Killer Cells in destroying blood cancer cells or virus-infected cells.

Veillette’s lab generated knock-out mice missing all three proteins, which led to their findings, which are published in the latest edition of Nature Immunology.

p53 is regulated by JNK: p53 is a tumor suppressor protein that plays an important role in regulating cell growth and survival.  Its critical functions in the cell require p53 to be highly regulated through multiple layers of control, both to turn on and to turn off the protein’s activities.  One such method recently described in Proceedings of the National Academy of Sciences is through phosphorylation by the enzyme JNK.  This phosphorylation protects p53 from being targeted for destruction, thereby allowing p53 complexes to form and continue with their gene activating activities.

This research project was a collaboration between the Burnam Institute in San Diego and Dr. Katherine Borden’s team at the Université de Montréal.

Jurassic Park (for real?): Can you convert a chicken embryo to develop into a dinosaur?  No, this is not the makings of a movie but the idea of paleontologist Hans Larsson of McGill University who is proposing to try to make it work.  The theory is that by manipulating or swapping certain “switch” genes during the chicken embryo’s development, he can reproduce some features of a dinosaur.  He does not actually intend to hatch live prehistoric animals – for obvious reasons:

“It’s a demonstration of evolution,” said Larsson, who has studied bird evolution for the last 10 years.

“If I can demonstrate clearly that the potential for dinosaur anatomical development exists in birds, then it again proves that birds are direct descendants of dinosaurs.”

“We’re not going to hatch a T. rex or something,” Larsson chuckles.

The idea came to him after meeting Jack Horner, author of the book “How to Build A Dinosaur” and the technical advisor behind the Hollywood version of Jurassic Park.

Come back to the Friday Science Review (perhaps in a few years) for an update on the “chickensaurus” experiment…

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Friday Science Review: August 21, 2009

This week… cancers, brains, and fruit flies.

Combinatorial therapy to fight melanoma: Malignant melanomas are aggressive cancers that are highly resistant to chemotherapy, possibly due to high levels of Bcl-2 family anti-cell death  proteins.  Although the small molecule inhibitor, ABT-737, is effective against Bcl-2 family proteins in other cancers, it is not very effective in melanoma cases.  The reason may be due to overexpression of another protein, Mcl-1, which confers resistance to ABT-737.  When  Dr. Victor Tron’s group at Queen’s University combined ABT-737 treatment with inhibitions of Mcl-1 by way of siRNA knockdown, the cancer cells lost their resistance and underwent cell death.  These findings, appearing this week in PloS One , suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma.

Understanding Stat3 in Breast Cancer: Elevated Stat3 levels in breast cancer patients often correlate with poor clinical outcome.  To understand how Stat3 may influence cancer progression, a Stat3 knockout mouse was combined with a mouse expressing the mutant form of the breast cancer gene, ErbB2, and predisposed to develop breast tumours.  What the researchers at McGill University found was that without Stat3, breast cancer still developed but the malignancy of the mammary tumours decreased significantly with fewer animals having metastatic lesions in the lung.  Genetic profiling of the tumours showed that without Stat3, angiogenic and inflammatory responses, which often play an important role in the metastatic process, were blunted.  Remember, last week I noted an article on Par6 and TGFb in breast cancer metastasis.

This recent study, hot off the press in Cancer Research, was led by Dr. William Muller, one the early pioneers in using transgenic mouse technology.

Gene expression differences in suicide brains: This is the first study to perform global gene expression analysis on the brains of suicide cases to try to broaden the scope of suicide research to other neurotransmitter systems.  The serotonergic system is well studied as the primary area of the brain involved in suicides but there are likely other contributing factors.  Dr. Turecki’s research team at McGill University performed microarray expression studies on a number of brain tissue samples from the cortical and subcortical regions to identify potentially new molecular pathways involved in depression and suicide.  Their results revealed a number of alterations including genes involved in synaptic neurotransmission, namely upregulation of glutamatergic (excitatory) and GABAergic (inhibitory) related genes in suicide brains.  This report in PLoS One should open the research field into exploring alternate treatment methods and better understanding the development of suicide and depression.

Male hormone discovery: A new male-specific pheromone was identified on fruit flies.  When the researchers transferred some of the compound onto female fruit flies, the male flies were suddenly uninterested.  How did they identify this pheromone?  They exposed a fruit fly to a laser in a MALDI-type mass spectrometer instrument where ions are ejected into the instrument and analyzed.  Some previously unidentified compounds were discovered including this hormone.  The research was conducted at the University of Toronto Mississauga by Joel Levine and Jocelyn Millar and appears in this week’s Current Biology.

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Friday Science Review: August 14, 2009

Great stuff this week in Canadian science news…

A GIFT for MS patients:  An experimental treatment tested in mice with multiple sclerosis was able to reverse the disorder with few side effects.   The new compound is called GIFT15 – a hybrid protein between GSM-CSF and Interleukin-15.  Surprisingly, it produces results that you would not expect from the action of the individual proteins.  GIFT15 causes B-cells to switch from immune responsive into immune-suppressive regulatory cells and this forces MS into remission.  The treatment method takes B-cells from the individual and exposes them in vitro to GIFT15 to convert them to regulatory B-cells before they are injected back into the patient – a form of personalized medicine.

As always, one should be cautious as these experiments were tested in mice and it is unknown how humans would respond .  It does, however, present a new approach to finding a treatment regime for MS and may also lead to similar therapies for other autoimmune disorders.

Dr. Jacques Galipeau led the study at the Lady Davis Institute for Medical Research, McGill University and it is presented in the early on-line edition of Nature Medicine.

An Epilepsy gene discovery:  A mouse that experiences seizures was identified in a mutagenesis screen that led to the discovery of an inactivating mutation in the Atp1a3 gene encoding the Na(+),K(+)-ATPase alpha3 isoform protein.  It is a sodium-potassium transporter protein having important roles in maintaining the electrochemical gradient across cell membranes.  When the mutant gene was augmented with a wild type Atp1a3 gene by breeding the mutant mouse with a transgenic mouse expressing normal Atp1a3, the protein function was rescued and more importantly, the seizures subsided completely.  The human ATP1A3 is almost identical to the mouse protein and studies are underway to try to find a similar mutation in patients.

Dr. Roder’s group at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto published these results in PNAS this week.

New forensic DNA extraction tool:  High quality nucleic acids can now be extracted from the smallest sample size or from highly contaminated samples.  The technology is based on the electrical properties of nucleic acids rather than on the chemical properties that traditional purification methods are based on.  It uses a novel electrophoresis technology called SCODA (Synchronous Coefficient of Drag Alteration), a fancy name for a type of rotating electrical field that selectively acts on long, charged polymers (e.g. DNA).  This electrical field will concentrate DNA while separating it from contaminants.

The research was performed by the biophysics team led by Dr. Andre Marziali at the University of British Columbia.  They have already teamed up with UBC spin-off company, Boreal Genomics to package the technology into a cool-looking device called the Aurora.  It is not surprising that it has garnered a lot of interest from law enforcement groups in Canada and the U.S.   Of course, there are a number of other applications for this technology such as in clinical research for the early detection of diseases or infections.

The research is described in a PNAS paper that will be coming out very soon but here is the UBC press release.  A great example of “Today’s Canadian science = tomorrow’s Canadian start-ups” (…if you caught the tweet last week).

Wow!  Canadians are on a roll… more research published in Proceedings of the National Academy of Sciences. Here are the headlines:

Dr. Jeffery Wrana’s team (Samuel Lunenfeld Research Institute) describes how this signaling pathway is involved in breast cancer metastasis.

Dr. Uzonna (University of Manitoba) reports on why in some cases, vaccination against Leishmaniasis (a parasitic disease) can actually make them more susceptible to future infections.

Dr. Brisson (Université de Montréal) studies the Whirly protein – need I say more?

Dr. Barry Honda (Simon Fraser University) uses Drosophila to help us better understand O-linked N-acetylglucosamine transferase (OGT), which has been implicated in a number of processes including insulin signaling, neurodegenerative disease and cellular stress response.

Dr. Zatorre (Université de Montréal) breaks down how our brain processes sound and suggests that it is similar to the visual system of our brain.

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Friday Science Review: July 31, 2009

My first post… a two week round-up.

New direction for treating obesity:  A study headed by Dr. Hans-Michael Dosch’s group at The Hostpital for Sick Children in Toronto demonstrated that killer T cells in visceral fat are activated to destroy fat cells and control insulin resistance.  With increasing weight gain, however, the killer T cells become overwhelmed as fat cells grow and inflammatory T cells move in.  Although these studies were performed in mice, it appears that humans also have a similar system in place.  The good news is that treatment with an anti-CD3 drug can give the immune system a boost and help reduce inflammatory T cells.  Even better news is that this drug is already in clinical use to protect against organ rejection, which means clinical trials to combat obesity may start as early as next year.  The article was published on-line this week in Nature Medicine.

Cool headed Toucan.  After decades of speculation over the purpose of the toucan’s over-sized beak – from sexual ornament to feeding purposes – researchers at Brock University in Ontario, in collaboration with scientists in Brazil, published an article in Science showing that the toucan’s beak acts as a highly efficient cooling unit.  They have the greatest beak-to-body size ratio and use this large surface area as a heat exchanger (akin to elephants’ ears) to regulate body temperature by modifying blood flow.  If only we had a ‘heat wave’ problem this summer…

Setback in Huntington’s Disease research.  A decade long study concluding with disappointing results was reported in PNAS this week.  Researchers at Laval University and University of South Florida analyzed the brains of HD patients who had undergone neural transplantations about ten years ago as a potential treatment.  Although there were mild clinical benefits, the grafts were short-lived and also had undergone disease-like degeneration.

Barcoding Nemo. As part of the International Barcode of Life Project to identify all plants and animals based on signature DNA sequences, spear-headed by Paul Herbert at the University of Guelph, the ornamental fish was added to the list.  Accurate identification of ornamental fish is important for establishing regulations, conservation practices and tracking origins.  The DNA barcode reference for these fish is based on the cytochrome c oxidase subunit I (COI) gene where 98% of the fish have distinct barcode clusters.  The article was published in PLoS One last week.

Funny etiology: two curious New York high schoolers initiated the project and recruited the Guelph lab, sparking headlines last summer when they discovered that some sushi restaurants were mislabeling cheaper fish as more expensive types.

Other DNA barcoding projects include other fish, butterflies, and birds.  To find out more, visit the Canadian Centre for DNA Barcoding or the International Barcode of Life Project (iBOL).

Weekend Science Review: Abba Edition

Pinky and the BrainTake a Chance on Rats:  Fiona Zeeb in Catharine Winstanley’s lab at UBC has created a rat experimental model for gambling that attracted some news coverage.  Unlike previous rat gambling experiments, this model responds to human physiological moderators of gambling behaviour, like serotonergic and dopaminergic agents, suggesting that it will be a useful system for future investigations.  Here’s the (free) full paper from this week’s Neuropsychopharmacology.

Thank You for the GWAS: A study led by Katherine Siminovich (cross-appointed (at least) at U of T, Mount Sinai and the Liver Center at Toronto Western Hospital) was published in The New England Journal of Medicine this week identifying 13 loci across the HLA class II region that were associated with primary biliary cirrhosis.

Does Your Mother Know (there’s no obvious link between fibrinolytic defects and the risk of ovarian cancer):  A PLoS One paper authored by Yaakov Bentov in Robert Casper’s lab at the Lunenfeld dismantles one widely speculated etiology of ovarian cancer.  The hypothesis — “that the inefficient removal of the blood clots and fibrin products which are deposited in the vicinity of the ovary by retrograde menstruation might be associated with an increased risk of ovarian cancer” — was not disproven, but none of the functional variants in the fibrinolytic sytem examined by Bentov et al. showed any significant association with risk of ovarian cancer.

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Friday Science Review: Studying for the Bar Edition

ErlenmeyersWhile I am studying for the Ontario Bar exams over the next few weeks (a jurisdictional hat trick if I pull it off), I will try to keep up with the blog by cutting down on the analysis and commentary and putting you a bit closer to the primary source material than usual.  For the science review, click on and get the full, uncolo(u)red PubMed results to see what Canadians have been up to this week…

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