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Tag Archives: Alzheimers

Friday Science Review: May 28, 2010

A Map to Better Beer? The key signaling protein-protein interactions in yeast have been mapped.  Mass spectrometry was used to discover the global network between protein kinases and phosphatases to generate the “kinome” map, which contains 1844 interactions.  Since yeasts are model organisms with similar signaling pathways as in human cells, this information is relevant for human disease research and drug design.  The data set in this study was so large that the research team created software to store and analyze the data (ProHits) and perform statistical analysis (SAINT).  Dr. Mike Tyers (Samuel Luenefeld Research Institute) is the lead author of the project described in Science magazine.  The entire data set is available at the yeastkinome.org resource website.

Shhhh… Improving Gene Silencing: Micro RNAs (miRNA) control gene expression by interfering with specific RNA transcripts and this requires the Argonaute proteins (AGOs) to perform this function.  Researchers isolated the specific key region in AGO and solved the crystal structure of this segment.  From this, they discovered that there are intricate and specific molecular interactions between the miRNA and AGO that can dictate specificity.  As RNA interference techniques are gaining traction in the therapeutic arena, this discovery may lead to modifications to enhance the effectiveness of these therapies.  Dr. Bhushan Nagar led the McGill University research team and published the findings in Nature or check out this video podcast.

E. coli Survival Switch: The AceK protein in some bacteria acts as a switch responding to stressful environmental cues, allowing the bacteria to bypass the energy-producing Krebs cycle and go into a conservation mode.  Bacteria such as E. coli and Salmonella can survive in low-nutrient environments such as water.  Therefore, the discovery of how AceK works provides a potential target to prevent bacterial contamination in drinking water by inhibiting the ability of the bacteria to go into survival mode.  Dr. Zongchao Jia and postdoctoral fellow Dr. Jimin Zheng at Queen’s University solved the structure of the protein that led to understanding the unique properties of the enzyme in having both phosphorylation and de-phosphorylation activities on the same protein.  This breakthrough is described in the latest edition of Nature.

Little Buggers All Over Us: The Human Microbiome Jumpstart Reference Strains Consortium is trying to catalog all the microbes in the human body.  We are covered by millions and millions of these little critters – as many as 10x more microbes than the number of cells in our body, but they’re not necessarily bad for us.  They actually play important roles in protecting against infection, aid with digestion, developing our immune system and keeping us healthy.  So far, 178 genomes have been sequenced with the goal to sequence around 900 genomes.  The NIH initiated the project and Dr. Michael Surette and his team at the University of Calgary is a major contributor to the study.  The first phase of this initiative is published in Science.

Genomic Modifications in Stem Cells: To further understand stem cells and embryonic development, scientists took a closer look at how the structural organization of genomic DNA (chromatin and histones) plays a role in determining what tissue they become.  They identified and compared specific modifications across the genome that either activates or represses gene expression in different stem cells.  The value of this information is that it suggests differential regulatory mechanisms controlling development and depends on the specific stem cell lineage.  The safety of regenerative medicine lies in these types of studies in basic stem cell biology.  Developmental biologist Dr. Janet Rossant at The Hospital for Sick Children led the study, which appears in the Proceedings of the National Academy of Sciences.  Also, congratulations to Dr. Rossant as a recent recipient of the 2010 Premier’s Summit Award for Medical Research.

Improving Alzheimer Immunotherapy: Delivering antibodies against amyloid-beta peptide (Abeta) directly into the brain is more effective than systemic delivery in reducing amyloid plaques, as demonstrated in a mouse model.  In this novel approach, transcranial focused ultrasound (FUS) was applied to improve permeability of the blood brain barrier without the need for high doses of the antibody.  The researchers administered the therapeutic antibody intravenously along with a contrast agent to follow the progress via MRI imaging.  Using this MRI guided FUS method, they could see the contrast agent enter the brain within minutes and amyloid pathology was improved in the mouse model after four days.  Drs. Kullervo Hynynen and Isabelle Aubert at Sunnybrook Research Institute published their study on-line in PLoS One.

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: 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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Trends in 2009: Direct-to-Consumer Genetic Tests Come to Canada

B&W_DNA_sequenceThis week saw the introduction of what I believe is Canada’s first personal genomics service offering.  Toronto’s Medcan Clinic paired up with California-based Navigenics to scan individuals’ genomes for a variety of disease markers.

Personal genomics is a burgeoning trend this year, which according to a special report in April’s Economist, will only be further boosted by a Moore’s Law-type improvement in sequencing power and price.  Available service offerings range from whole genome sequencing (e.g., Illumina and Knome) that costs tens of thousands of dollars to targeted scans typically offered for under $500 by a much wider variety of providers (Navigenics, 23andMe, deCODE and Pathway Genomics).

Regulation of DTC Testing:

In the U.S., the regulatory environment has settled down somewhat over the last 6 months, with most U.S. states regulating DTC genetics companies as clinical labs and the providers registering as such on a regular basis, including CLIA certification.  However, the HHS Secretary’s Advisory Committee on Genetics, Health and Society is due to meet in October to further discuss whether DTC genetic tests should be regulated as medical devices.  The CDC has released a report entitled “Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions” setting out best practices both for testing and interpretation.

In Ontario, there are a number of regulatory considerations (thanks on these points for input from Will Chung, of our renowned Life Sciences team):

  1. Private labs and specimen collection centres require licenses and are governed by the Laboratory and Specimen Collection Centre Licensing Act (LSCCLA). However, blood collection at such facilities is governed by separate legislation which controls who may draw blood and for what purpose.
  2. The LSCCLA requires that only “legally qualified medical practitioners” are permitted to examine specimens, which means that patients may not directly order testing of their own blood at private licensed labs.
  3. Ontario’s Regulated Health Professions Act stipulates that communicating a “diagnosis” is a “controlled act” which may only be performed by a person authorized by a health profession Act, although it is not clear that DTC genomics results are a “diagnosis.”

Medscan seems to have navigated the regulatory waters, but time will tell how these laws are applied and/or modified.

In the EU, the European Society for Human Genetics advocates for pre-market review for “truthful labeling and promotion” as well as post-market evaluation of DTC genetic tests. In May, Germany passed a law restricting the availability of DTC genomics services by requiring testing to be carried out by a licensed doctor following the patient’s consent.”

How much protection do consumers need?

Many commentators are concerned with the public’s ability to understand these tests and distinguish between those that are clinically meaningful and those that are more … snake-oily.  Others object on the basis that there is little value added absent any available treatment — many preventive measures are things we already know we should do, like eat well, exercise, etc.  A number of groups, including advocacy group Genetic Alliance and the Genetics and Public Policy Center at Johns Hopkins University have called for a national registry of DTC genetic tests that would include performance data.

Others (and not just 23andMe’s founders) take a more libertarian view.  Ronald Bailey, the science columnist at Reason, agrees that people probably don’t need to be “protected against learning such information without the guidance of a knowledgeable physician or genetic counselor.”  In fact, a lawsuit in May brought by a girl born with Fragile X syndrome against the sperm bank that didn’t test for the predisposition may drive  higher demand for genetic testing in the fertility context which may in turn drive supply of services and diagnostic tools and may contribute to normalizing broader parental testing and pre-implantation screening.

Interestingly, a NEJM report a couple of weeks ago showed no lasting psychological damage from a genetic prognosis of increased Alzheimer’s risk.  By the time a year passed after the results, subjects who had an increased Alzheimer’s risk were no more depressed, anxious, or distressed than when they started the study.

Most importantly, 98% of patients in the Alzheimer’s study who tested positive said they would still get tested if offered the choice again.  98% is a lot. It suggests that DTC services will be increasingly popular, particularly as the price drops and the quality of the data, the analytics and the available counseling continue to improve.

Stay tuned to this page for further DTC genetics news and analysis.

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Wednesday Brain Dump: February 11, 2009

Deep Appreciation:for Phillip Terrence Ragon, founder and sole proprietor of database-software provider InterSystems who donated $100 million to establish a research institute that focuses on expediting the development of an AIDS vaccine, and to Pfizer Canada which contributed a further $2 million to British Columbia’s Center for Drug Research and Development (CDRD); and The State of Georgia is contemplating a $180 million bioscience research park.

Social Agitation: French scientists decided their street protests were their best approach to halting the government’s science and higher education reforms and rejected mediation.

Better Cogitation:Brain-Derived Neurotrophic Factor (BDNF) shows neuroprotective effects in animal models of Alzheimers’, but it won’t stop cries of ‘brain drain’ following Canada’s 2009 Budget.

Free Publication: ScienceInsider reports that Rep. Conyers’ (D-MI) bill that would eliminate free full-text publication of NIH-funded research is back on the table this session.

Self Regulation:More Pharma companies are implementing voluntary disclosure of physician payments (under threat of legislation); and some researchers are taking steps to prevent disclosures of potentially harmful research (under threat of annihilation).

Reconsideration: Researchers at Emory decided that flu pandemic deaths in 1918 may have been primarily from bacterial superinfections rather than the virus itself; Icahn decided to nominate another slate of Biogen-Idec directors; Everybody decided to take another look at their luciferase screening assay controls; and the Ontario Health Insurance Plan (OHIP) decided to take another look at payment for PSA testing for prostate cancer detection.

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