The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: June 11, 2010

Catch up on these genetics stories between World Cup soccer games…

Genetic Links to Autism: Phase 2 results of the Autism Genome Project mapping the genetics of autism is reported this week in Nature. Researchers used the latest microarray technology to identify a trend that autism patients carry more insertion and deletion mutations affecting their genes.  Several genes were also labelled as potential autism risk factor genes and could be very useful for diagnostic purposes. “Guided by these massive genomic data sets, we can start to see the forest through the trees, offering answers and hope for families with autism,” says Dr. Stephen Scherer at The Hospital for Sick Children who led the consortium along with Dr. Peter Szatmari at McMaster University.  You can read about it here or sit back and watch this interview with Dr. Scherer.

Note that this study contrasts the controversial 1998 Lancet paper by Dr. Andrew Wakefield who suggested a strong link between the MMR (measles, mumps, rubella) vaccine and autism, leading to many parents withdrawing their children from the effective vaccine program.  The Lancet journal retracted the paper in February 2010.

Nature versus Nurture: Epigenetics is at the crossroads of genetics and environmental factors – the science of how the environment affects gene regulation at the molecular level that leads to a disease pathway.  “With the concepts of epigenetics we can start to understand how a disease risk factor is alternately switched on and off,” Dr. Arturas Petronis at the Centre for Addiction and Mental Health (CAMH) explains in this new perspective article published in Nature.

Epigenetics provides a new theoretical framework that addresses the vast complexities, irregularities, and controversies detected in common human diseases. For instance, epigenetics explains why one identical twin may be affected with cancer or diabetes although the co-twin is perfectly healthy. “In a case like this, the inherited genes are identical and the environment is similar. But one twin’s risk factor has been triggered, while the other twin’s risk factor has not been triggered,” says Dr. Petronis.

For personalized medicine to move forward, it is imperative to understand the mechanism of how environmental cues lead to genetic changes and how this process can be controlled.

Friday Science Review: June 4, 2010

New fixes for spinal injury, Staph infection and cancers…

Spinal Cord Self-Repair: A natural repair mechanism in our bodies may be the key to treating spinal-cord injuries.  Following a spinal cord injury, there is an increase in expression of serotonin receptors and the receptors are spontaneously active even in the absence of serotonin.  This autoactivation is thought to be a response or repair mechanism that is initiated as a result of the injury.  Pharmacological agents may be used to try to enhance this receptor activity to promote recovery.  The caveat, however, is that the receptors remain “on” and may explain the spasms experienced by spinal injury patients.  In this case, inhibitory drugs may be beneficial to preventing these muscle spasms.  Dr. Karim Fouad and his team conducted the research at the University of Alberta (Edmonton) and present their work in Nature Medicine.

Super Bug’s Magic Revealed:  MRSA, or methicillin-resistant Staphylococcus aureus, is a strain of Staph that has become resistant to most types of antibiotics.  Scientists now know why and what makes a harmless bacteria become pathogenic Super Bugs.  A small chemical (aureusimines) made by MRSA bugs is the key factor that determines their virulence and ability to cause severe disease.  The researchers discovered how these chemicals are made in the bacterium and then tried to shut off the different pathways involved in the synthesis of these chemicals.   Blocking aureusimine production resulted in a much weaker and less virulent bug, which allowed the mouse model patients to recover from S. aureus infections.  This information comes at a crucial time when drug resistance is on the rise and new anti-bacterial targets are desperately needed.  McMaster University scientists led by Dr. Nathan Magarvey describe their breakthrough discovery in the latest Science magazine.

Controlling Cell Growth: The research of Dr. Nahaum Sonenberg and his McGill University team on the mechanisms controlling cell growth and proliferation have had significant impact in advancing the field.  They continue their key discoveries with the delineation of mTORC1 and the 4E-BP proteins.  Although mTORC1 is known to be involved in connecting growth and nutrient signals to control cell size and cell division, 4E-BPs are only involved in mediating the cell proliferation pathway and not cell growth.  This distinction is important because mTORC1 is implicated in a variety of diseases and these related pathways are targets for therapeutic drugs, so further refinements can be made accordingly.  The report is published here in Science magazine.

A Cancer Cure in Sponge? A peptide found in sea sponge can inhibit tumour cell metastasis.  The Neopetrosiamide A (NeoA) peptide prevents tumour cells from sticking to surfaces by decreasing cell surface proteins such as integrins and inducing the disassembly of structural complexes called focal adhesions.  Its mechanism of action is unknown but it somehow causes important “sticky” proteins to be kicked out of the cell rather than trafficking to their proper locations.  This is a developing story to keep an eye on.  The study is published in PLoS One by Dr. Calvin Roskelley’s team at the University of British Columbia.

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: May 21, 2010

A slightly different FSR this week with a spotlight on Global Health, right on the heels of the recent Grand Challenges Canada announcement.  An interesting report in Nature Biotechnology, led by Drs. Abdallah Daar and Peter Singer at the McLaughlin-Rotman Centre for Global Health, mapped the collaborations between health biotech companies in developing countries.  The study is a first for tracking “South-South” partnerships and they offer some interesting insights:

South-South collaborations have become a widely chosen path for health biotech companies:

  • About a quarter (27%), participate in collaborations with another developing country and many (21%) are involved in multiple initiatives.
  • South-North collaborations with developed countries are still more common (53%).
  • The most active countries with the highest percentage of firms engaged in South-South collaborations are Cuba (~75%) and South Africa (~45%), followed by Egypt, Brazil, India, and China.
  • These leading developing countries in health biotech make up the majority of the linkages (see figure below)
  • Many of the collaborations are within their own regions such that they are establishing free trade zones to encourage trade with one another.

South-South Collaboration Network

Some of the motivations for companies in developing to collaborate include:

  • Minimizing risk and cost by sharing the burden with a partner.
  • Expanding their potential markets with an easier or facilitated access to a foreign market.
  • Gaining specific knowledge or skills, particularly since there are many specialized skills and technologies involved in biotech research that may not be available locally.

The nature of the collaborations, however, is mainly end-stage commercialization agreements rather than R&D.

  • Distribution agreements (72%) and marketing activities (34%) account for the majority of the collaborations with only 13% involving R&D and 9% involving clinical trials activities.
  • Innovation based knowledge sharing would likely have greater long-term benefits and future policies should encourage more of these types of collaborations.

To further promote such initiatives, Government organizations and other third parties can, and should, play a larger role to cultivate joint ventures since the majority of the South-South collaborations were initiated by the participating companies themselves.  It is important to realize that  South-South collaborations in the biotech sector are just as valuable as North-South collaborations to sustain a growing culture that addresses global health issues.

Also note that this study follows a pair of Nature Biotechnology publications last year by the same group at MRC – one explores “South-North” health biotech collaborations and the other focuses on Canadian biotech collaborations with developing countries.

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Friday Science Review: May 14, 2010

A Cure for Brain Cancer: An aggressive type of brain cancer called glioblastoma may be cured using the small molecule dichloracetate (DCA), a cheap and safe generic compound.  The drug works by altering the metabolism of the cancer cells, which is an emerging concept that exploits the different (higher) energy demand of cancer cells.  DCA’s target in the cells is the metabolic enzyme pyruvate dehydrogenase kinase II and it also promotes cell death in glioblastoma cancer cells and cancer stem cells.  In an 18-month study, some of the five patients’ tumours either regressed in size or did not grow any more.  Drs. Kenn Petruk and Evangelos Michelakis at the University of Alberta describe their study showing efficacy of DCA in humans for the first time in the journal Science Translational Medicine.  It is interesting to note that these and future studies are funded by government grants and private donations since the pharmaceutical industry is not interested in a compound that is readily available and without intellectual property protection (ie. no $cha-ching$).

Embryonic Cells Can Stop Viruses: Embryonic cells have a natural defence mechanism to limit the ability of viruses to express their genes and thereby prevent infection and further spread of the virus.  Researchers also determined that the different layers of cells in the developing embryo have different capacities to silence viral activation.  This “graphical abstract” published in Cell Stem Cell shows the outer layer of extraembryonic endoderm stem cells as the first line of defence with the strongest abilities to extinguish viral gene expression.  Several proteins including chromatin remodelling and repressor complex proteins were also identified to play key roles in this process.  The study was lead by Dr. Mellissa Mann at the University of Western Ontario.

If Only Mice Could Talk: This one is a bit strange.  It looks like mice express pain through facial expressions similar to the way humans do.  McGill University researchers developed the Mouse Grimace Scale to aid scientists working with lab animals to better ‘communicate’ with the animals.  Not only will this help to minimize and manage the stress that is inflicted on the animals but they can read the facial responses to determine whether a drug treatment is working or as an indicator of negative side effects.  Check out the study by Dr. Jeffrey Mogil in the issue of Nature Methods.

Pathogens Are Our Friends: Diphtheria Toxin (DT) is a potent cytotoxin that kills the cells that it binds to.  The DT385 is a recombinant version that is truncated and can be targeted to cancer cells to be used as a therapeutic agent.  In the present study, 15 of the18 human cancer lines tested were inhibited by DT385 as a result of increased apoptosis and decreased protein synthesis.  Dr. David Waisman at Dalhousie University published his study online in PLoS One.  Using pathogen proteins as therapeutic agents is not a new concept.  Oncolytics Biotech’s REOLYSIN® is derived from the Reovirus and Advaxis, Inc. exploits the Listeria bacterium to activate the immune system in an immunotherapy approach.

Studying Herpes Infection: Dr. Karen Mossman (McMaster University) investigated Herpes Simplex Virus-1 infection and how a viral protein, ICP0, is localized properly in the cell to block Interferon Regulatory Factor 3 (IRF3), the cell’s innate antiviral mechanism.  The study is described in PLoS One journal.

Friday Science Review: May 7, 2010

Amazing!  Three Nature papers this week…

Cracking the Code: The human body is much more complex than the 20,000 or so genes that are encoded in our DNA.  This multiplicity of genetic messages is enhanced by alternative gene splicing, a process where different segments of DNA exons are spliced together to create a different gene message.  It is possible to create hundreds of new messages from a single gene.  The so called “splicing code” or rules that determines how and where a particular part of a gene is spliced with another segment was deciphered by researchers at the University of Toronto.  They can now accurately predict how genetic messages are rearranged on a large scale.  Hundreds of different RNA features are taken into account including certain factors in specific tissues to give rise to tissue specific expression.  This is an amazing discovery by Drs. Brendan Frey and Benjamin Blencowe that garnered the cover story in this week’s Nature journal.

Stem Cells on Hormones: The ovarian hormone, progesterone, stimulates breast stem cells as its levels peak during the natural reproductive cycle.  Researchers observed up to a 14-fold expansion of breast stem cells at peak progesterone levels in a mouse model.  This is the first evidence of a direct link between hormones and breast stem cells.  Since cancers are thought to initiate from stem cells, if there are other oncogenic factors pushing the system this may be a critical point that ultimately drives the start of a cancer.  There are implications of this study to further understanding how reproductive history is a strong risk factor for breast cancer and may lead to therapeutic intervention.  The research team at Princess Margaret Hospital, University Health Network was led by Dr. Rama Khokha and describes their work in Nature.

Reversing HER2 Breast Cancer: Through genomic studies of HER2 positive breast cancer, it was noted that the 14-3-3sigma gene was frequently missing.  After several years of hard work focusing on this gene, researchers have demonstrated that the 14-3-3sigma gene does indeed play a specific role in the development and function of breast epithelial tissue.  In the absence of 14-3-3sigma, the normally organized and polarized sheets of epithelial cells clump together and lose polarity.  It is this loss of organization without 14-3-3sigma that likely contributes to breast cancer progression.  From a therapeutic standpoint, the reintroduction of 14-3-3sigma into HER2 positive breast cancer cells resulted in the restoration of cell polarity and opens a window for further studies as a pathway to target.  Dr. William Muller (my former mentor) and his team at McGill University describe their research in the early edition of Genes and Development.

Bionic Muscle: Artificial proteins were assembled together in a fashion that mimics the molecular spring structure of a muscle protein called Titin, which is a very large protein that gives muscle tissue its unique properties of strength, extensibility and resilience.  This is why muscle has superior elasticity.  The biomaterial looks like a string of beads and although it exhibits only some of the mechanical characteristics of muscle tissue, its structure can be adjusted to provide specific properties of different types of muscle.  There are obvious future applications of this technology in regenerative medicine and tissue engineering.  Drs. Hongbin Li and John Gosline at the University of British Columbia present their work in this week’s Nature journal.

Friday Science Review: April 30, 2010

Maybe these primary research projects will lead to the next great “Dendreon” story…

Mirror-rorriM Movement Disorder: Defects in the proper connections between the left and right sides of the brain can lead to involuntary movements where one side of the body follows or mirrors the movement of the other side.  A study of two families affected by inherited cases of mirror movements led to the identification of mutations in the DCC gene (Deleted in Colorectal Carcinoma).  DCC is a receptor for netrin-1, which is a factor that is important for guiding neural axons across the midline to make the proper left-right connections.  This is a key finding in understanding the complexities of how our brains are wired.  Dr. Guy Rouleau (Université de Montréal) and Dr. Frédéric Charron (Institut de recherches cliniques de Montréal) collaborated on the study and is published in the prestigious Science journal.

Improving RNA Therapeutics: RNA interference based therapeutics is gaining traction in the biotech world (eg. Tekmira, Alnylam, MDRNA).  Enhancing the potency of siRNA is the focus of this research study published in Nucleic Acids Research journal.  The technology uses a combination of DNA and RNA analogs to increase the stability of the siRNA agent against nucleases and helps them to evade immune responses that often limit their effectiveness.  Dr. Masad Damha led his group at McGill University.

Also in Montreal, Drs. François Major and Gerardo Ferbeyre (Université de Montréal) announced the launch of the first ribonucleic acid (RNA) engineering laboratory in Canada.  They are using bioinformatics and biochemistry to come up with designer microRNAs that can control the behaviour of RNAs to control or cure cancers.

New Tumour Suppressor:  A recent study demonstrates the tumour suppressor properties of the Cdh11 gene.  The first hint of this function arose from studies showing a frequent loss Cdh11 in retinoblastoma cancers.  Using a series of animal models to determine the role of Cdh11, Dr. Brenda Gallie’s team (Ontario Cancer Institute) demonstrated the tumour suppressor properties of Cdh11 through a mechanism promoting cell death or apoptosis.  The full text article appears online in PLoS Genetics.

Lung Cancer Drug Target: CXCR4 may be the next therapeutic target for treating lung cancer.  Its overexpression in about 10% of lung cancers is associated with poor patient outcome (2.7 vs. 6.1 months survival), likely due to CXCR4’s support for the rapid growth and metastasis of tumours.  On the brighter side, anti-CXCR4 drugs, which are already in existence for the treatment of HIV/AIDS, may be “fast tracked” for testing in lung cancer patients.  Dr. Gwyn Bebb, from the University of Calgary, presented her data recently at the 2nd European Lung Cancer Conference.

Friday Science Review: April 23, 2010

Iron Man 2: Actually, this is about IRP2 – Iron Regulatory Protein 2.  Ok, not quite as exciting as the superhero movie but it is interesting/unexpected that overexpression of IRP2 promotes cancer cell growth.  In contrast, the very similar IRP1 protein suppresses tumour growth.  The difference seems to lie within a 73 amino acid sequence in IRP2 that is required for its growth promoting properties.  It is a long stretch to try to make any link between iron intake and cancer based on this preliminary study but it does warrant further research to understand the roles of IRP1 and IRP2.  Dr. Kostas Pantopoulos (McGill University) published his study in PLoS One.

Not All Herpes are the Same: There are many different strains of herpes viruses, each with slightly different properties and responses to drugs.  Human herpesvirus 6A and 6B (HHV-6A, HHV-6B) variants are prime examples of this.  Classic anti-viral drugs based on type 1 Interferon (IFN) are effective against HHV-6A infected cells but not cells infected with HHV-6B.  Dr. Louis Flamand’s group at Université Laval’s Centre de Recherche en Rhumatologie et Immunologie (CRRI) worked out some of the molecular details explaining this difference.    They mapped a 41 amino acid region in the IE1 protein that is present only in the HHV-6B strain, which acts to block any further genetic responses to the IFN drugs.  These small differences between herpes strains make it difficult to effectively treat infected patients but research such as this one are very important to identify how to better target each specific strain.  The study is reported in this week’s issue of the Proceedings of the National Academy of Sciences.

Hippos are Your (Kidney’s) Friend: Polycystic Kidney Disease (PKD) is a common genetic disease affecting an estimated 12.5 million people worldwide and is the forth leading cause of kidney failure.  Researchers are unraveling the key molecular players involved in PKD.  In this study, Dr. Liliana Attisano’s team (University of Toronto) took a closer look at the Hippo pathway and identified a new function for the transcriptional activator, TAZ. TAZ modulates the beta-Catenin/Wnt signalling pathway, which is important in development and morphogenetic events.  Mouse knockouts that do not express TAZ develop polycystic kidneys and demonstrate the role that these pathways play in kidney disease.  This study is reported in the latest edition of Developmental Cell.

Ovarian Cancer Cells Avoid Death: Researchers studying ovarian cancer determined the mechanism by which ovarian cancer cells thrive.  The sequence goes like this:  ovarian cancer ascites triggers an adhesion protein called alphavbeta5 integrin; this activates FAK phosphorylation and correlates with Akt activation; the Akt pathway inhibits the molecular events leading to cell death or apoptosis.  Thus, ovarian ascites confers protection against cell death.  This study reveals some possible key target points for therapeutic intervention in the treatment of ovarian cancer.  Dr. Alain Piche at the Université de Sherbrooke describes his work in the journal Oncogene.

Friday Science Review: April 16, 2010

An amazing week of Canadian research advancements…

Cancer Genome Project is Well Underway: The Ontario Institute for Cancer Research (OICR), who is leading the International Cancer Genome Consortium (ICGC), published a report this week in Nature outlining the international effort to sequence 25,000 cancer genomes – 500 genomes from each of the 50 most common cancers such as breast, colon, liver, lung, and pancreatic cancers.  Some partial datasets are already available to the global research community at www.icgc.org.  This is truly a Herculean effort that is only possible because of the international collaborative effort of over 200 members around the globe.  Whole cancer genome sequencing will provide a fundamental base to advance personalized medicine to the next level.  Here is the original OICR press release and you can read a more comprehensive ‘Scientific American’ style news feature article on the cancer genome project here in the same issue of Nature.

Seek and Destory: Non-Hodgkins lymphoma cancer is taking a big hit from a newly discovered compound that destroys lymphoma cells.  The small molecule compound targets and blocks a transcription factor called BCL6, which is responsible for half of non-Hodgkins lymphoma cases.  Scientists started with the 3D structure of the BCL6 protein and used computer-aided drug design to perform in silico screening of over a million compounds.  They eventually narrowed it down to this one compound that proved to be efficacious and also non-toxic.  Dr. Gilbert Prive at the University Health Network led the innovative project that demonstrates the success of a computational approach to drug design and the ability to target transcriptions factors with minimal side effects.  Read all about it! – in the free full text article in Cancer Cell.

Divide and Conquer: Cell division is a complicated process with the synchronized dance of chromosomes segregating to each new cell.  It is a poorly understood process but research is this field is advancing with the discovery of new essential proteins involved in cell divisionDr. Laurence Pelletier (Samuel Lunenfeld Research Institute) and his collaborators in Europe used a combination of RNAi tools and mass spectrometry techniques to identify the components of protein complexes involved in cell division.  As cancer cells are hyperactive dividing cells, this new information will also aid in the advancement of cancer targeting therapeutics.  The study appears in the journal Science.

The Missing Link: Many have suspected that there must be some link or relationship between stress, anxiety and depression.  Now there is molecular evidence that this is true.  The connection involves the interaction between corticotropin releasing factor receptor 1 (CRFR1) and certain types of serotonin receptors (5-HTRs).  CRFR1 activity leads to stress related anxiety and it also stimulates an increase in the number of 5-HTRs in the brain, which can lead to signaling abnormalities causing depression.  The team headed by Dr. Stephen Ferguson at the University of Western Ontario also developed a small molecule inhibitor that blocks 5-HTRs.  Let’s hope this inhibitor and knowledge of the molecular links lead to more effective treatments for these disorders.  Check out the free full-text article in Nature Neuroscience.

Smart Buggers:  Understanding how bacteria become resistant to last-resort antibiotic drugs just got a boost from a McMaster University study.  Vancomycin resistant methicillin-resistant staphylococcus aureus (VMRSA), also known as the hospital superbug, is a rapidly growing problem with limited effective solutions.  The research team identified the histidine kinase VanSsc protein as the direct vancomycin detector in bacteria, which then triggers the expression of three genes that provide the drug resistance.  This is the first important step in redesigning antibiotic drugs to effectively fight these little buggers.   Dr. Gerry Wright and his collaborators published their exciting work in Nature Chemical Biology.

Not Just a Bad Golf Shot: Scientists have identified mutations in the SHANK3 gene that are associated with schizophrenia.  SHANK3 is a scaffolding protein involved in the formation of the synapse and maintains the structure of nerve cells.  Dr. Guy Rouleau’s team at the Université de Montréal discovered the new mutations (R1117X and R536W) in two families with schizophrenia patients where one of these families had three affected brothers.  Further molecular and genetic studies in zebrafish models confirmed that the R1117X mutation causes behavioural defects.  Earlier studies linked SHANK3 mutations to autism, which suggests that there is a molecular connection between the two neurological disorders.  The findings are reported in this week’s edition of the Proceedings of the National Academy of Sciences.

Gene Therapy is Still Alive: The promise of gene therapeutics to cure diseases may not have lived up to the hype presented a decade ago but there are still some hopeful successes using gene therapy.  One recent example comes from Laval University where researchers repaired the defective dystrophin gene responsible for Duchenne muscular dystrophy (DMD). In some cases of DMD, the dystrophin gene is misread causing a frame-shift mutation.  These frame-shift mutations may be targeted and repaired by enzymes called meganucleases.  A proof-of-principle project by Dr. Jacques Tremblay demonstrated that expression of specific meganucleases in the muscle of a DMD mouse model can restore the normal reading frame of a mutated dystrophin gene.  More details in this week’s edition of Gene Therapy.

Friday Science Review: April 9, 2010

New fixes for diabetes, HIV, and nerve damage…

Nano-Vaccine Cures Diabetes: To prevent the immune system from attacking pancreatic cells in Type 1 diabetes, a nanotechnology based “vaccine” was used successfully to stop the disease in mice.  The strategy involves nanoparticles that are coated with diabetes specific peptides and bound to MHC molecules. When injected into the body, they stimulate regulatory T cells – the “friendly” T cells that prevent the “bad” T cells from destroying the insulin producing beta cells in the pancreas.  The advantage of this method is that it is specific to the ‘diabetes T cells’ and there are no negative effects on the rest of the immune system.  Other autoimmune diseases may also benefit from a nanoparticle vaccine approach.  Dr. Pere Santamaria’s team at the University of Calgary describes their work in the online edition of Immunity and has licensed this innovative technology to Parvus Therapeutics, Inc., a U of C spin-off company.

Allowing Neural Regeneration: The p75NTR receptor is important for the development of the nervous system during childhood.  A new research study published in Nature Neuroscience describes an inhibitory effect of p75 neurotrophin receptors (p75NTR) in the adult nervous system.  Not only does it prevent adult nerve cells from regenerating, it actively destroys axons as necessary if any aberrant connections try to form.  This monitoring system is likely skewed in neurological diseases or disorders.  Thus, further molecular information surrounding p75NTR in the nervous system can lead to developing strategies to facilitate nerve regeneration to occur or prevent degenerative disorders.  Dr. Freda Miller and her team conducted the research at The Hospital for Sick Children in Toronto.

HIV’s Secret Weapon Revealed: The discovery of how the viral protein called Vpu facilitates HIV-1 proliferation in a host may present opportunities to block this pathway with a small molecule inhibitor.  Vpu binds to and blocks Tetherin, a natural antiviral protein on the cell surface that can sense and capture the virus and prevent production and further transmission of HIV-1.  HIV-1 has evolved with Vpu as its weapon to impede Tetherin from reaching the cell surface where it acts to tether viruses.  Now it is time for scientists to outsmart the virus and find a method to block Vpu.  Dr. Éric A. Cohen directed his team at the Institut de Recherches Cliniques de Montréal and reports the study in this week’s PLoS Pathogens journal.

Cell-Cell Krazy Glue: The integrity of cell-cell contacts is important for the maintenance of the epithelial cell layer and aberrations may contribute to disease progression such as in cancer metastasis.   Two proteins involved in this cell-cell adhesion are p120 catenin and E-cadherin.  Dr. Mitsuhiko Ikura at the Ontario Cancer Institute performed NMR structural studies to provide a detailed map and understanding of the protein-protein interaction between catenin and cadherin.  The detailed study, published in the journal Cell, describe both dynamic and static interactions that contribute to the stability of the adhesion interaction between cells.

Bring out the Bazooka: Following the article above on the epithelial cell layer, this study examines a protein called Bazooka (Par3 in mammalian cells) in fruit flies.  It is expressed on epithelial cells and acts a protein interaction hub to regulate the integrity of the epithelial structure.  Using a series of gene mutants, gene mapping and bioinformatics techniques, researchers identified up to 17 genes that associate with Bazooka to regulate epithelial structure, many of these are novel interactions with Bazooka.  Further study is necessary to determine how they work together and how this translates to human tissues.  The list of genes is available in the article online in PLoS One journal and was reported by lead researcher Dr. Tony Harris at the University of Toronto.

Friday Science Review: March 26, 2010

Why Did the Duck Kill the Chicken? Well… a scientific explanation is RIG-I.  Ducks are resistant to influenza viruses but may by asymptomatic carriers.  One of the reasons for ducks’ resistance is because ducks express the RIG-I protein that senses the presence of the viruses.  Chickens, however, do not appear to express RIG-I or a similar protein and have no method to detect the presence of viruses to illicit an immune response.  This could have implications to the poultry industry who do not want to see their entire farm wiped out by a viral outbreak and may want to start breeding transgenic chickens expressing RIG-I.  The discovery was led by Dr. Katharine Magor and her team at the University of Alberta and is published in the early edition of the Proceedings of the National Academy of Sciences.

Promoting Cancer Cell Growth: The YB-1 (Y-box binding protein-1) transcription factor is a known oncogene that is expressed in a significant percentage of breast cancers.  In this study, scientists demonstrated that YB-1 induces the expression of CD44 and CD49f, which are associated with cancer stem cells and used as stem cell markers.  Although they do not make a direct link to breast cancer stem cells, they suggest that it is this link that explains why YB-1 expressing cancers are resistant to drugs such as paclitaxel and are associated with disease recurrence and poor outcome.  The principal investigator of the study was Dr. Sandra Dunn at the University of British Columbia. Details of the study were reported in Cancer Research.

Knock, knock… Let Me In: A transporter protein that is selectively expressed in blood cells can be manipulated to facilitate the entry of cancer drugs into the cell.  This is extremely important for new treatment regimes against blood cancers such as AML and other leukemias.  Researchers found that the Human Carnitine Transporter encoded by the SLC22A16 gene acts as a gateway and can mediate the uptake of the polyamine class of drugs such as the anti-cancer agent Bleomycin.  Dr. Dindial Ramotar, Université de Montréal, first demonstrated this in yeast cells and now in human cells as reported in the Journal of Biological Chemistry.

Please, No More Radiation: A genetic mutation in the p53 gene in children with a rare type of brain cancer – choroid plexus carcinoma (CPC) – is a new marker indicating a poor response to radiation therapy.  It is unfortunate that this signals a more aggressive disease, however, this finding would relieve the patient of having to suffer through the difficulties of radiation.  The inherited p53 mutation is associated with a condition called Li-Fraumeni syndrome and is found in about 50% of CPC cases.  Without the mutation, CPC patients treated by radiation have a good chance of recovery.  The study, led by Dr. David Malkin at the Hospital for Sick Children, Toronto, is published in the advance online issue of the Journal of Clinical Oncology.

Mooooooooo: Scientists have finished sequencing the genome of two different types of cows – one beef and one dairy – using Life Technologies’ next generation SOLiD™ 3 System.  It cost $130K and took only seven months to complete.  In comparison, it cost $50M and four years, finishing in 2009, to sequence the first cow.  The genomic information is important to the industry for making breeding decisions and to identify genetic markers of specific desirable traits.  So that T-bone steak waiting for you to grill up this summer will be even juicier and tastier.  The Bovine Genomics Program at the University of Alberta led by Dr. Stephen Moore performed the sequencing study.

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Friday Science Review: March 19, 2010

Friday Science Review: March 12, 2010

Good viruses, bad viruses, biomarkers and protein structures in this week’s research highlights…

Biomarker for Hodgkin’s Lymphoma Subset: Using a high-throughput genomic approach to associate gene expression profile with treatment outcomes for Hodgkin lymphoma, researchers identified an overexpression of genes typically expressed by macrophages in samples from patients who had experienced a relapse after treatment.  This was confirmed histologically by looking at stained tissue samples and tallying the number of macrophages – high numbers of macrophages are associated with treatment resistance in Hodgkin lymphoma.  About 25% of patients fall into this category where a biomarker test could shuttle them into a more aggressive or experimental treatment option and may prevent them from being exposed to the side effects of primary treatments that are likely to fail.  The study, led by B.C. Cancer Agency researcher Dr. Randy Gascoyne, is reported in The New England Journal of Medicine with an editorial that is touting this as the “breakthrough we have been looking for.”

Immune System Boost for HIV Patients:  A very important molecular discovery may give a boost to restoring immune function in HIV infected patients.  Renowned HIV scientist, Dr. Rafick-Pierre Sékaly, and his cross-border research teams at the Université de Montréal and Vaccine and Gene Therapy Institute of Florida identified that the protein PD-1 is up-regulated by the release of bacterial products from the gut.  Another factor, IL-10, is subsequently increased and together this is what shuts down the CD4+ T-cell immune system in HIV patients.  Therefore, the scientists suggest that new immunotherapies should aim to block PD-1 and IL-10 to help restore the debilitated immune system in HIV infected patients.  The research article appears in this week’s Nature Medicine.

Not All Viruses are Bad: The ubiquitous reovirus has oncolytic actions against different types of cancer when used as a therapeutic approach.  Now, prostate cancer may be added to the growing list of cancers, which includes ovarian, breast, pancreatic and gliomas, that may be treated with a reovirus based strategy.  In fact, the Calgary-based Oncolytics Biotech Inc. technology platform and pipeline are based on the reovirus and contributed to the prostate study.  In the prostate cancer clinical study, a viral concoction was injected into prostate cancer nodules and three weeks later, the prostates were resected.  There was evidence of cancer cell death and overall, the procedure was deemed safe with only mild side effects experienced by the patients.  The success of this pilot study should draw interest to expand the clinical trial novel treatment for prostate cancer.  Dr. Donald Morris led the research and medical team at the University of Calgary and reports the study in Cancer Research.

Having Fun with Names: This study provides more molecular and structural details than you probably need to know but I want to point out the cool protein domain name: Really Interesting New Gene or RING domain.  It is an important component of a group of proteins that regulate the potent oncogene called eIF4E (eukaryotic translation initiation factor).  The details of the Université de Montréal study are described in the Proceedings of the National Academy of Sciences.

Pump It Up: Another structural study that I want to point out because of its importance: the V-ATPase.  This is a membrane proton pump that controls the acidity of the cellular environment and can play critical roles for the cell in promoting a diseased state.  SickKids Research Instiute scientist, Dr. John Rubinstein explains “In some types of cancer, the pumps are “hijacked” to acidify the external environment of tumours, allowing the cancer to invade surrounding tissues and spread throughout the body.  The cells that take up bone minerals also use V-ATPases to dissolve bone, a process that must be limited in treating osteoporosis.”  More details on the study are found here in the Proceedings of the National Academy of Sciences.

Paradoxical Signalling Interaction: The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a well studied signaling module and its aberrant activity is implicated in a number of diseases including cancer.  It is also the target of a handful of therapeutic drugs currently under study or in trials.  However, the new study led by Dr. Deborah Anderson at the Saskatchewan Cancer Agency throws a new twist into the pathway.  Their data identifies a paradoxical interaction between the p85 regulatory subunit of PI3K and the PTEN phosphatase enzyme since these two enzymes have opposing actions.  This is certainly food for thought for researchers in this field to rethink their signalling models.  A recent news article headlines this study as the “on switch” for cancer cell growth but it is really a much more complicated puzzle than that.  The data is presented in the early edition of the Proceedings of the National Academy of Sciences.

Friday Science Review: March 5, 2010

Missing Enzyme Improves Metabolism: Mice lacking the TGH gene for the enzyme triacylglycerol hydrolase showed an unexpected dramatic improvement in their metabolic profile.  TGH is an enzyme that helps to release stored fat or triglycerides into the blood stream where it circulates to be used as an energy source or, if in excess, ends up being stored at tissue sites that do not normally store fat depots.  This contributes to cardiovascular diseases, diabetes, and liver dysfunction.  Researchers were correct in hypothesizing that deleting TGH would prevent this from happening but they were surprised to discover global metabolic benefits.  These mice not only have better lipid profiles but they also burn more fat and are also more physically active compared to mice that have the enzyme.  Additional research is required but this study demonstrates the potential of TGH as a therapeutic target for lowering blood lipid levels and likely other related benefits in humans.  The study was led Dr. Richard Lehner and his team at the University of Alberta and is published in this month’s issue of Cell Metabolism.

Gene Duplication Causes Bleeding Disorder: The genetic cause of the rare blood clotting disorder, Quebec Platelet Disorder (QPD) was recently discovered by researchers at McMaster University.  QPD is caused by a mutation involving an extra copy of the gene encoding the enzyme urokinase plasminogen activator (uPA), resulting in an overproduction of the enzyme that accelerates blood clot breakdown.  This transforms blood platelets from clot forming to clot busters.   A genetic test for the mutation, the first gene duplication mutation causing a bleeding disorder, is in development and will be an invaluable diagnostic tool.  Dr. Catherine Hayward led the discovery team and their study is published in the journal Blood.

Blocking Metabolic Genes: Prox1 is the newest player in the control of our body’s energy balance.  It binds to and inhibits two well known transcription factors for metabolic genes, estrogen-related receptor alpha (ERRalpha) and proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha).  These are significant findings along the long road to understanding the complex regulation and homeostasis of our metabolic system.  Dr. Vincent Giguère and his team at McGill University’s new Goodman Cancer Centre describe their work in the latest issue of Genes and Development.

Molecular Clues to Chemotherapy Resistance: Scientists at The Campbell Family Institute for Breast Cancer Research knocked out a specific isoform of the p73 protein family, DeltaNp73, to try to delineate the specific function of this protein.  They discovered a novel function whereby the DeltaNp73 protein targets the DNA damage site and partners with another protein, 53BP1, to block the subsequent DNA damage molecular response pathway involving p53.  This has significance in explaining chemotherapy resistance in human tumors with high levels of DeltaNp73 expression.  Dr. Tak Mak reports the study in Genes and Development.

Friday Science Review: February 26, 2010

A few medical research applications this week…

Personalized Medicine – for Lung Cancer: To develop a personalized medicine approach to treating non-small cell lung cancer (NSCLC), researchers generated a xenograft model where they implant human tumour tissue into the renal capsule of a host mouse.  As the tumour establishes itself, the mouse then becomes the platform for testing various chemotherapy regimes (cisplatin+vinorelbine; cisplatin+docetaxel; cisplatin+gemcitabine) to determine which one or combination therapy is the most effective against each of the different tumours.  They compared the results of the treatments in mice to retrospective patient outcomes and found significant correlation to consider the xenograft model a success.  Although it takes about 6-8 weeks for the results, they believe that it is quick enough to gain an insightful preliminary assessment of the potential therapeutic outcome.  Dr. Yuzhuo Wang led his team at the BC Cancer Agency and reports their work in Clinical Cancer Research.

HIV-1 Molecular Manipulations: HIV-1 infected patients exhibit a loss of CD4+ T cells, which are essential players in the defense against viral infections.  A new study reveals how the HIV-1 protein, Vpr, activates the Natural Killer (NK) cells by inducing the expression of stress-related proteins at the cell surface of CD4+ T cells.  The NK cells recognize the stress signals on CD4+ T cells and attacks and destroy these cells, leaving the patient with severely reduced CD4+ T cells.  Researchers also noticed that the continuous activation of NK cells eventually desensitizes them and they eventually lose their ability to perform their normal duties in attacking infected cells.  The molecular mechanisms of Vpr discovered in this study should help in future research leading to new therapeutic strategies.  Dr. Éric Cohen and his team at the Institut de recherches cliniques de Montréal describe their research in last week’s issue of Blood.

Protecting Your Heart: The blood pressure cuff you see in every doctor’s office can be used to limit the severity of heart attacks by triggering a molecular response in the body that protects the heart during an attack.  It is called remote ischemic preconditioning where the blood pressure cuff is used to intermittently cut off blood flow to the arm during an attack.  This triggers an innate response warning message throughout the body to release molecules to protect itself from the lack of blood flow.  In this particular study, the size of the heart attacks were reduced by 30-50% compared to control groups.  It is one of the most effective treatments and is relatively simple to administer.  Dr. Andrew Redington at The Hospital for Sick Children led the international study and is published in the The Lancet.

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.

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