The Cross-Border Biotech Blog

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

Category Archives: Friday Science Review

Friday Science Review: December 31, 2010

Just a couple papers to squeeze in this year before the clock strikes 12. I look forward to 2011 and the research it will bring in the Canadian realm. For those readers heading out tonight for some fun on the city, enjoy! More science reviews to come in the new year..

Porcine Adenovirus PAV3, A Novel and Promising Candidate for H5N1 Protection

National Microbiology Laboratory, Winnipeg ♦ Published in PLoS ONE, Dec. 16, 2010

Researchers have provided evidence that suggests a porcine adenovirus, PAV3, has greater vaccine efficacy than the human adenovirus AdHu5 in protecting against H5N1. An avian influenza H5N1 mouse model was used to compare immune response and protection following vaccination with the two different vectors. Mice that were vaccinated with a replication defective PAV3 vector carrying an H5N1 antigen expressed higher concentrations of neutralizing antibody post-vaccination and had stronger cellular immune responses than mice vaccinated with AdHu5. After challenging vaccinated mice with H5N1 infection, Dr. Gary Kobinger and his team demonstrated that mice inoculated with PAV3 showed higher overall survival. Another notable finding was that the porcine adenovirus did not become significantly neutralized when exposed to a pool of antibodies generated from 10,000 humans.

Study of Human Heart Microsomes Gives Insight into Cardiac CYP450s

University of Montreal ♦ Published in PLoS ONE, Dec. 14, 2010

Enzymes from the cytochrome P450 (CYP450) superfamily play an important role in drug metabolism. Variation in CYP450 isoforms can lead to inter-subject and inter-organ variability in drug metabolism, thus their study is crucial to understanding the metabolism of specific drugs. Dr. Jacques Turgeon and his colleagues at the University of Montreal gathered data on CYP450 mRNA levels in left and right ventricular samples taken from the explanted hearts of patients with end-stage heart failure. Samples were processed in the lab to extract microsomes, small vesicle-like structures composed of endoplasmic reticulum that contain large quantities of CYP450s. Among the interesting findings of this body of work is that CYP2J2 was the most abundant isoform found in cardiac tissue samples. Levels of CYP450 mRNA were similar across ischemic and non-ischemic samples and between left and right ventricles. Another principal and interesting finding was that the stereoselectivity of cardiac CYP450s was reversed compared to those in the liver. After exposing heart microsomes to the calcium channel blocker verapamil, higher levels of CYP450-dependent metabolites were observed in the presence of the R-enantiomer.

Friday Science Review: December 24, 2010

Given that the UN Climate Change Conference has just wrapped up in Mexico, I thought for the Christmas edition of the FSR I would lay out some articles from Nature focused on global warming and its impact on one of Canada’s most iconic animals — the polar bear. University of Alberta’s Andrew Derocher reports on recent findings that suggest we can curb the polar bear’s extinction, but only if policy-makers move quickly. Steven Amstrup of the Alaska Science Center created a number of greenhouse gas emission scenarios and examined them within a projection model of sea-ice loss. The results indicated that mitigation has the potential to greatly improve the polar bear’s situation in the snowy north. Amstrup believes that reducing emissions by sufficient amounts could increase the abundance of polar bears and broaden their distribution.

Melting ice also places the genetic diversity of Arctic animals at risk. A recent Nature commentary piece describes how the loss of habitat forces Arctic animals into environmental niches they would otherwise remain clear of, which can lead to interbreeding with different species. Brendan Kelly of the National Marine Mammal Laboratory in Alaska refers to this effect as a “melting pot”. In 2006, a white bear with brown patches was shot and killed by hunters in the Arctic. Genetic analysis would later show what many feared, that the animal was a hybrid between a polar bear and a grizzly (the polar bear in the photo above hasn’t been rolling in the mud, it’s a suspected hybrid). This year an even more unlikely event occurred when hunters in the Canadian north shot and killed a 2nd generation hybrid bear — its mother was a hybrid and its father a grizzly.

The outcome of the recent UN climate talks was positive, with unanimous adoption of the Cancún agreement. Developing countries will also be required to take heed to global warming policy and act to reduce greenhouse gas emissions. Steps are being made in the right direction but execution and adherence will be essential to seeing results that benefit the earth and its animal populations in the coming decades.

As we approach year end I thought I would also reference you Nature’s “2010 Gallery: Images of the year“, which provides a fascinating look at some of the natural wonders that amazed (and scared) us over last 12 months. I should also point you towards an excellent article on nanomedicine recently published in NEJM; written by Dr. Betty Kim of the Institute for Biomaterials and Biomedical Research and the Terrence Donnelly Centre for Cellular and Biomolecular Research in Toronto, the review covers the properties of nanomaterials and the myriad in vivo and  in vitro applications of these tiny tools.

Friday Science Review: December 17, 2010

I’ll begin the FSR this week with a few comments regarding some investigational work coming from the McLaughlin-Rotman Centre for Global Health.   Professors Dr. Peter Singer and Dr. Abdallah Daar, and PhD student Ken Simiyu, traveled to Africa to better understand why commercialization in the biotechnology and healthcare industry has been so poor of late.

Stagnant Technologies Need Stimulus

University of Toronto ♦ Published in Science, Dec. 10, 2010

After visiting some 23 academic institutions in six countries and interviewing 39 scientists, researchers have dug up some of the underlying issues preventing Africa’s biotechnological innovations from migrating to commercial success. Although previous studies in Africa have analyzed health innovation at the country level there has never been a systematic evaluation highlighting the troubles of specific technologies. Some of the technologies identified in the study include traditional plant products, new chemical entities, diagnostics, vaccines, and medical devices. In their travels the group came across some very interesting technologies indeed; researchers at the University of Ghana are developing a visually readable point of care diagnostic that uses monoclonal antibodies to detect the malaria parasite in urine; other work from Tanzania’s National Institute for Medical Research is being invested in the development of novel extraction techniques, specifically those to extract and purify artemisinin from the plant Artemisia annua for the preparation of derivatives to fight artemisinin resistance in malarial therapy. So why aren’t these technologies making a move towards market? A number of reasons. The mindsets of many researchers interviewed were simply not commercially oriented, with most scientists focusing on teaching and publishing to disseminate knowledge. Finding funding for validation studies of early stage technologies is another issue. African scientists need support from institutional investors but there are very few African funds in existence that support the biotechnology and healthcare space. Other issues identified by interviewees included a lack of commercially oriented government policy, poorly understood intellectual property regimes, and regulatory red tape. Peter Singer previously identified three areas that would help spur technology development in Africa: proof-of-concept funds, networks to link scientists and entrepreneurs together, and innovation centres that provide shared research infrastructure. Some have proposed establishing ‘Life Sciences Innovation Centres’ throughout Africa. These would serve a similar purpose as MaRS, here in Toronto, and the newly proposed Clerk-Maxwell Centres in the UK, with the goal of uniting researchers, industry, and entrepreneurs to accelerate commercial development of life science assets. This integrative approach is catching on, and could be the ingredient that will remedy the static nature of Africa’s commercial environment in the life sciences sector.

RD3 at the Root of Congenital Blindness

University of British Columbia ♦ Published in PNAS, Dec. 7, 2010

The protein RD3, previously of unknown function, has been implicated in the development of Leber Congenital Amaurosis Type 12 (LCA12). The disease is characterized by rapid degeneration of the photoreceptor cells during fetal development leading to blindness at birth or in the first year of life. Dr. Robert Molday and his team at the Centre for Macular Research show that RD3 interacts with two different forms of guanylate cyclase, GC1 and GC2, mediating their export from the endoplasmic reticulum. GC1 and GC2 are essential for the production of cGMP — a secondary messenger of phototransduction — and in their absence cGMP production is impaired. Dr. Molday believes that LCA12 may be caused by cGMP deficiency which leads to constitutive closure of cGMP gated calcium channels. Proper gradients of calcium across the membranes of photoreceptor cells is likely required for their long-term survival.

New Target for Chronic Pain Unveiled

University of Toronto ♦ Published in Science, Dec. 3, 2010

Synaptic plasticity is the ability of neural connections to vary in strength based on the extent of use or disuse of a neural pathway. This characteristic of the nervous system is key to the process of learning and memorizing sensory experiences, and it is also believed to play a role in pathological pain. Most researchers have focused on proteins that lead to synaptic plasticity as opposed to those that maintain synaptic plasticity over the long-term. A new study led by Dr. Min Zhuo implicates protein kinase M zeta (PKMξ) in the maintenance of chronic pain. Peripheral damage in a mouse model upregulated PKMξ in the anterior cingulate cortex, a region of the brain known to be involved in the onset of chronic pain. Zhou went on to show that microinjections of a PKMξ inhibitory peptide ZIP into the anterior cingulate cortex dampened synaptic potentiation and behavioural sensitization. This research uncovers an excellent target for chronic pain.

Friday Science Review: December 10, 2010

CD8+ Cytotoxic T-cells, Weapons of Selective Destruction

McMaster University ♦ Published in Molecular Therapy (npg), Nov. 30, 2010

Oncolytic viruses (OVs) are being investigated as a means to destroy tumour cells. They exert their cytotoxic effects either directly through infection, or indirectly, if they have been engineered to flag down cancer cells by delivering tumour-associated antigens for later destruction by cytotoxic T-cell lymphocytes. After an OV infects and bursts a cancer cell, a cascade of anti-tumour immune events is initiated. Antigens that are liberated by the destruction of cancer cells are internalized by a cell-type known as an antigen presenting cell (APC), broken down once inside, and then re-expressed on the surface of the APC. After migrating to the lymph nodes the APC ‘presents’ this protein signature to T-cells which deliver the final blow. Recognition of tumour antigens by T-cells drives the expansion of T-cell populations into cytotoxic T-lymphocytes (CTLs) and memory populations that seek out cancer cells. Upon finding cancer cells, CTLs latch on to their surface and release granules containing perforin and granzyme inducing cell breakdown. In recent work coming from the lab of Dr. Karen Mossman at McMaster University, researchers showed that a replication-defective Herpes Simplex Virus (HSV) possesses oncolytic properties in a breast cancer model. New work by this lab group stresses the importance of choosing appropriate in vitro models to study oncolytic viruses. Mossman found that the sensitivities of different cancer cell lines to in vitro oncolysis did not correlate well with in vivo oncolysis in more than one virus under study. These findings illustrate the importance of adaptive antiviral CD8+ cytotoxic T-cells in producing effective oncolytic viruses for virotherapy. Examples of such a therapies in late-stage clinical development include the OncoVEX technology being developed by BioVex for advanced melanoma and JX-594, an oncolytic virus being developed by Jennerex for the treatment of hepatocellular carcinoma.

Insulin Expression Driven by Synthetic Promoter

University of Calgary ♦ Published in Molecular Therapy (npg), Nov. 30, 2010

A step forward for gene therapy in the diabetes arena as researchers have engineered an adenovirus containing the insulin gene under the expression of a highly active and liver-specific promoter. Following IV delivery of the virus into a diabetic mouse model normal glycemia was maintained for greater than 30 days. Glucose tolerance tests also showed that diabetic mice were able to produce insulin and clear exogenous glucose from the bloodstream in a fashion similar to healthy mice. Scientists chose the liver as a target for gene therapy because hepatocytes are particularly sensitive to glucose. The strength of these preclinical findings is in part due to the promoter used to stimulate expression of the insulin DNA component. Dr. Hee-Sook Jun and his team generated a synthetic promoter library and scanned it for promoter components and arrangements that had the strongest transcriptional activity.

Friday Science Review: December 3, 2010

It’s all about microscopic machinery this week with two articles in Molecular Cell (Cell Press) and a third in Nature Cell Biology.

The MMS22L-TONSL Complex to the Rescue: A Sine Qua Non for Genome Integrity

Samuel Lunenfeld Research Institute ♦ University of Toronto

Published in Molecular Cell, November 24, 2010

In order for DNA replication to occur smoothly, a large complex of DNA polymerases and other proteins must work in harmony and navigate their way down the length of double-stranded DNA to synthesize daughter strands. This machinery, known as the ‘replisome’, frequently stumbles upon genomic glitches and other impediments that have the potential to hinder its progress. As a result, the cell has evolved a basket of mechanisms to ensure that the replisome avoids stalling and the replication fork continues to move. In a study led by Dr. Anne-Claude Gingras of the Samuel Lunenfeld Research Insitute, scientists use an RNAi screen to identify MMS22L-TONSL — a complex that appears to rescue the replisome during times of replicative stress. The newly identified complex exerts its rescue effects by interacting with single-stranded DNA (ssDNA) during end processing or in regions where the replication fork has stalled. After seeking out ssDNA MMS22L-TONSL goes to work catalyzing the repair of faulty DNA lesions, opening a path forward for the replisome.

MicroRNA Families Modulate Embryonic Messenger Transcripts

McGill University

Published in Molecular Cell, November 24, 2010

It appears microRNA (miRNA) controls expression of messenger RNA targets at the embryonic stage. These special RNA molecules originate in the nucleus, much like mRNA, but are subsequently modified by the enzyme RNaseIII and then exported to the cytoplasm. It is here that they are cleaved and manipulated into their mature form by the enzyme Dicer. After being processed miRNAs are incorporated into silencing complexes that then sort through the mRNA content of the cytoplasm, silencing specific transcripts as they go.  Dr. Thomas Duchaine and his colleagues utilized a C. elegans model to show that two embryonic miRNA families contribute to a natural RNAi process by suppressing expression of target mRNAs. The group also shows that silencing, achieved through epigenetic modification of targets, occurs in a target-specific manner with a unique modification pattern provided to each mRNA target.

Molecular Maintenance of Centromeres, GTPase Pulls the Switch

University of Montreal

Published in Nature Cell Biology, November 21, 2010

The central region of the chromosome has the responsibility of controlling chromosomal separation during cellular division. Like almost all parts of the genome, this region, known as the centromere, is subject to epigenetic regulation. The specialized H3 histone CENP-A is found exclusively at centromeres and is believed to be the epigenetic label of the region. Dr. Paul Maddox and his team at the University of Montreal have recently discovered new agents that maintain the assembly of CENP-A following its addition to the centromere region. A GTPase activating protein interacts with a CENP-A factor to recruit a number of auxiliary proteins that play an essential role in stabilizing newly added CENP-A. This stabilization process early on in the cell cycle is critical in ensuring that each new chromosome receives a sufficient quantity of CENP-A following cell division.

Friday Science Review: November 26, 2010

Ivermectin Nails Neurotransmission in Brugia malayi

McGill University

Published in PNAS, November 16, 2010

Well over 100 million people are currently infected with Brugia malayi, a microscopic nematode that causes lymphatic filariasis. Infection can eventually lead to the chronic inflammatory disease known as elephantiasis. In an effort to better understand this parasitic creature Dr. Timothy Geary and his team in the Institute of Parasitology at McGill University took a closer look at its glutamate-gated chloride channels (GluCls). These channels are localized to a very specific muscle structure surrounding an excretory vesicle in B. malayi and are essential for controlling protein release. Researchers show that ivermectin, a broad-spectrum anti-parasitic medication commonly deployed to reduce B. malayi infection, directly interferes with GluCl function preventing excretion of proteins from this excretory site. As protein excretion is known to be a very important aspect of the parasites survival system, allowing it to evade the immune system of the host it colonizes, researchers attribute the effectiveness of ivermectin to its ability to interfere with neurotransmission at GluCls. Screening for additional compounds that interact with GuCls could provide new treatment paradigms for B. malayi infection in the future.

Prion Disease: A Sticky Situation

University of Toronto ♦ University of British Columbia

Published in PNAS, November 16, 2010

Prion diseases include the infamous mad-cow disease (bovine spongiform encephalopathy), fatal familial insomnia, and the human disease ‘kuru’. The latter of these, believe it or not, being caused by human cannibalism and documented in small tribes located in Papua New Guinea that partake in strange funeral rituals following the deaths of relatives (I’ll spare you the details). These neurodegenerative diseases are often terminal and are caused by proteins, known as a prions, that have a propensity to aggregate together forming dangerous plaques that ultimately destroy neural tissue. Not all prion proteins are bad however, their behaviour depends on structural state. A switch from the α-helical conformation to the pathological β-form leads to rogue prion proteins that ‘stick’ to one another. Researchers at the University of Toronto were curious as to why animals of different sizes have different susceptibilities to prion diseases. In this study led by Dr. Avijit Chakrabartty, scientists used X-ray crystallographic structure analysis and a rabbit model to identify cellular mechanisms that explain the rabbit’s relative immunity to prion diseases. A helix-capping motif found in rabbits prevents folding of prion proteins into the pathological state. Findings like these, elucidating the underlying mechanisms driving transformation to the pathological state, should help us brainstorm future therapies for these deadly diseases.

Friday Science Review: November 19, 2010

Mobile Phones Increase Patient Adherence in HIV Clinical Study

University of Nairobi ♦ University of Manitoba ♦ University of British Columbia

Published in Lancet, November 9, 2010

Researchers recently demonstrated the effectiveness of mobile phones as a tool to bolster patient adherence to an HIV treatment regime. Better adherence to treatment reduced HIV-1 RNA load and may improve patient outcome. Patients receiving anti-retroviral therapy (ART) in Kenya were placed into one of two treatment groups. Both treatment groups received ART but only one received SMS support from healthcare workers. Clinicians sent weekly reminders to patients in the SMS intervention group, upon which they had to reply to confirm adherence within 48h. Adherence to therapy was observed in 168 of 273 patients in the SMS intervention group, and 132 of 265 in the control group, confirming that communication between healthcare workers and patients increased adherence. Suppressed viral loads were documented in 156 of 273 and 128 of 265 patients in the SMS intervention and control groups respectively, providing clear evidence that mobile phone reminders can improve outcome in patients receiving ART. Mobile phone usage is expected to be a useful mechanism to promote ART adherence in resource limiting environments, such as Africa, and is also an important measure for program cost containment. UNAIDS, the Joint United Nations Program on HIV/AIDS, is supporting the use of mobile technologies for future AIDS response.

A Molecular Circuit of Congenital Heart Disease Revealed

University of Ottawa ♦ University of Montreal

Published in PNAS, November 9, 2010

Congenital heart disease (CHD) is the primary (non-infectious) cause of death in infants within the first year of life. The incidence of CHD is now estimated to be a shocking 5% of live births, with less severe undiagnosed cases leading to increased risk of mortality, stroke, and ischemic heart disease. By elucidating a pathway contributing to congenital heart defects, researchers are now closer to grasping the causes of these developmental mishaps. Normal heart development requires differentiation, proliferation, and communication between two adjacent layers of tissue composed of endocardial and myocardial cells. The transcription factors Tbx5 and GATA4 are key players in this process, ensuring that correct myocardial patterning and chamber specification occur. In this study led by Dr. Mona Nemer of the University of Ottawa, researchers implicate Tbx5 in normal heart development by showing that its deletion in mice causes severe atrial defects. After going on the hunt for modifiers of Tbx5 they later identified the gene Nos3. Interestingly, Nos3 is known to be regulated by several factors that increase risk of congenital heart disease including stress and diabetes. These findings illustrate a direct link between environmental cues and the development of atrial defects.

Cisplatin and ING4-carrying Adenovirus Elicit Synergistic Anticancer Activity

Soochow University ♦ University of Saskatchewan

Published in Cell Gene Therapy (npg), November 5, 2010

Combinatorial approaches to the treatment of cancer have been of great interest to the scientific and medical communities as they provide a means to sensitize cancer cells to small molecule drugs. The combination of sensitizing agents and conventional chemotherapeutics has been shown to reduce tumour size more rapidly, prevent cancer cell resistance, and reduce side effects by lowering the dose of cytotoxic small molecule drugs required for therapy. In a joint study between Soochow University, China; and the University of Saskatchewan, researchers have shown that the adenoviral delivery of the tumour supressor ING4 (Ad-ING4) along with cisplatin induces synergistic growth inhibition and apoptosis in a hepatocarcinoma cell line both in vitro and in vivo. In this study researchers reported the upregulation of several protein markers associated with apoptosis and down regulation of the oncogene Bcl-2 in the presence of the Ad-ING4 vector and cisplatin. Importantly, the combination of these agents did not elicit overlapping toxicities in in vivo normal liver tissues of mice suggesting that it could have potential as a future treatment for hepatocarcinoma.

Friday Science Review: November 12, 2010

Although I already commented on the stem cell discovery that came out of McMaster earlier this week, I felt that a more detailed look at the methods section would be needed to do justice to the science. After all, the true value of this discovery is in the protocol utilized to make it.

On Fibroblasts and Blood: Just to recap, Dr. Mick Bhatia and his colleagues at McMaster University published findings in Nature earlier this week explaining how they have managed to convert human skin cells to various cellular components of blood. In order to do this they first cultured human fibroblasts in a regular mix of cell culture media atop a thin layer of extracellular matrix protein known as matrigel. By supplementing the media with two growth factors essential for early hematopoiesis, FLT3LG (FMS-like tyrosine kinase 3 Ligand) and SCF (stem cell factor), and transfecting the cells with a lentivirus carrying the stem cell gene OCT4, they were able to stimulate formation of a multipotent hematopoietic progenitor expressing the lineage marker CD45+. This cell type could then be coerced into different blood cells with the addition of a few more hematopoietic cytokines; after which Dr. Bhatia observed the formation of three distinct cell types – monocytes, granulocytes, and myeloid cells, all expressing unique lineage markers. Amazingly, the monocytes could be grown in the presence of M-CSF (macrophage-colony stimulating factor) and IL-4 (interleukin-4) to produce macrophages that actually engulfed FITC-labelled beads. To produce red blood cells, EPO (erythropoietin) had to be added during the initial step of the protocol along with FLT3LG and SCF, upon which enucleated red blood cell-like cells emerged expressing the erythroblast marker CD71. The next step is figuring out how a single efficient differentiation protocol can produce the full spectrum of blood components in one shot, which will be a challenge, but one I’m sure the team at McMaster’s Stem Cell and Cancer Research Institute are up to.

Bacterial Immune System: Some bacteria have their own micro-immune system in the form of the CRISPR/Cas locus. After bacteria are infected with viruses this immune locus takes up small pieces of viral DNA known as ‘spacer’ DNA. These provide a mode of protection by allowing the bacteria to recognize and destroy foreign viral DNA upon subsequent infections. In a recent Nature study, researchers discovered that bacteria are also able to incorporate spacer DNA from plasmids that contain antibiotic resistance genes. Bacteria that do so inadvertently lose antibiotic resistance by destroying the plasmid, and as a result, are unable to pass these genes on to other bacteria. Exploitation of the CRISPR/Cas locus could allow for the generation of safer bacterial strains with greater resistance to bacteriophages and less antibiotic resistance. This study was led by Dr. Sylvain Moineau of the Department of Biochemistry at Laval University.

A Hidden Hotspot: Scientists at the University of British Columbia have recently solved the crystal structure of the ryanodine receptor found within the endoplasmic and sarcoplasmic reticulum – cellular organelles that surround the nucleus. Mutations in the receptor, which governs the release of calcium ions in muscle cells, have led to serious cardiac and skeletal diseases in humans. Several mutation ‘hotspots’ were identified in the hidden cytoplasmic domain of the receptor, explaining why scientists were previously unable to find any. The findings of Dr. Filip Van Petegem and his team, published in Nature, will allow for the development of new methods to target abnormalities in ryanodine receptors.

Robotic Precision: A new feat from the Department of Mechanical and Industrial Engineering at the University of Toronto – single cell manipulation and patterning with a robotic system. Dr. Yu Sun and his team developed motion control algorithms and integrated this with computer ‘vision’ to allow a robot to track cells in real time, pick single cells up, and then drop them off at precise locations. The machine uses a glass pipette, similar to those used in manual manipulation of cells, and can carry out its daily job at a rate of 15 seconds per cell with a 95% success rate. The device is expected to greatly bolster the speed of single-cell studies, and should prove useful for any studies requiring fine manipulation. Find the study in PloS ONE.

Friday Science Review: November 5, 2010

A Deadly Competitor: The marine bacterium Vibrio cholerae has built-in mechanisms that may allow it to compete with other species of bacteria and better colonize its host. Researchers recently discovered a secretion system (T6SS) in V. cholerae allowing it to inject toxic substrates directly into the cytoplasm of prey. Now a group at the University of Alberta, led by Dr. Stefan Pukatzki, has shown that this strain of bacteria aggressively competes against a number of gram-negative bacteria including Escherichia coli and Salmonella and was able to reduce E. coli survival by 100,000-fold. It would be interesting to see whether the disruption of T6SS could be used as a tool to put a damper on cholera outbreaks and/or increase the time between outbreaks. Find the study published in PNAS.

Signature of Kidney Disease: The most common form of glomerular-based kidney disease is IgA nephropathy (IgAN). Roughly 40% of patients suffering from the disease will experience kidney failure in 10 years. The strongest predictor of clinical outcome in IgAN is proteinuria, or elevated levels of protein in the blood – often albumin. Researchers at the University of Toronto have identified what appears to be a genetic signature of the disease. An in vitro model of proteinuria was created by exposing primary human kidney tubular epithelial cells to high levels of albumin. Gene expression in these cells was then measured with a microarray to derive a panel of 231 “albumin-regulated genes” that were upregulated or repressed as a result of albumin exposure. Researchers then translated this to the clinic by analyzing biopsy samples from patients with IgAN. What they found is that they were able to perfectly segregate biopsy samples from control samples. Convincingly, the panel could be reduced to 11 genes and be used to distinguish any form of primary glomerulonephritis from control, suggesting that this signature could have great utility in predicting clinical outcome in glomerular-based kidney disease in the future. This study included researchers from the University of Toronto, University of Michigan, and University Hospital Zurich in Switzerland. Find it here in PLoS ONE.

Thyroid On the Move: The congenital endocrine disorder hypothyroidism results from improper differentiation, migration, or growth of thyroid tissue. In a majority of cases (~80%), incomplete migration leads to ectopic thyroid tissue. Previous studies with identical twins suggest that the disease is almost certainly caused by somatic mutations or epigenetics as in some cases there have been discordance rates of up to 92%. In a recent study published in PLoS ONE, scientists used microarray analysis to uncover 1011 genes that were either induced or repressed by a factor of 2-fold in ectopic thyroid nodules. Grouping of these genes into gene ontology groups using DAVID (Database for Annotation, Visualization, and Integrated Discovery) identified several clusters of genes related to development and organogenesis. After validating many of these genes, 19 were isolated as being exclusively related to thyroid ectopy. Genes involved in embyronic development (TXNIP) and the Wnt pathway were among those that contributed most to formation. Further work on a larger cohort of patients may allow for elucidation of the molecular mechanisms behind defective thyroid migration during early embryogenesis.

Friday Science Review: October 29, 2010

One announcement to make this week before delving into the FSR – Gordon Ramsay and a handful of well known Canadian chefs, including Toronto’s Mark McEwan, Jamie Kennedy, and Lynn Crawford, will be attending Mount Sinai Hospital on November 20th for the Chef’s Challenge. Participants must raise $2500 to attend the event and the top 50 fundraisers get to go head to head with Ramsay in a kitchen battle. Proceeds raised will go towards funding breast and ovarian cancer research at the Samuel Lunenfeld Research Institute and the Marvelle Koffler Breast Centre both of Mount Sinai Hospital. Check it out.

Oxygen Sensors Down: Preeclampsia is a serious pregnancy disorder, affecting 5-10% of all pregnancies, and results from the dysregulation of oxygen sensing mechanisms during early formation of the placenta. Ultimately, this defective development leads to hypertension and drastic increases in urinary protein that can damage the kidney and liver of women who suffer from the disorder. The Hypoxia Inducible Factor (HIF) family transcription factors have a key role in physiological response to acute and chronic hypoxia. One member of this family, HIF-1, is important for healthy placental development and is found in abnormally high concentrations in preeclamptic placental tissue. By establishing cultures of villous explants derived from human placental tissue and growing them under varying oxygen tensions, researchers at the Samuel Lunenfeld Research Institute were able to demonstrate that HIF-1 accumulation results from the diminished function of the oxygen sensing molecules PHD2, FIH, and the SIAHs. Under normal circumstances, PHD2 controls the abundance of HIF-1 by marking it for degradation. In the absence of a functional oxygen sensing mechanism, HIF-1 accumulates beyond normal levels and alters the expression of molecules necessary for proper modeling of maternal arteries at the maternal-placental interface, leading to preeclamptic symptoms. The study was led by Dr. Isabella Caniggia, and is published in PloS ONE.

Microsatellites Need Repair: In a large-scale multi-center study, published in PLoS ONE, researchers describe how single nucleotide polymorphisms contribute to colorectal cancer (CRC).  Typically CRC arises either through abnormalities in the APC/wingless signaling pathway causing somatic mutations in oncogenes (~80% of the time), or results from deficiencies in a mismatch-repair (MMR) system causing genome-wide microsatellite instability (~20% of the time). Building on their previous work which identified several single nucleotide polymorphisms (SNPs) associated with microsatellite instability-colorectal cancer (MSI-CRC), researchers have elucidated a mechanism that explains how these SNPs contribute to the onset and formation of the disease. After removing lymphocytes from the blood of patients, researchers genotyped SNPs located in a specific region of chromosome 3 surrounding the mismatch repair gene MLH1. They were then able to use logistical regression to test for the association between these SNPs and MLH1 gene expression in CRC, and DNA methylation in CRC. Results of this analysis suggest that SNPs near or in the promoter of the MLH1 gene make this segment of DNA more susceptible to methylation, which reduces its expression causing mismatch-repair deficiency and eventually genome-wide instability. This study, led by Dr. Bharati Bapat of the Samuel Lunenfeld Research Institute, included large patient samples from Ontario, Newfoundland, and the Seattle metropolitan area.

Death by Synergy: Researchers have discovered yet another way to sensitize drug resistant cancer cells to chemotherapeutics. A group at the University of Ottawa, led by Dr. Mary-Ellen Harper, has found that a molecule known as genipin can sensitize drug-resistant cancer cells (MX2) to a number of cancer fighting small molecule drugs including menadione, doxorubicin, and epirubicin. How does it do this? Drug resistant cancer cells respond to oxidative stresses by activating uncoupling protein-2 (UCP2). This protein, a component of the mitochondrial membrane, is responsible for ushering reactive oxygen species (ROS) from the cytoplasm into the matrix of the mitochondria. By activating UCP2, drug-resistant cancer cells have a way of evading oxidative damage to essential cellular macromolecules by storing these ROS in the mitochondria. Genipin happens to be an inhibitor of UCP2 and its presence increases the concentration of ROS in the cytoplasm leading to increased cell death in the presence of cytotoxic drugs. Find the study in PLoS ONE.

Friday Science Review: October 22, 2010

Some great research to touch on this week in top-notch journals including Science, Cell, and NEJM. The first publication really emphasizes the strength of collaborative research projects around the globe.

Understanding Endometriosis: Ovarian clear-cell carcinomas are less common than high-grade serous carcinomas (12% and 70% of total respectively), but still remain the second leading cause of death from ovarian cancer. It is important that the mechanisms behind the formation of this rare subtype are elucidated because it is not responsive to conventional platinum-taxane chemotherapeutic regimes that are currently the first-line treatment for ovarian cancer. In a comprehensive study published in The New England Journal of Medicine, researchers sequence the entire transcriptomes of 18 ovarian clear-cell carcinomas  and identify frequent somatic mutations in the tumor suppressor gene ARID1A (the AT-rich interactive domain 1A). ARID1A encodes the protein BAF250a which in turn is part of the chromatin remodeling complex SWI-SNF that regulates a diversity of cellular processes including DNA repair and tumor suppression. Interestingly, the mutation appears specific to the clear-cell and endometrioid subtypes. After identifying the ARID1A mutation, researchers carried out targeted re-sequencing in a mutation-validation cohort consisting of an additional 210 carcinoma samples from all subtypes. Combining the discovery cohort and validation cohort, the ARID1A mutation was found in 55 of 119 clear cell carcinomas (46%), 10 of 33 endometrioid  carcinomas (30%), but not one of 76 high-grade serous ovarian carcinomas. These findings strongly implicate ARID1A mutation in the early transformation of endometriosis into cancer and the genesis of clear-cell and endometrioid ovarian carcinomas. This exhaustive work was carried out by some 45 researchers in a dozen or so institutions found in Canada, the United States, and Australia.

Danger Signaling: Physical injury to tissue leads to cell necrosis and the release of special patterning molecules, including proteins, nucleic acids, extra-cellular matrix proteins, and various lipids as a complex milieu of chemotaxic signals. Neutrophils are able to use these unique signals to guide themselves to the site of a wound, and play an important role in recycling debris from dying cells. In a study published in Science, led by Dr. Paul Kubes of the Immunology Research Group at the University of Calgary, researchers used a mouse model of sterile injury and an in vivo imaging technique known as spinning disk confocal microscopy to observe the kinetics of eGFP-expressing neutrophils in response to thermal induced necrotic injury. Experiments revealed that necrotic cells activated a multistep hierarchy of cues that lured neutrophils to the site of danger. Another interesting finding of the study is that neutrophils appear to travel to the site of injury intravascularly as opposed to taking the most direct route through tissue. The group proposes that danger sensing and recruitment mechanisms may have evolved to prioritize intravascular travel in order to reduce the collateral damage incurred if neutrophils were to migrate directly through healthy tissue.

In Pursuit of Perfection: The fundamental limit of minimally invasive surgery is at the level of the single cell. In principal, lasers are capable of operating at this spatial resolution however efforts to achieve this have been limited by thermal and shock wave induced collateral damage to surrounding tissue. The long-held promise of a fine surgical laser has been delivered by two investigators in the Toronto research community with the creation of a novel laser source – the Picosecond IR Laser (PIRL). As a cutting modality the PIRL has a shorter pulse duration than conventional surgical lasers, vaporizing tissue on the picosecond timescale rather than burning on the nanosecond, and exploits a new cutting mechanism that selectively energizes water molecules. Researchers created full thickness wounds in CD1 mice using PIRL to demonstrate that it caused neither cavitation or any associated shock wave induced damage, and also showed that PIRL greatly reduced scar formation by comparison to conventional surgical laser or scalpel. The technology is expected to be useful in surgical procedures where scarring is particularly debilitating. Dr. Benjamin Alman, Head of the Division of Orthopedic Surgery at Sick Kids, and Dr. Dwayne Miller, in the Department of Chemistry at the University of Toronto, were co-principal investigators in this study published in PloS ONE.

At the Junction: The RAS/MAPK signaling pathway contributes to a number of important cellular processes including proliferation, differentiation, and survival. In its most basic form the pathway is regulated by the small GTPase RAS, and the three core kinases RAF, MEK, and ERK/MAPK. Like most signaling pathways, the RAS/MAPK pathway is controlled by a diversity of post-translational modifications but much less is known about regulation of its core protein components at the mRNA stage. Using a genome-wide RNAi screen in Drosophila S2 cells, researchers set out to identify other proteins involved in the pathway that could modulate MAPK protein levels. In doing so they identified the Exon Junction Complex (EJC) as a regulator of mapk transcripts. The complex is believed to contribute to the regulation of exon definition and suggests that the EJC has a key role in early regulation the RAS/MAPK pathway. This study, published in Cell, was led by Dr. Marc Therrien at the University of Montreal.


Friday Science Review: October 15, 2010

A world first

It has been almost 12 years since James Thomson published his groundbreaking paper in Science providing details on how he and his colleagues had managed to isolate embryonic stem cells from human blastocysts, and maintain them indefinitely in culture. This work provided the foundation upon which future therapies could be built. Stem cells are once again in the spotlight as we begin to transcend conventional medical therapies into unchartered waters. Earlier this week, Geron Corp. initiated the world’s first embryonic stem cell-based clinical trial in patients suffering spinal cord injury. In this phase 1 study, oligodendrocyte progenitor cells (GRNOPC1) derived from human embryonic stem cells will be investigated for their safety, and potentially for their ability to remyelinate neurons and stimulate nerve growth in the spinal column of patients.

The stem cell community is no doubt experiencing a whirlwind of conflicting emotions in the face of this progress – excitement and relief, that a new milestone in stem cell-based therapy has been reached; hope, that the patients may indeed benefit from the treatment; and fear, that the study may have arrived too early and could prove unsafe in its course. While the outcome of the study remains uncertain, what is more clear is that its results will have far reaching effects and set the tone for stem cell transplantation therapy for years to come. No doubt, the study will agitate the already heated interchange between stem cell proponents (researchers, advocates, and otherwise) and those staunchly opposed due to ethical and moral objections. It seems it may not be long before one side or the other has new material to buoy its argument.

A recently published letter in Cell Stem Cell, focusing on induced pluripotent stem (iPS) cells, discusses a transplantation approach that may help the scientific and medical communities maximize the value of early stem cell transplantation studies in humans, like that of Geron’s.

Moving iPS cells to the clinic: It has been well established in the scientific community that if induced pluripotent stem (iPS) cells are to be of therapeutic value in the clinic they must be free of any genetic factors used in the reprogramming process. If left behind, reactivation of any of these ‘stem cell’ genes could result in tumor formation following transplantation. In line with this goal, the Canadian research community was taken aback last year when Dr. Andras Nagy of Mount Sinai Hospital in Toronto managed to create human iPS cells using a jumping gene which allowed for complete excision of reprogramming factors (this was also some of the first work illustrating that iPS cells could be generated without viruses, find it here).

In a recent letter in Cell Stem Cell, James Ellis of the Ontario Human iPS Cell Facility reinforces the importance of transgene-free iPS cell lines like Nagy’s for future therapeutic use. In addition, Ellis points out that in the absence of cell tracking technology in early autologous transplantation procedures in humans we will have difficulty in knowing whether transplanted cells survive, localize to pathological sites, or exert positive or negative effects on the recipient. Gene therapy is an example of a field that would have benefited early on from basic information related to clinical outcome. An NIH review of gene therapy trials published in the mid-90’s noted that of over 100 approved clinical protocols virtually none had demonstrated definitive clinical efficacy.  To ensure that stem cell transplantation protocols do not meet the same end, Ellis proposes that transgenes be investigated for their ability to act as reporters to facilitate monitoring of therapeutic cells following transplantation. It’s only early days, but this is excellent foresight.

In other Canadian research news we find therapeutic value in natural compounds..

It’s in the skin: Studies show that a ‘Mediterranean diet’ reduces the incidence of certain age-related diseases such as heart disease, cancer, and dementia. Efforts to deconstruct this effect have put scientists on to polyphenols, a class of compounds found in abundance in Mediterranean foods with pronounced anti-oxidant and protective activity. One highly potent polyphenol, resveratrol, happens to be found in the skins of grapes (another reason to enjoy wine). Dr. Remi Quirion and his colleagues at McGill University previously showed that polyphenols bind receptors in the brain. This observation led them to believe that resveratrol may exert positive effects on the skin. Indeed, experiments revealed that resveratrol has specific binding sites in human skin tissue and is able to reduce the incidence of apoptosis in toxicity models. The molecule is currently being investigated by many groups around the globe for use in life extension, prevention of cancer, and a number of other disease-related applications.

Extracts for insulin: After scanning a library of 1319 marine invertebrate extracts using a high-throughput platform, researchers identified a number of compounds that modulate insulin and pdx1 expression in human pancreatic islet cells. In order to confirm up-regulation of relevant genes, pancreatic islet cells were transfected with a dual-reporter lentivirus containing eGFP driven by the insulin promoter and mRFP driven by the pdx1 promoter. Each compound was examined for four parameters, including insulin promoter activity, pdx1 promoter activity, nuclear morphology, and cell number. Bivittoside D was identified as a positive regulator of insulin gene expression. This study is the first example of a high-throughput, high-content, multi-parameter screen in living pancreatic beta-cells, and was led by Dr. James Johnson of the Department of Cellular and Physiological Sciences at the University of British Columbia.

Friday Science Review: October 8, 2010

This week I’ll take the opportunity to discuss a Nature Biotechnology commentary that has generated a little buzz in the health-biotech community, in addition to a recent publication in Science that is particularly impressive.

Making the Invisible “Visible”: The elucidation of protein structure is essential for our understanding of protein function. Despite having sound methods for the determination of protein structure in the native folded state, thus far it has been particularly challenging to determine the structure of transient intermediates along the protein folding pathway. Now researchers have developed a protocol combining a unique form of nuclear magnetic resonance (NMR) with chemical shift-based methodology (CS-Rosetta) allowing for structural determination of “invisible” metastable intermediates. These rare conformational states form rapidly and last only for microseconds before folding to the native state. The methodology, published in Science, can also be used for the determination of excited states crucial to function, for example enzyme catalysis and ligand bonding, and is expected to provide a wealth of data on conformational states that so far have proven highly elusive. The study was led by Dr. Lewis Kay of the Department of Molecular Genetics at the University of Toronto.

A fine balance

Peter A. Singer and Rahim Rezaie, both of the McLaughlin-Rotman Centre for Global Health at the University of Toronto, bring an interesting debate to the table in a recent Nature Biotechnology commentary:

“As health biotech enterprises in emerging economies move from imitation to innovation, will they become less relevant to local global health priorities?”

Countries such as China, India, and Brazil have played a pivotal role in supporting local and global health priorities through the production of low-cost health products. Now it seems we may begin to see more and more integration of health-biotech companies in the developing world into the global product development value-chain. The concern, however, is that a movement towards more costly innovative products and lucrative markets may lead to the neglect of poorer market segments that health-biotech firms in the developing world have traditionally focused on. Rezaie and Singer pose an eloquent question:

“..as enterprises in the emerging markets take on more costly innovative projects, would they be compelled to choose between global health and global wealth?”

A force driving integration is the exchange of service-provision arrangements between health-biotech enterprises in emerging economies and large multinational pharmaceutical companies (MNCs). For example, China’s Wuxi PharmaTech and India’s Advinus Therapeutics have entered service-provision arrangements with MNCs. The movement is further supported by an increase in collaborative development between firms in developing countries and MNCs, as they work together to produce innovative health products.

Despite the “innovative” interests of health-biotech firms in emerging economies, data suggests the priorities of global health may continue to be met. Growth in pharmaceutical markets in emerging economies has risen sharply over the last several years. India and Brazil have seen average annual growth rates of 10% in their pharma markets, and China even greater at 21%, suggesting the interests of MNCs may be shifting from developed to developing markets. Hence, the global integration of health-biotech firms operating in the developing world may in part be balanced by the evolving mindset of multinationals towards less developed markets.

Rezaie and Singer believe that the objectives of global health and global wealth can be satisfied simultaneously. Providing the proper support mechanisms are put in place, they argue, development of health products for poor market segments can be secured. An interesting instrument discussed is an orphan drug-like legislation plan for emerging economies, where the intended purpose is to incentivize products for diseases of the poor rather than diseases of low prevalence. The Global Health Accelerator platform, health funds directed at emerging economies (see NY-based Acumen Fund, Ventureast Biotechnology Fund in India, Bioveda China Fund, among others), and tactics such as public-private partnerships, advance market commitments, and patent pools to share intellectual property are also posed as mechanisms for bolstering interest and investment in global health challenges.

This article, published in Nature, is well worth a read for any interested in the evolving trajectories of the healthcare and biotech sectors, and the implications these changes will have on global health.

Friday Science Review: October 1, 2010

I am pleased to see the Friday Science Review back online, and very much look forward to contributing to the Cross-Border Biotech Blog. This week I will play a little catch up and provide details on a number of publications from the Canadian research realm spanning the last month or so. Future posts will of course focus on weekly hits. So without further delay..

Early Epigenetic Experience: Some of the earliest adverse events humans experience may occur even before we are born. Roughly 15% of mothers suffer mood disturbances while pregnant, and an increasing amount of evidence is implicating maternal depression and anxiety in the development of neurobehavioural disturbances during childhood. A reduced concentration of the neurotransmitter serotonin (5-HT) in the brain has long been associated with depression, and can be directly linked to weak expression of the transmembrane serotonin transporter 5-HTT. A study led by Dr. Tim Oberlander of the Department of Pediatrics at the University of British Columbia shows that maternal depression during the 2nd trimester is associated with a decrease in both maternal and neonatal methylation in the 5-HTT promoter region. These findings suggest that maternal mood can alter epigenetic patterns in newborns, and may to some extent “program” infant and childhood behaviour.

A Sensitive Subject: As male fertility in the human population continues to decline, researchers are pressed to investigate links between environmental factors and the development of spermatozoa. New findings implicate environmental-epigenetic modification in the regulation of two key stem cell genes involved in spermatogenesis. Using the chromatin modifying drugs tranylcypromine and trichostatin, researchers were able to show that increases in histone H3 methylation and acetylation led to activation of the genes Pou51 and Gfra1. Chemicals with chromatin modifying capabilities may be able to influence the expression of genes necessary for normal and healthy spermatogenesis, and illustrates the sensitivity of these precious cells to chemical cues in our environment. The study was led by Dr. Sarah Kimmins from the Department of Animal Science at McGill University.

One Gene, Many Proteins: The lethality of different cancer cell types is often directly related to their ability to metastasize, or move from their place of origin to distant sites in the body.  A study led by Dr. Jacek Majewski from the Department of Human Genetics at McGill University, suggests there could be an intimate relationship between alternative splicing and the metastatic abilities of breast cancer cells. Using splicing-sensitive microarray technology (Affymetrix Exon Microarrays), researchers analyzed genome-wide mRNA isoforms derived from three mouse mammary carcinoma cell lines with varying propensities to metastasize. What they found was a large  group of genes, 2623 to be exact, that underwent gene expression variations specific to metastatic characteristics. This research, published in PLoS, suggests that metastasis of breast cancer cells may be facilitated by splicing variations or splicing defects that affect a number of biological processes including cell adhesion, migration, apoptosis, and proliferation.

Biomimicry: The transcriptional and translational factor YB-1 (Y-box binding protein-1) has been known to exacerbate breast cancer by binding DNA and enhancing the expression of several genes related to drug resistance and tumour growth including EGFR and HER-2. Dr. Sandra Dunn and her colleagues in the Laboratory for Oncogenic Research at UBC recently identified a kinase, RSK, that activates YB-1 by phosphorylation allowing it to bind DNA. Their solution? A molecular decoy protein. In this recent study in PLoS, researchers design a cell permeable peptide (CPP) that mimics the activation site of YB-1, thus competing for RSK’s attention. The result was a drastic reduction in phosphorylation of YB-1 and concomitant reduction in the expression of EGFR and HER-2. The beauty of this approach is that YB-1 has been broadly implicated in cancers including those of the bone, lung, colon, and brain. The findings also give hope to patients with the most aggressive form of breast cancer that fail to respond to other therapeutics such as trastuzumab; the decoy protein was found to reduce growth in a dose-dependent manner in an incurable model of breast cancer (triple-negative, HER-2+).

Cross-Border Biotech Blog News: Favourite Features Returning With New Authors

I’m excited to announce that the Monday Biotech Deal Review and the Friday Science Review will be back next week to restart your regular dosing of Canada’s Biotech inventions and transactions.

The Monday Deal Review will be authored by Jacob Cawker, who has worked with me on the blog in various capacities over the past three years. Jake recently joined Ogilvy Renault LLP as an associate in the Business Law group, and will be part of our Life Sciences transactional team.  He has an Honours Bachelor of Science from the University of Toronto at Mississauga with a specialist in Psychology and a particular interest in neuroscience, and he worked in a behaviour genetics lab at the University of Toronto before entering law school at Osgoode Hall University.

The Friday Science Review will be authored by Mark Curtis, who recently left scientific research to pursue various consulting positions in the biotechnology sector. He has frequently worked as a consultant to Bloom Burton & Co., a boutique investment bank in Toronto that focuses exclusively on the biotechnology and healthcare industries. Prior to this he carried out research at the Ontario Cancer Institute where he focused on cellular reprogramming of human cells. Mark completed a Master’s degree in Biotechnology, with a specialization in stem cell biology, at the University of New South Wales in Sydney, Australia.

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.

Bookmark and Share

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.

Bookmark and Share

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.

Follow

Get every new post delivered to your Inbox.

Join 130 other followers