January 7, 2011
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Symmetry Saves the Day
University of Toronto ♦ Published in Stem Cells, Dec. 29, 2010
One of the hallmarks of stem cells is their ability to maintain the stem cell pool indefinitely through the process of asymmetric division. When they divide they give rise to one slightly more differentiated cell and one daughter stem cell identical to the original. By carrying out cell division in this manner, stem cell populations, at least in theory, are capable of living indefinitely. David Piccin and Cindi Morshead — researchers at the Donnelly Centre for Cellular and Biomolecular Research — discovered that the Wnt (pronounced ‘wint’) signaling pathway is involved in damage response in neural stem cells found in the brain. Using a mouse model Piccin and Morshead show that when neural stem cells sense it is time to replenish the stem cell population, for example during the period following a stroke, Wnt signaling contributes to a signaling cascade that promotes symmetric division. When stem cells divide symmetrically they produce two identical daughter stem cells rather than one daughter stem cell and a differentiated progenitor, ensuring that the stem cell pool does not become depleted.
H5N1 Vaccine Derived from Tobacco Plants Shows Results in the Clinic
Medicago Inc. ♦ Published in PLoS ONE, Dec. 22, 2010
Egg-based vaccine manufacturing failed to live up to its promise of rapidly producing large quantities of live vaccine for control of viral outbreaks. During the recent H1N1 influenza pandemic only 3 million doses of live vaccine had been produced by the 5 month mark, when 60 million had been expected. Canadian biotechnology company Medicago Inc. has come up with an all together different approach that could make fast and efficient vaccine production a reality — a plant-based manufacturing technology that produces influenza vaccines using Nicotiana benthamiana. At the core of the vaccine technology is something known as a “Virus-Like Particle” (VLP). VLPs are small entities containing the hemagglutinin protein of H5N1, and are produced by infecting tobacco plants with an Agrobacterium inoculum containing an H5 expression cassette. VLPs are then harvested from the aerial portions of the plant. Although a VLP resembles a viral particle, it lacks the genetic content within, thus is replication defective and non-infectious. Another aspect differentiating Medicago’s approach is that the technology only requires the genetic sequence of the virus, not an actual sample, as is the case with technologies using inactivated virus in vaccines. In a preclinical study led by Medicago’s Dr. Louis Vezina, researchers show that a VLP vaccine could induce cross-reactive antibodies in ferrets. After challenging the animals with lethal doses of H5N1 researchers observed reduced pathology and suppressed viral loads in vaccinated animals. The paper also reports on clinical results: a phase 1 trial of the H5 VLP vaccine in healthy adults between the ages of 18 and 60 revealed that the plant-derived vaccine was tolerated well at all doses and had strong immunogenicity as detected by microneutralization assays. These results taken together hold promise for Medicago’s plant-based manufacturing technology. Another plus? The vaccine can be produced in 3 weeks of sequence release! This is no doubt why DARPA made a non-repayable contribution of $21 million to Medicago back in August to build a 90,000 square foot cGMP facility in North Carolina for VLP vaccine production.
December 31, 2010
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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.