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Tag Archives: McMaster University

Friday Science Review: February 25, 2011

Fusion Construct Promotes Erythropoietic Development from Human Embryonic Stem Cells

McMaster University ♦ The Ottawa Hospital ♦ British Columbia Cancer Agency

Published in Stem Cells, Feb. 15, 2011

The homeobox (Hox) genes encode a group of highly conserved transcription factors that have been known to regulate hematopoietic differentiation. As a result of their involvement in hematopoietic proliferation and lineage commitment, Hox genes have also been implicated in leukemogenesis. Researchers from Dr. Mick Bhatia’s lab have created a fusion construct that alters the hematopoietic differentiation program of human embryonic stem cells (hESCs). They chose the homeobox gene HOXA10, and partnered this with NUP98, a gene that is often found fused to Hox genes in human leukemias. After introduction of the fusion construct into undifferentiated hESCs or early-stage blood progenitors there was a marked increase in the level of erythroid progenitors founds in culture. Introduction of the construct to later-stage cells already committed to the hematopoietic lineage had no effect on the yield of erythropoietic cells. Apparently, unlike some of the fusion constructs observed in leukemias, the combination of HOXA10 and NUP98 does not lead to malignant expansion. Given the interest Dr. Bhatia and his group have in the production of blood cells, it is foreseeable that this fusion construct could be used in future differentiation protocols to bias the differentiation of hESCs towards the erythropoietic lineage.

Ubiquitination Factor E4B, A Novel Target for Brain Cancer

University of Alberta ♦ Published in Nature Medicine, Feb. 13, 2011

The tumour supressor gene TP53 and its protein product p53 are at the root of many cancers. TP53 is inactivated in 50% of human tumours. The resulting deficiency in p53 allows fledgling cancer cells to circumvent apoptotic programs and proliferate wildly. Deficiency in p53 protein may result from a mutation in the TP53 gene, or as is more frequently the case, inactivation of the p53 protein. Inactivation is often the result of ubiquitination. A specific class of enzymes in the body has the ability to add ubiquitin to proteins which marks them for degradation by other protein machinery. However, the molecular mechanisms behind inactivation of p53 in the brain remain largely understood.  Dr. Roger Leng and his team at the University of Alberta have identified a novel mechanism of inactivation in brain tumours: a ubiquitination factor (UBE4B) that directly interacts with the p53 protein destabilizing it and marking it for destruction. The factor was found to interact with an enzyme (Hdm2) that is also involved in ubiquitination. Silencing UBE4B in xenotransplanted tumours led to impaired tumour growth while over-expression of the factor was associated with amplification of its gene suggestive of a positive feedback mechanism. This discovery elucidates a potential target for treating medulloblastoma and ependymoma, two brain cancer types that exhibit inactivation of the p53 protein.

Friday Science Review: January 14, 2011

The Eukaryotic Tree of Life Expands

Dalhousie University ♦ Published in PNAS, Jan. 4, 2011

Photosynthetic marine organisms carry out roughly half of the primary production on the planet today. Tracing the lineages of these tiny creatures has helped us document eukaryotic evolution and draw conclusions on the events that led to their current distribution and the distribution of the genetic content hidden within them. A new lineage of photosynthetic algae, being referred to as rappemonads, has been discovered by Dr. John Archibald’s lab group in the Department of Biochemistry and Molecular Biology at Dalhousie University. Phylogenetic analysis using operons from plastid ribosomal DNA indicates that this new group is indeed evolutionarily distinct. Furthermore, scientists revealed that the habitat distribution of rappemonads is wide; environmental DNA sequencing in the North Atlantic, North Pacific, and at European fresh water sites suggests an extensive diversity. Although flare-ups of this new species are rare, they are believed to be able to form transient blooms. Quantitative PCR analysis was able to detect large quantities of rappemonads rRNA in the Sargasso Sea. Discoveries of this nature bring to mind the Sorcerer II expedition — launched by Craig Venter in 2004 — where researchers traveled the world’s oceans to discover new microbial species. The field of environmental genomics is in its infancy, and has the potential to help us alleviate some of our environmental issues and elucidate many aspects of biodiversity and evolution.

Novel Vaccine Delivery Formulation Protects Against Respiratory Pathogen Challenge

Institute for Biological Sciences, NRCC ♦ Published in PLoS ONE, Dec. 29, 2011

Mucosal surfaces represent an excellent opportunity for microbial pathogens to invade the body and give rise to infections. Currently many systemic vaccines targeting these pathogens fail to elicit adequate mucosal immunity in the host. It is for these reasons that Dr. Wangxue Chen and his colleagues at the NRCC are developing mucosal vaccines that specifically target these entry points. Creating long lasting and memory boostable immune responses has proven difficult with mucosal vaccines however, and they typically require an adjuvant, or delivery vehicle, to be successful.  The team at NRCC has found that intranasal immunization of mice with a cell free extract of Fransicella tularensis has much more pronounced effects when it is paired with archael lipid mucosal vaccine adjuvant and delivery (AMVAD). The technology incorporates cell free extract, from the organism against which immunity is desired, into liposomes which can then be delivered as a vaccine. Mice receiving the AMVAD/extract preparation had lower pathogen burden in the lungs and spleen, longer mean time to death, and significantly greater overall survival than mice that received just the cell free extract or naive mice receiving no vaccination.

Oxidative Stress of Surrogate Tissues Mirrors that of the Prostate

McMaster University ♦ University of Toronto ♦ Published in PLoS ONE, Dec. 28, 2011

Researchers believe that surrogate androgen regulated tissues from the same host can be used to determine the oxidative stress (OS) status of the prostate. Androgens have long been known to drive the formation of prostate cancer. Oxidative stress is regulated by androgens, so reducing OS is a key target in the prevention of prostate cancer. Using a mouse model researchers show that the level of prostatic OS is correlated with the OS of Dermal Papillary Cells, a cell type found in hair follicles, and also the salivary glands – two exocrine glands that express the androgen receptor and are morphologically similar to the prostate. Determining the OS status of the prostate and patient response to prevention strategies directly, would require taking a biopsy sample from the prostate itself. Thus, the findings of Dr. Jehonathan Pinthus and his team at McMaster University could have great implications for the non-invasive and indirect evaluation of prostate OS status and patient response to prevention strategies.

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.

Stem Cell Breakthrough: Direct Conversion of Human Skin to Blood

A breakthrough in Canadian stem cell research this week, published in Nature, as researchers led by Dr. Mick Bhatia of the Stem Cell and Cancer Research Institute at McMaster University have devised methods to differentiate human skin cells into blood cells. In many differentiation protocols researchers are forced to first reprogram cells to a pluripotent intermediate before differentiating these primitive cells into the desired cell type. The protocol developed by Dr. Bhatia utilizes a ‘trans-differentiation’ process where skin cells are turned directly into blood cells without the need for reprogramming to a primordial state. As a result, the differentiation process is not only simpler, but safer from a therapeutic standpoint. Read more of this post

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