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Tag Archives: SickKids

Friday Science Review: February 11, 2011

Cardiac Differentiation: A Customized Approach

McEwen Centre for Regenerative Medicine ♦ University of Toronto ♦ SickKids

Published in Cell Stem Cell, Feb. 4, 2011

Dr. Gordon Keller of the McEwen Centre for Regenerative Medicine has been a pioneer in the stem cell world and was the first researcher to produce functioning cardiomyocytes from embyronic stem cells. These cells form clusters in the petri-dish that beat in unison, a rather marvelous sight to behold. The efficient differentiation of embryonic stem cells to cardiac cells requires monitoring the very earliest stages of their development. Monitoring the expression of one gene, Flk-1, has been instrumental in recognizing the formation of cardiac mesoderm, an early step in the developmental path of cardiomyocytes. A problem that remains however, is that Flk-1 is expressed in different forms of mesoderm, not all of which lead to the cardiac lineage. A second gene, PdgfR-α, can be used to separate cardiac and hematopoietic lineages when monitored in conjunction with Flk-1. Fractions of differentiating cells that coexpress the two genes have greater cardiomyocyte potential. Keller’s lab group used these two genes to study the stage-specific effects that Activin/Nodal and BMP signaling have on the development of cardiomyoctyes. They found that very small changes in the amount of Activin/Nodal or BMP had profound effects on the proportion of Flk-1+/PdgfR-α+ cells that appeared early on in the differentiation protocol, and that optimization of these concentrations in cultures of human pluripotent stem cells could give rise to structures that contain more than 50% Flk-1+/PdgfR-α+ cells. A major finding by Keller’s team is that different mouse and human pluripotent stem cell lines required unique optimization to produce maximal results, stressing the importance of using differentiation protocols that are in effect customized to individual pluripotent stem cell lines.

β-Catenin Maintains Pluripotency of Stem Cells with Two Divergent Signaling Cascades

Stem Cell and Cancer Research Institute ♦ McMaster University ♦ University of Guelph

Published in Cell Stem Cell, Feb. 4, 2011

It is widely assumed that β-catenin, a key molecule in the Wnt/β-catenin signaling pathway, helps sustain pluripotency through its interaction with TCL/LEF transcription factors. However, recent research shows that β-catenin also promotes pluripotency by complexing with and stabilizing Oct-4, a key member of the transcriptional network that maintains the pluripotent nature of stem cells. Glycogen synthase kinase-3 (GSK-3) has emerged as an important regulatory of pluripotency, in part because β-catenin is one of its primary substrates. After GSK-3 phosphorylates β-catenin it is degraded, which encourages stem cells to exit the pluripotent state and differentiate to other cell types. Dr. Bradley Doble and his colleagues previously showed that mouse embryonic stem cells (mESCs) that are entirely deficient in GSK-3 express very high levels of β-catenin and exhibit a severe impairment in their capacity to differentiate into the three germ layers. In this recent work, Doble and his team hypothesized that hyperactivated β-catenin/TCF was responsible for the pluripotent “lock” that was imposed on mESCs lacking GSK-3 expression. To the surprise of researchers, GSK-3α/β double knock out mESCs still maintained pluripotency even when they stably expressed a dominant negative form of the TCF transcription factor. How were they doing this? Apparently β-catenin can maintain pluripotency independent of functioning TCF. Researchers showed that β-catenin promotes the maintenance of pluripotency by interacting with Oct-4 in a divergent signaling cascade.

Next Generation Gene Therapy for Hemophilia A: Pre-clinical Progress

Queen’s University ♦ Published in Molecular Therapy, Feb. 1, 2011

Researchers pursuing therapies for Hemophilia A have turned to gene therapy for answers but have struggled to provide convincing pre-clinical results. Patients with the disorder have vastly decreased plasma concentrations of FVIII, a clotting factor that prevents blood loss after injury. Although viral vectors can produce the protein following system injection into animal models, its efficacy is compromised by the introduction of neutralizing anti-FVIII antibodies. Researchers hypothesized that the development of neutralizing antibodies was the result of transgene expression in the antigen presenting cells of mice. The solution to this problem was to “hide” the transgene by placing it under the control of a liver-specific promoter. This approach worked in normal mice, however researchers studying mice with hemophilia B still found that an anti-FVIII immune response was mounted in the presence of the new tissue-specific promoter. As a second layer of defense against this response researchers incorporated target sequences into the transgenic construct that had perfect complementarity to hematopoietic-specific miRNA sequences. These target sequences led to suppression of the transgene specifically in hematopoietic cells, including antigen expressing cells, limiting the neutralizing response. Dr. David Lillicrap and his team at Queen’s University have now used a similar approach to produce some very promising results in a mouse model of hemophilia A. A combination of a liver-restricted promoter, a miRNA regulated FVIII transgene, and a pseudotyped viral envelope seemed to do the trick.

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.

Monday Biotech Deal Review: March 22, 2010

Bought deals are all the rage this week, with BioExx and Osta Biotechnologies both heading in that direction.  Also, everywhere we look, warrants are being exercised and debentures are being converted. We even noted the green shoots of a new Canadian listed biotech company poking through the ground via a CPC transaction.  Is there a Spring thaw in Canada’s biotech capital markets?  Read more of this post

Trends Update — Social Media: Upopolis Keeps SickKids’ Patients Connected

One of the fantastic uses for social media in healthcare (a trend we will be following this coming year) is to connect communities of patients to each other and to their friends and families when those connections would be difficult to make or maintain IRL (in real life). 

The Hospital for Sick Children (SickKids) in Toronto started up an initiative to do just that, with the added twist that it’s built entirely for young patients.  It offers  personal profiles, personal blogs, instant chat and child-friendly games, and as spokesperson/nephrotic syndrome patient Zachary Starkman says:

“When I’m here for long periods and I’m not able to get to Marnie’s Lounge (the patient recreation room at SickKids) and chat with my friends, I feel isolated, lonely… This will really help me feel connected with everyone.”

The SickKids network is called/run by Upopolis.  It was founded by Christina Papaevangelou, who watched the struggles of her friend Katy McDonald when she was treated for cancer in 2002.  The network was developed by Kids’ Health Links Foundation, in partnership with TELUS and McMaster Children’s Hospital and runs as a SaaS solution hosted by TELUS.

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Friday Science Review: October 9, 2009

Breast cancer, genomics and two cover stories in prestigious journals…

Cancer Evolution and Progression:  Scientists at the BC Cancer Agency have sequenced and compared the entire cancer genome of a metastatic tumour versus the primary breast tumour that originated nine years earlier.  They used next generation DNA sequencing technology to reveal 32 mutations in the metastatic cancer but surprisingly only five of these were present in the original tumour.  Six mutations were present at lower frequencies in the primary tumour, 19 were not detected and 2 were undetermined.  These differences may provide clues about how cancer becomes resistant to therapy or how a tumour switches to aggressive metastasis that spreads to other sites in the body.  The study demonstrated that cancers evolve and that there may be significant heterogeneity within the tumours.  These findings emphasize the importance of ongoing research efforts to sequence all cancer genomes and buttress arguments in favour of personalized medicine.

The study was lead by Dr. Samuel Aparicio at the BC Cancer Agency and appears as the cover story in the latest edition of Nature.

Honey, I shrunk the lab: The “lab-on-a-chip” concept has been in use for a number of years but Dr. Aaron Wheeler’s Microfluidics Laboratory at the University of Toronto has designed a new module for use in breast cancer detection and care.  The hand-held sized device can extract and quantify estrogen in a very small sample size – as little as a 1 microliter sample of tissue or blood – by using electrical charges to move liquids around in a precise manner over a microchip.  Current methods require a much larger sample, about the size of a penny, which is often impractical to obtain.  Since elevated estrogen levels are associated with breast cancer risk and pathogenesis, this new device could be used at point-of-care to screen at-risk patients or to monitor therapies and provide results within minutes instead of days.

Dr. Wheeler collaborated with Dr. Robert Casper (University of Toronto and Samuel Lunenfeld Research Institute) on this project, which garnered the inaugural cover story in the new journal, Science Translational Medicine.

Genome Map Upgrade: Researchers have generated a comprehensive structural map of the human genome in identifying and marking regions that are duplicated or deleted, the so-called copy number variation (CNV).  Genetic variation is what makes us different and certain areas of the genome reflect these differences whereas other genetic regions show very little variation and are likely essential function genes.  It also provides important clues to understanding evolution and provides the foundation for future research in developing personalized medicine.   The international study was co-lead by Dr. Stephen Scherer at The Centre for Applied Genomics (Hospital for Sick Children, Toronto) and provides the following comments:

“The scale of this current project is 100 times the scale of all others.”

“Previous work in this field would be like a paper fold-up map; this advancement is like a GPS that takes you where you need to go. It allows you to navigate the landscape of the genome, from its peaks where there is vast genetic variation, to its valleys devoid of it.”

“Variation is indeed the spice of life and we now know that nature buffers this variation by using CNVs. We are harnessing this knowledge to fight disease.”

Dr. Scherer is also involved in maintaining the Database of Genomic Variants, which provides researchers around the world access to a curated catalog of CNVs.  Details of the research report appear in the advanced on-line edition of Nature.

Congratulations to McGill University alumni Jack Szostak and Willard Boyle for winning the 2009 Nobel Prize in their respective disciplines.

Dr. Jack Szostak started at McGill when he was 15 years old and graduated in 1972, specializing in cell biology.  This was the start of a brilliant research career where he co-discovered how telomeres and telomerase protects chromosomes from losing genetic material during cell division.  He shares the 2009 Nobel Prize for Medicine.

Dr. Willard Boyle completed his BSc (1947), MSc (1948) and PhD (1950) from McGill.   He shares the Nobel Prize for Physics for the 1969 co-invention of the charged-couple device (CCD) that is used in today’s digital photography technology.

Monday Biotech Deal Review: September 28, 2009

B&W_BigNickelLots of deal news this week, including the Canadian action noted at the time: the iCo-CPDD deal and ethica’s in-license transaction.  Plus there was plenty of international excitement today (repentance notwithstanding) with Abbott’s $6.6 billion Solvay play and J&J’s new 18% stake in Crucell.  Keep reading for a securities-palooza and plenty more after the jump…

Friday Science Review: July 31, 2009

My first post… a two week round-up.

New direction for treating obesity:  A study headed by Dr. Hans-Michael Dosch’s group at The Hostpital for Sick Children in Toronto demonstrated that killer T cells in visceral fat are activated to destroy fat cells and control insulin resistance.  With increasing weight gain, however, the killer T cells become overwhelmed as fat cells grow and inflammatory T cells move in.  Although these studies were performed in mice, it appears that humans also have a similar system in place.  The good news is that treatment with an anti-CD3 drug can give the immune system a boost and help reduce inflammatory T cells.  Even better news is that this drug is already in clinical use to protect against organ rejection, which means clinical trials to combat obesity may start as early as next year.  The article was published on-line this week in Nature Medicine.

Cool headed Toucan.  After decades of speculation over the purpose of the toucan’s over-sized beak – from sexual ornament to feeding purposes – researchers at Brock University in Ontario, in collaboration with scientists in Brazil, published an article in Science showing that the toucan’s beak acts as a highly efficient cooling unit.  They have the greatest beak-to-body size ratio and use this large surface area as a heat exchanger (akin to elephants’ ears) to regulate body temperature by modifying blood flow.  If only we had a ‘heat wave’ problem this summer…

Setback in Huntington’s Disease research.  A decade long study concluding with disappointing results was reported in PNAS this week.  Researchers at Laval University and University of South Florida analyzed the brains of HD patients who had undergone neural transplantations about ten years ago as a potential treatment.  Although there were mild clinical benefits, the grafts were short-lived and also had undergone disease-like degeneration.

Barcoding Nemo. As part of the International Barcode of Life Project to identify all plants and animals based on signature DNA sequences, spear-headed by Paul Herbert at the University of Guelph, the ornamental fish was added to the list.  Accurate identification of ornamental fish is important for establishing regulations, conservation practices and tracking origins.  The DNA barcode reference for these fish is based on the cytochrome c oxidase subunit I (COI) gene where 98% of the fish have distinct barcode clusters.  The article was published in PLoS One last week.

Funny etiology: two curious New York high schoolers initiated the project and recruited the Guelph lab, sparking headlines last summer when they discovered that some sushi restaurants were mislabeling cheaper fish as more expensive types.

Other DNA barcoding projects include other fish, butterflies, and birds.  To find out more, visit the Canadian Centre for DNA Barcoding or the International Barcode of Life Project (iBOL).

Friday Science Review: Sunday Edition

ErlenmeyersHello, loyal readers.  Welcome to the Sunday Edition of the Friday Science Review.  Sorry for the delay … turns out my day job is sometimes a day and night and next day and next night job.  Anyway, this one’s worth the wait.  Lots of cool science on a cool Spring weekend here in Canada after the jump…

Friday Science Review: March 13, 2009

Training Brains:  Sheena Josselyn’s lab at SickKids specifically erased a fear memory in mice by selectively ablating CREB neurons using an inducible diptheria toxin.  Let me break this down, because it’s so unbelievably cool: 

  • they trained mice to be afraid of a sound,
  • then they destroyed some specific cells in the brains of the mice,
  • then the mice forgot that they were afraid of the sound.

The mice were subsequently able to learn new things, like how to find cheese in a maze, and were even able to learn to be afraid of the same sound again.  Between this and the mind-reading experiment in the UK this week, it’s enough to give you a serious bout of insomnia … which often lasts over a year, according to researchers at Laval.

Gout Rout: Dr. Hyon Choi and colleagues at the University of British Columbia reported in Monday’s issue of the Archives of Internal Medicine, that Vitamin C appeared to lower the levels of uric acid in the blood, and that men who take in more vitamin C appear to be less likely to develop gout, a painful type of arthritis.

Beef Relief: Researchers using Bioniche’s E. coli O157 vaccine, Econiche™, published a study in Foodborne Pathogens and Disease showing that vaccinated cattle were 92% less likely to be colonized with E. coli O157:H7 than non-vaccinated cattle (odds ratio (OR)=0.07, p=0.0008). This is the second published study demonstrating more than 90% effectiveness of the Bioniche vaccine against colonization.

Anti-cancer Advancers:

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Friday Science Review: March 6, 2009

Cool Canadian science stories this week…

Stem Cells: The big Canadian science news this week was the report by Dr. Nagy’s lab at the Lunenfeld that they have found a much safer way to make pluripotent stem cells from adult tissue.  Their publication (co-authored with Keisuke Kaji’s team at the University of Edinburgh) appeared in Nature this week.

Also on the stem cell front, Dr. Kremer, the co-director of the Musculoskeletal Axis of the Research Institute of the McGill University Health Centre, used Interferon gamma to induce the differentiation of mesenchymal stem cells into osteoblasts in vitro, and that IFNγ knockout mice also show reduced bone density and that isolated mesenchymal stem cells from the knockout mice show a differentiation defect.  Long story short: a potential new target for improving bone density.

Clinical Trials: Good news for GSK and for scientists at McMaster University, who showed that GSK’s Mepolizumab (pdf), an anti-IL5 humanized antibody that blocks eosinophil production, helps severe asthmatics improve asthma and reduce their need for prednisone by close to 90 per cent, a result that was seconded by a group in the UK.

Nanotechnology Costs: We noted a few weeks ago that there were changes coming to nanotechnology regulatory environment, and now researchers in BC and Minnessota estimate that testing the toxicity of existing nanomaterials in the United States could cost between $249 million and $1.18 billion and that full-scale testing could take decades to complete. They propose a tiered approach, similar to the EU’s REACH program for testing toxic chemicals, to define priorities.  Hat tip to ScienceInsider.

Hosted Services: Canadians, being hospitable types, are hosting World Diabetes Congress in Montreal in October, as well as a new Occupational Cancer Research Centre – charged with “improving knowledge and evidence to help identify, prevent and ultimately eliminate exposures to cancer-causing substances in the workplace.”

Musical Chairs: A group at Ryerson University’s centre for learning technologies in conjunction with the science of music, auditory research and technology (SMART) lab have developed a chair that allows the hearing-impaired to experience music by using the skin as a hearing membrane. 

Global Issues: An Amazon drought caused a major release of carbon dioxide; but don’t worry, because we’ll find a new planet in no time.  Sound painful? Don’t worry – a spoonful of sugar really does help the medicine go down.

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Friday Science Review: February 27, 2009

Cool Canadian science developments this week:

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Friday Science Review: February 20, 2009

Cool Canadian science stories this week…

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Friday Science Review: February 13, 2009

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