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Category Archives: Mark Curtis

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.

Regenerative Medicine Takes Off: En Route to Reality?

A month or so after Geron Corp. initiated the world’s first embryonic stem cell-based clinical trial, UK-based ReNeuron has announced that it has treated its first stroke patient with expanded populations of neural stem cells at the Institute of Neurological Sciences, Southern General Hospital, in Glasgow. The PISCES (Pilot Investigation of Stem Cells in Stroke) study is the first stem cell-based clinical trial to be given the go-ahead by the UK government. ReNeuron’s phase 1 study of ReN001 will involve transplanting neural stem cells into the brains of patients that have been left disabled by stroke. Assessing the safety of the implantation technique will be top priority in the study, however ReNeuron hopes to collect at least some preliminary efficacy data. Patients will be watched closely for two years following surgery, after which a longer-term monitoring process will begin. Contingent on a positive safety review of the first patient in December, a larger cohort of patients will be treated shortly thereafter. Keith Muir, the principal investigator overlooking the trial said:

“We are pleased that the first patient in the PISCES trial has undergone surgery successfully. Stroke is a common and serious condition that leaves a large number of people with significant disability. In this trial, we are seeking to establish the safety and feasibility of stem cell implantation, which will require careful follow-up of the patients who take part. We hope that in future it will lead on to larger studies to determine the effects of stem cells on the disabilities that result from stroke.”

There are three typical treatment modalities for stroke: prevention, acute-phase stroke treatment, and post-stroke rehabilitation. It is the final of these that ReNeuron aims to provide with ReN001 treatment. Contrary to Geron’s oligodendrocyte progenitors being used to treat spinal cord injury, ReNeuron’s ReN001 therapeutic cells are generated from adult sources. Neural stem cells are selected from human tissue samples and expanded in vitro under cGMP manufacturing standards. ReNeuron has also developed quality control measures to select cells that have the proper phenotype, the ability to expand rapidly, and a propensity to engraft well with little immune rejection.

On our side of the ocean California-based StemCells Inc. has filed for Swiss regulatory approval to begin testing its neural stem cells in patients with non-acute spinal cord injury. This contrasts Geron’s approach in its ongoing study which is directed at acute-phase injury. A comparison of these clinical approaches down the line should yield useful information as to when stem cell-based biological intervention is most helpful to patients with spinal cord injury. Massachusetts-based Advanced Cell Technology (ACT) has also announced FDA approval of the world’s second embryonic stem cell-based clinical trial in patients suffering from Stargardt’s Macular Degeneration. The disease, characterized by degeneration of the retinal pigment epithelium, manifests itself early on in life. Twelve patients are expected to participate in the study where retinal pigment epithelial (RPE) cells derived from embryonic stem cells will be transplanted into the  eye. The FDA has granted ACT’s RPE cells orphan status. As a result, the technology will be eligible for accelerated FDA approval and ACT may receive grant money from the government to fund clinical trials.

UK Invests £200M In Technology Innovation Centres, Goes with Fraunhofer Model

Prime Minister David Cameron recently made an announcement outlining the UK government’s plan to allocate £200M for the development of a series of technology innovation centres. They will be designed around the Fraunhofer model implemented in Germany with the vision of creating a multitude of specialized incubators each with a unique technological interest. The announcement comes after an address made by former UK business secretary Peter Mandelson to the Work Foundation earlier this year. In this address Mandelson made it clear that deficit reduction would not only require spending cuts, but would necessitate new modes of spurring economic growth. A top priority was a comprehensive evaluation of technology innovation in the UK. Mandelson pointed out that a “basic skeleton of an industrial innovation system” had been established in the UK, but it would need to be bulked up to increase competitiveness on the international stage and further encourage external collaboration with UK health research centres. Mandelson stated:

“Our challenge now is to build and consolidate that innovation landscape into something like the Fraunhofer network in Germany which actively connects industry and the German research base. With this objective in mind I have asked technology entrepreneur Hermann Hauser to undertake an urgent but systematic evaluation of the UK’s existing innovation network to see how Britain can best emulate the outcomes of the Fraunhofer model.”

Hermann Hauser founded the tech company Acorn Computers (broken into several operations in 1998) and is a partner with the venture capital firm Amadeus Capital Partners. It was Hauser’s recommendation to Mandelson to establish intermediate technology innovation centers in the UK similar to those in Germany. The Fraunhofer-Gesellschaft was founded after the Second World War to bring industry and research in Germany closer together to drive economic growth. Institutions within the Fraunhofer network have traditionally focused on the applied sciences but have also incorporated basic sciences into their agenda, including many areas of biology. There are well over 60 centres in Germany and seven in the United States (Fraunhofer USA) with a diversity of specializations spanning everything from manufacturing technology and advanced materials to marine biotechnology and experimental medicine.

The proposed institutions, tentatively being branded as Clerk Maxwell Centres, will encourage intensive collaboration between academia, industry, and the National Health Service (NHS), and act as translational channels to bring university-level innovations through to market. They will also act as staging grounds for start-ups providing access to equipment, lab space, and supportive expertise that would otherwise be prohibitively expensive to obtain. Another key responsibility will be disseminating information related to funding sources to ensure that industry is aware of all its options in trying to secure funding for early development.

In many ways the centres will be to the UK what MaRS Innovation is to Toronto – with a fundamental mandate of nurturing early stage innovations and guiding them forward to commercial exploitation. The primary differences, of course, being the subdivision of technological interests and national scope in the case of the Fraunhofer model. Hauser foresees a small handful of centres being developed at first, each costing in the vicinity of £50M – £100M over 10 years, and proposes that the UK leverages strengths it already has. Given the depth of stem cell research underway in Britain, an obvious choice for the first Clerk Maxwell Centre is regenerative medicine. As Hauser put it:

“It’s obvious that something exciting is happening in regenerative medicine; we produce more quality stem-cell papers than anywhere else in the world and it has the potential to completely restructure the pharma industry.”

One-third of funding for Clerk Maxwell Centres will come from industry, so the focus of these institutions will have to align with industry interests. Additional funding will come from government and be dispersed over the coming four years. A Technology Strategy Board will then decide how to stream the funds into businesses and research projects at each centre. With each Clerk Maxwell Centre focusing exclusively on one (bio)technological area, companies in industry will have the opportunity to associate with institutions that are more closely tailored to their requirements than would be a general technology hub. By the nature of the model, research and industry will be united, accelerating the commercialization process in select technological areas.

In a similar initiative designed to foster public-private relationships, the UK government plans to support a “UK Life Sciences Super Cluster” with the introduction of a Therapeutic Capability Clusters program. In July of 2009 the UK government published the Life Sciences Blueprint, an expansive document outlining a novel approach to collaboration in the life sciences industry. The integrated approach outlined in the blueprint is expected to generate the critical mass required to develop new therapeutics and “support economic growth and strong healthcare delivery”. It was from this overarching plan that the therapeutic clusters program was born.

Like the new technology centres, each therapeutic cluster in the program will have a discrete specialization. They will be composed of centres of excellence with complementary capabilities, enabling technologies, and commercial goals. Importantly, the formation of clusters will provide a single point of contact for industry through collective organization of cluster activities at one interface. The first two pilot projects, announced by UK Science Minister David Willetts on October 25th (follow link to his speech), will be a cluster for inflammatory respiratory diseases, and another for joint and related inflammatory diseases. Initially, the focus will be on translational medicine, particularly early stage clinical trials where industry has historically had strong interest in collaborating with academia. The fate of the program will be dependent on the success of these initial projects, but if they are successful, and the UK government decides to give the greenlight, it could be the world’s first large scale effort to set up clusters of this nature.

The UK’s drive for self-improvement is impressive. At the end of the day the described technology innovation centres and therapeutic capability clusters come down to public-private relationship building and a trend towards full integration to support commercialization and economic growth. With the proper execution and allocation of funds, these initiatives have the potential to profoundly impact innovation in the UK and reaffirm Britain’s role as a fierce competitor in life sciences innovation.

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.

Approval Pathway for Biosimilars and Interchangeable Biological Products: Issues from the FDA’s Public Hearing

On November 2nd and 3rd the FDA held a public hearing to address the challenges it will face in the implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). This act established an abbreviated pathway for follow-on biologics (a.k.a. biosimilars) that are either “highly similar” or “interchangeable” with previously approved biologics. Many industry stakeholders were in attendance to voice their opinion on the matter including Pfizer, Roche, Merck, Novo Nordisk, Novartis, Amgen, Shire, and TEVA, amongst others. I tuned into these webcasts to extract the salient areas of debate. Read more of this post

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

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.

Technology Transfer at Canadian Universities

The technology transfer office (TTO) lies at the interface between university researchers and the university’s external environment, including industry and government. The presumed role of the TTO has been to mobilize knowledge and foster research relationships between academia and industry, and in doing so support the commercialization agenda of the university by monetizing its innovations and technological assets. It is becoming more and more evident, however, that there is a misalignment in the expectations that the government has of the TTO and the role that the TTO actually fulfills.

Read more of this post

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:

“ 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.


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