The Cross-Border Biotech Blog

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

Tag Archives: University of British Columbia

Monday Biotech Deal Review: April 4, 2011

Welcome to your Monday Biotech Deal Review for April 4, 2011.  Valeant was a major headline last week with its hostile $5.7 billion leveraged-buyout offer for Cephalon, Inc., which some are suggesting may herald a new era of M&A activity in the biotech sector (you’ll recall that Valeant itself is the product of the recent merger with biotech heavyweight Biovail Corporation).   In addition, CCAA-protected Angiotech has filed a second amended and restated plan of compromise or arrangement and has made amendments to its support agreements, which plan is scheduled to be voted by creditors this week.  Last week continued the previous weeks’ pick-up in financing, with some newly announced and closed private placements.  And to top it off there were also a number of interesting commercial and licensing transactions.  Read on to learn more.   Read more of this post

Monday Biotech Deal Review: March 21, 2011

Welcome to your Monday Biotech Deal Review for March 21, 2011.  There was some interesting investment and commercial transactions announced and closed last week, including the $15M private placement announced by Novadaq, the $4M bond financing closed by SemBioSys and Pacgen’s announcement of a corporate makeover to accommodate its recent investments in the products of General Biologicals Corporation.  Read on to learn more.  Read more of this post

Friday Science Review: March 11, 2011

Insulin + Pancreatic Stem Cells, Proof of Life

University of Toronto ♦ Published in Cell Stem Cell, Mar. 4, 2011

The origin of insulin-producing pancreatic β-cells has been a matter of contentious debate. Some research groups have produced findings that would suggest β-cells duplicate themselves and that new β-cells do not arise from the differentiation of a more primitive pancreatic progenitor. Other groups have proven the existence of pancreas-derived multipotent progenitors (PMPs) that are capable of giving rise to a spectrum of cells from both the pancreatic and neural lineage. So where do β-cells come from?

New results from the lab of Dr. Derek van der Kooy point in the direction of PMPs. Lineage labeling experiments in mice showed that PMPs originate from the embryonic pancreas, as opposed to the neural crest, which has often been cited as the source of pancreatic progenitors. These findings are in conflict with previous studies which could not provide evidence of pancreatic progenitors in the developing embryo or the adult. Convincingly, Dr. van der Kooy’s group was able to show that PMPs express insulin in vivo, an attribute that has often been considered prerequisite for the production of β-cells.

Analysis of human islet tissue showed that PMPs also exist in humans, and, similar to the mouse PMPs under observation, were capable of differentiation to both the pancreatic and neural lineages. Both mouse and human PMPs were able to alleviate diabetic conditions in mice and may provide another avenue to explore in the pursuit of therapeutic cells for transplantation therapy.

Selective Pressures Shape the Genomic Integrity of Human iPS Cells During Reprogramming

Samuel Lunenfeld Research Institute ♦ Ontario Institute for Cancer Research ♦ The Hospital for Sick Children ♦ University of Toronto

Published in Nature, Mar. 3, 2011

Coercing fibroblasts to revert to an embryonic stem cell-like state places a good deal of stress on the genome. The consequences of reprogramming can affect the development of safe populations of cells for therapeutics, which is why researchers at the Samuel Lunenfeld Research Institute have been interested in understanding how the reprogramming process affects genomic integrity. The integrity of a genome can be measured using copy number variation (CNV) within a population of cells. CNVs arise from deletions or duplications in DNA; as variation increases, the integrity of the genome declines.

In this study supervised by Dr. Andras Nagy and Dr. Timo Otonkoski, researchers characterized the CNV content of 22 human iPS cell lines and 17 human ES cell lines using Affymetrix SNP arrays. Induced pluripotent cell lines were created by way of retroviral transduction or with the use of a transposon known as piggybac. The number of CNVs in iPS cells was roughly twice that found in ES cells on average and many CNVs found in iPS cells were undetectable in ES cells suggesting that CNVs are generated during the reprogramming process. To the surprise of the group the number of CNVs in iPS cells was greatest at early stages, and decreased as cells were passaged in culture.

Researchers hypothesized that the reduction in copy number variation could be the result of two things, firstly, a DNA repair mechanism that corrects deletions and additions as the cells grow and divide in vitro, or mosaicism in early cultures followed by selection of iPS cells that have lower variation and greater genomic stability; a survival of the fittest in a way. It is unlikely that a DNA repair mechanism could operate fast enough to account for the rapid reduction of CNVs observed in iPS cells in culture and indeed, after using fluorescence in situ hybridization (FISH), it was confirmed by the lab group that mosaicism did exist in early cultures of iPS cells. In order to prove that selection was driving the decrease in CNVs researchers focused on deletions that cannot be corrected by DNA repair mechanisms. They found that several of these deletions were selected against during passaging of iPS cell lines. This pressure was bidirectional however, as some CNVs were selected for, not against.

CIITA, A Promiscuous Partner in Lymphoid Cancers

Centre for Translational and Applied Genomics ♦ BC Cancer Agency ♦ University of British Columbia

Published in Nature, Mar. 2, 2011

Chromosomal translocation events are a common abnormality leading to the development of cancer but few have been described as contributors to the development of lymphoid cancers. A new chromosomal translocation event has been implicated in the development of Hodgkin lymphoma and primary mediastinal B-cell lymphoma (PMBCL). Large scale mutations of this nature occur when non-homologous chromosomes transiently stick together and cause breakages that lead to the exchange of genetic information. If genes are placed next to one another following the translocation event, fusion transcripts are created which can lead to cellular abnormalities and malignant expansion.

Genome-wide mapping of translocation events can be carried out using paired-end sequencing of expressed transcripts. Researchers used such a platform to analyze two Hodgkin lymphoma cell lines. Analysis uncovered a highly expressed gene fusion between the MHC class II complex (CIITA) and an uncharacterized gene. Further analysis of 263 B-cell lymphoma cell lines went on to show that the CIITA translocation was highly recurrent in PMBCL (38%) and Hodgkin lymphoma (15%). The genetic event appears to be quite specific to PMBCL as it was observed in only 3% of diffuse large B-cell lymphoma cell lines.

Researchers note that although certain translocation events of very specific rearrangements are key contributors to some B-cell lymphomas, resulting in unique clinopathological features, many well characterized B-cell lymphomas still lack identifiable translocations that define the disease. Translocations in B-cell lymphomas are a rare occurrence, and until the publication of this research, no translocations had ever been reported in PMBCL.

Friday Science Review: March 4, 2011

The Origin of Meier-Gorlin Syndrome

Dalhousie University ♦ University of Montreal ♦ University of British Columbia

Published in Nature Genetics, Feb. 27, 2011

Researchers have mapped a locus for Meier-Gorlin syndrome (MGS), a rare genetic condition characterized by short stature, small ears, and reduced or absent kneecaps. A mutation in the ORC4 gene seems to be at the root of the disorder. ORC4 is a component of the eukaryotic origin recognition complex.

To map the locus responsible for MGS researchers performed high density genome-wide SNP genotyping using a panel of 600,000 markers provided by Illumina. The next stop involved PLINK, a whole genome analysis toolset, which was able to identify a haplotype on chromosome 2 within a number of affected individuals. Sequencing of coding exons located in the ORC4 gene led to the identification of a missense mutation that causes a tyrosine (residue 174) to cysteine switch in the ORC4 protein. The tyrosine residue affected in MGS is completely conserved across eukaryotes suggesting it has an important function; the amino acid is also believed to interact with a conserved arginine residue on a nearby helix motif in the protein structure. In the absence of this interaction the structural integrity of the protein could be compromised in part.

The origin recognition complex consists of six proteins in humans and is essential for DNA replication. It plays a critical role in recognizing origin sites on DNA and in the formation of DNA replication forks. This is the first report of an inherited mutation in any gene of the origin recognition complex in the vertebrate literature.

The Human Serum Metabolome

University of Alberta ♦ National Institute of Nanotechnology

Published in PLoS ONE, Feb. 16, 2011

Human biofluids are very important from a clinical standpoint given the insight they can provide into the disease conditions of a human being. The study of metabolomics attempts to identify, on a large scale, the composition of metabolites found in these biofluids. The advent of advanced analytical techniques along with mounting pressures for scientists in the metabolomics community to document the entire human metabolome, led to the development of the Human Metabolome Project. The project is supported by Genome Alberta and Genome Canada, the latter of which is a private, non-profit, corporation that received $600 million in funding from the Canadian government to develop and implement a national strategy in genomics and proteomics.

The most recent contribution to the project is a comprehensive multicentre study led by Dr. David Wishart at the University of Alberta. Using a diversity of metabolomics platforms researchers were able to identify, and quantify, metabolites found in human serum. The use of different methods, including nuclear magnetic resonance (NMR), and various mass-spectrometry platforms (GC-MS, LC-MS), increased the overall coverage of the serum metabolome. Data gathered via these platforms was linked to computer-aided literature mining which allowed for the development of a virtually complete set of metabolites. In total the group found 4,229 metabolites, but this number may increase in coming years as more powerful characterization techniques are developed.

Dr. Wishart and his colleagues previously characterized the human cerebrospinal fluid metabolome.

Friday Science Review: February 4, 2011

Precious GEMMs: Mouse Models Simulate Metastatic Disease for Tomorrow’s Cancer Therapeutics

Sunnybrook Health Sciences Centre ♦ Published in Nature Reviews Cancer, Feb., 2011

Before cancer therapeutics are moved to the clinic for testing in humans, they must first be assessed in laboratory animals for both safety and efficacy. Developing efficacious therapeutics for cancer treatment is a challenge, by any standard of the word. The process requires animal models of disease that closely simulate similar disease conditions in humans. The introduction of the xenograft mouse model was a large step forward in the development of new treatment regimes for cancer. When carrying out xenograft experiments in mice, researchers transplant human cancer cells into a specific location in the mouse, often subcutaneously, to observe tumour formation and how the tumour responds to treatment with different therapeutics.

Dr. Robert Kerbel and his colleagues at the Sunnybrook Health Sciences Centre reiterate the importance of improving the mouse model for the generation of more effective cancer treatments. With respect to the selection of new drugs for cancer treatment, the predictive abilities of xenograft models suffer from the fact that they fail to adequately simulate the corresponding disease in humans. Human cancer cells, when transplanted subcutaneously into the mouse, grow considerably faster than they do in humans. As a result, xenograft tumours are somewhat hyper-sensitive to chemotherapeutics, which have been designed to target rapidly dividing cells. The location of transplantation plays an important role in how a tumour will respond to treatment. As an example, a tumour found in a human breast will respond differently to cancer treatment than a breast cancer tumour beneath the skin of a mouse. The biological niches in which these tumours reside are quite different, and given the importance the cellular niche plays in cell processes, a difference in niche will translate to a difference in response to therapeutics.

Genetically engineered mouse models (GEMMs) provide a solution to at least some of the problems encountered with the more simple xenograft model. The genetic code of these mice can be altered through the deletion or over-expression of genes that are involved in the tumorigenic processes of specific cancer types. These genetic alterations give rise to tumours in selected tissues such as the breast and lung that are composed of cells and vasculature that are the host’s own. Although GEMMs are a one-up on xenograft models, and have proven valuable for the study of formation and early onset of different cancers, they fall short on one cylinder — primary tumours found in GEMMs rarely metastasize — a hallmark of many cancers. Thus, the clinical predictive power of GEMMs is higher than xenograft models, but is still fundamentally limited.

Dr. Kerbel and his team have addressed this issue using an in vivo selection technique to generate melanoma and breast cancer cells lines that exhibit extensive metastatic capacities following their transplantation into the skin or breast respectively. The selection protocol is rather logical. To create a breast cancer cell line with metastatic abilities a breast cancer cell line is transplanted into the mammary fat pads of an immune compromised mouse. Roughly 4-6 months later some mice will have tumour metastases in the lung. These tumours are dissected, a new cell line is established in vitro, and these cells are then transplanted into the mammary tissue of a second mouse. After two rounds of this selection, mice exhibit extensive metastases to the lung and in some cases, at later stages, the brain. So why is this clinically relevant?

Well, beyond mimicking the normal “metastatic cascade”, treatment of mice that have primary tumours and distant metastases has actually mirrored observations we have made in the clinic for some time. Dr. Kerbel provides a nice example using two monoclonal antibodies. Treating mice with trastuzumab as a monotherapy potently inhibited primary tumours but had very little effect on metastases. Similarly, treatment of mice with a VEGF receptor 2 antibody (DC101) inhibited primary tumour growth but failed to elicit a reduction in the growth of metastases. On the contrary, mice treated with the chemotherapeutic CTX in combination with DC101 inhibited primary tumour growth and the appearance of metastases. This finding is in keeping with the clinical observation that treatment with trastuzumab or DC101 alone as monotherapies has very little clinical benefit for cancer patients, and a combination of antibody and chemotherapy is required for successful treatment in a metastatic setting. We have come a long way with animal disease models and as their predictive powers continue to rise, so should our ability to chose the most effective cancer therapies for the clinic.

TrkC & PTPσ, the Velcro at Neural Junctions

University of British Columbia ♦ Published in Neuron, Jan. 27, 2011

The development of healthy synapses requires a confluence of biological events to occur in harmony at the site where the axon and dendrite meet. The axon of one neuron extends from its cell body towards a dendrite, a short projection radiating from the cell body of an adjacent neuron. Once these two neural components are in close proximity, two key events must occur to drive synaptogenesis. Firstly, “synapse organizing” proteins must help locally recruit pre-synaptic and post-synaptic elements to the ends of the axon and dendrite respectively, and secondly, the axon and dendrite must come into physical contact, a process that is mediated by cell-adhesion molecules. Researchers at the University of British Columbia have discovered a new complex that spans the synapse to bridge axon and dendrite. Dr. Ann Marie Craig and her team used a functional expression screen to identify TrkC, a post-synaptic adhesion molecule, and PTPσ, a high-affinity pre-synaptic receptor of TrkC, which when bound maintain tight synaptic junctions. Neurotrophin receptor tyrosine kinases (Trks) have been known to contribute to nervous system development by interacting with soluble neurotrophins at the post-synaptic membrane. Activation of Trks by neurotrophins leads to signaling cascades that modulate synaptic development. The finding that TrkC interacts with PTPσ on the pre-synaptic membrane is currently the best explanation for why Trks, which are typically catalytic proteins, have cell-adhesion domains and non-catalytic isoforms.

Biotech Trends in 2011: Commercialization by Non-Profit Foundations

Financing for biotech companies is a major part of my work at my real job, and the horrible financing environment in the wake of 2008′s financial crisis was one of the motivators for starting this blog. So, when nonprofit foundations started financing commercialization and product development in addition to their traditional role in financing research, it was a trend this blog was quick to note.

In the years since, a steady stream of new entrants have financed a wide variety of companies and projects, and the trend has appeared in the last year as a panel and the BIO convention and in E&Y’s annual biotech industry report.

Most recently, the Canadian Cystic Fibrosis Foundation gave a $750,000 grant to a new Cystic Fibrosis Technology Initiative (CFTI) which was launched in partnership with the University of British Columbia and the Centre for Drug Research and Development (CDRD). The CFTI will “assemble researchers and identify promising discoveries from across Canada to create new medicines” for CF. Selected promising new drug candidates will be developed with CDRD. The initial application deadline is January 28th and details are available here.

With MJFF and Gates leading the way and with a continued shortage of traditional development and commercialization funding for the industry, expect to see lots more of these deals in Canada and internationally in the coming year.

This post is the third in a series briefly outlining the biotech industry trends we’ve been following on the blog and noting some recent developments, plus directions for 2011.

Friday Science Review: December 17, 2010

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

Stagnant Technologies Need Stimulus

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

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

RD3 at the Root of Congenital Blindness

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

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

New Target for Chronic Pain Unveiled

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

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

Monday Biotech Deal Review: November 29, 2010

Welcome to your Monday Biotech Deal Review.  I hope our American readers had a very happy thanksgiving weekend, but hopefully there’s still some room left for your weekly digest of biotech deals.  This week witnessed the closing of the US$52M IMRIS financing [Ed. -- as well as a rafter of other deals].  Read on to learn more about these and other deals from the previous week.  Read more of this post

Friday Science Review: November 26, 2010

Ivermectin Nails Neurotransmission in Brugia malayi

McGill University

Published in PNAS, November 16, 2010

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

Prion Disease: A Sticky Situation

University of Toronto ♦ University of British Columbia

Published in PNAS, November 16, 2010

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

Friday Science Review: November 19, 2010

Mobile Phones Increase Patient Adherence in HIV Clinical Study

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

Published in Lancet, November 9, 2010

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

A Molecular Circuit of Congenital Heart Disease Revealed

University of Ottawa ♦ University of Montreal

Published in PNAS, November 9, 2010

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

Cisplatin and ING4-carrying Adenovirus Elicit Synergistic Anticancer Activity

Soochow University ♦ University of Saskatchewan

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

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

Friday Science Review: November 12, 2010

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

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

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

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

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

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

Canada — and MaRS — Draw Notice on List of Biotechnology Clusters

world_map_2002A report at Genetic Engineering and Biotechnology News, picked up today by FierceBiotech, discusses emerging biotechnology clusters.  It’s worth excerpting the whole bit on Canada:

Both Toronto and Vancouver have good, small companies, but they’re struggling for capital. They have the benefit of government support and strong universities, particularly the University of Toronto, the University of Guelph, and the University of British Columbia. Entrepreneurship skills need to be honed, however.

In the heart of Toronto, the MaRS Center incubates a host of companies within about a mile of five teaching hospitals, the University of Toronto, the provincial parliament, and the financial district. The local government takes a close interest in the Center’s success, and several promising research projects are moving toward commercialization.

Vancouver, on Canada’s west coast, consistently ranks as a fast-growing cluster, attracting more than 90 companies, some with late-stage trials. The University of British Columbia has an active tech-transfer department that has spun out several companies.

The report also discusses innovative activity in China and India, among others, that fits with the trend we have observed.  Read the whole report here.

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