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6 posts from July 2010

July 29, 2010

Model behaviour

By Katie Moisse

Buried deep within our bony skulls and spinal columns, and separated from our blood by an infallible barrier, our neurons are, I would argue, the most protected cells in our bodies. This is a good thing for obvious reasons. This is a bad thing, however, for scientists studying neurodegeneration. 

When induced pluripotent stem cells hit the scene four years ago, neuroscientists hoped for a lucky break: perhaps reprogramming fibroblasts from patients with Parkinson’s, Huntington’s and ALS into iPS cells and differentiating them into neurons genetically identical (almost) to the very cells that die off in their hosts would shed light on the cellular events unraveling in the depths of the central nervous system. Even better, maybe those sick, cultured neurons could be used to rapidly screen drugs aimed at slowing or even stopping the process. 

But efforts to model diseases in culture using patient-derived iPS cells have generated mixed results. In some cases, the neurons harbour characteristics linked to their demise in vivo; whereas in others, the cells persist without incident despite expressing some of the deadliest disease-causing mutations. 

Two years ago, researchers led by Harvard’s Kevin Eggan successfully generated iPS cells from an 82-year-old woman with familial (genetic) ALS and differentiated them into motor neurons—the subset of neurons selectively targeted causing progressive paralysis and death. The report, published in Science, was exciting 1) because aged fibroblasts could be reprogrammed at all and 2) because, for the first time, scientists could look at human motor neurons genetically destined to develop ALS under a microscope. But, so far, the cells appear to be disappointingly normal.

In contrast, when University of Wisconsin-Madison researchers led by Clive Svendsen (who I’ve blogged about before) concurrently derived iPS cells from a child with spinal muscular atrophy—a group of neuromuscular diseases similar to ALS but with earlier onset caused by mutations or deletions in the gene encoding SMN protein—the cells died at a higher frequency than iPS cell-derived neurons from the patient’s unaffected mother. Even better, the patient-derived iPS cells expressed protein aggregates considered to be a pathological hallmark that correlates with disease severity. Better still, drugs that promoted SMN protein expression in those patient-derived iPS cells reversed the pathology, demonstrating for the first time the potential for iPS cells in drug discovery. This work was published in Nature.

Could the neurodegenerative disease’s age of onset and genetic complexity influence its modelabilty? IPS cells from patients with Parkinson’s disease, Huntington’s disease and Down’s syndrome (which has characteristics of Alzheimer’s disease) lack any remarkable phenotype, according to a recent review published in Human Molecular Genetics. According to authors Maria Marchetto, Beate Winner and Fred Gage from La Jolla’s Salk Institute, “modeling late-onset neurodegenerative diseases and multifactorial neurodevelopmental diseases will require additional advances.”

So don’t discount iPS cells in neurodegenerative disease modeling yet, for their potential is “limited only by human creativity and ethical guidelines,” Marchetto and colleagues urge. “Neuroscientists in the past could not have imagined a scenario in which patient-derived neural cell types would be readily accessible to thousands of laboratories around the world, and researchers in the future will never imagine neuroscience without it.”

July 20, 2010

Stressing cells to improve transplant outcomes and cardiac function

by Chris Kamel

There's a scene in The Simpsons, after Homer suffers from a heart attack, where he paraphrases Friedrich Nietzsche's famous words, "That which does not kill us makes us stronger." Those words, in this situation, are overly optimistic. After an ischemic event like a heart attack or a stroke, not only is there massive cell death and tissue damage, but the affected area remains a harsh environment due to poor blood supply and oxygen shortage. Despite the promise of regenerative stem cell transplants, the damaged heart remains hostile and massive death of transplanted cells represents a major challenge. There are two approaches to beating this problem: improve the transplant environment, or improve the hardiness of the cells.

Nietzsche, of course, was a philosopher not a biologist, but he was prescient of a possible solution. For over 20 years, scientists have studied the concept of preconditioning. As described in Nature Reviews Neuroscience, preconditioning is:

“Presenting a stressful but nondamaging stimulus to cells, tissues or organisms to promote a transient adaptive response so that injury resulting from subsequent exposure to a harmful stimulus is reduced.”

In other words, in particular situations, a cellular insult that doesn't kill it makes it stronger.

Recent research, published in Antioxidants and Redox Signaling is the latest in a line of attempts to harness preconditioning response to improve stem cell transplants (reviewed here). In their experiments, the group pre-treated mesenchymal stem cells with the drug diazoxide as a preconditioning agent and found that the cells had better survival after oxygen-glucose deprivation both in the short and long term (i.e. 24 hours after removal of the drug). The preconditioned cells also showed increased levels of pro-survival molecules, including dependence on NF-κB activation, a protein known to be involved in preconditioning response. When injected into a rat model of heart attack, the preconditioned cells showed improved survival seven days post-transplant, increased activation of pro-survival factors, and improved cardiac function compared to non-preconditioned cells or sham transplant. Six weeks after transplant, the hearts treated with preconditioned cells continued to perform better than the other groups and showed increased blood vessel formation and reduced area of tissue damage - all signs that the damaged heart is being repaired.

With stem cell transplants to repair heart damage already making their way through clinical trials, and the difficulties scaling up cells for use, methods for improving transplant survival and efficiency are certainly welcome. Harnessing NF-κB dependent preconditioning is one strategy for prepping stem cells for survival in certain harsh transplant micro-environments.

July 15, 2010

New summary on liver failure and stem cells

The liver is the largest solid organ in the human body, and performs a critical function in keeping us alive: it removes waste from our bodies, detoxifies our blood, and helps in various other capacities to protect us from harm. Liver disease can severely compromise the liver's ability to perform its everyday tasks, in part, by damaging the hepatocytes (liver cells) that are normally able to renew themselves.

Currently, at least three million Canadians are living with some form of liver disease, and that number is increasing - some experts estimate it will triple in the next 20 years. With that in mind, finding new ways to treat liver failure is becoming increasingly important. Stem cells may hold a key to addressing liver failure and, hopefully with time, restoring damaged livers to their full functionality—and to restoring patients to their normal lives. 

Although stem cell therapies for liver failure are still in their infancy, there is hope for patients afflicted by liver failure. The Stem Cell Network has just published another in its series of disease summaries, this one focused on liver failure—its causes and current treatment options, and how stem cells can help. 

July 12, 2010

CIHR updates human pluripotent stem cell guidelines

by Ubaka Ogbogu

On June 30, the Canadian Institutes of Health Research (CIHR) released updated Guidelines for Human Pluripotent Stem Cell Research. The Guidelines apply to all research involving human pluripotent stem cells conducted with funding from, or under the auspices of institutions receiving funding from the three federal granting agencies, known as the Tri-Council: CIHR, Natural Sciences and Engineering Research Council (NSERC) and Social Sciences and Humanities Research Council (SSHRC). First created in 2002 and last updated in 2007, the Guidelines complement the Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans and provide the basis for ethical oversight of all Tri-Council supported human pluripotent stem cell research. The Guidelines also guide the deliberations and activities of the Stem Cell Oversight Committee (SCOC), the national research ethics review committee that provides ethical oversight of all human stem cell research protocols to be conducted with or under the auspices of institutions receiving Tri-Council funds. The Guidelines apply to both to derivation of new stem cell lines and use of existing ones.    

The updates consist mainly of editorial revisions aimed at clarifying the content of the Guidelines. The only substantive revisions address the treatment of induced pluripotent stem (iPS) cells, which were already covered but not specifically mentioned in the Guidelines. In general, the Guidelines were designed to cover all human pluripotent stem cells regardless of the derivation source. The revisions relating to iPS cells include the following:

  • iPS cell lines are exempt from the requirement for mandatory listing in the publicly accessible National Registry of Human Embryonic Stem Cell Lines, as they are not derived from embryonic sources.
  • With the exception of research aimed at combining iPS cells with a human or non-human embryo, or engrafting the same into a human or non-human fetus, all iPS cell research can be undertaken with Tri-Council support, provided that the research is SCOC-approved and conforms to the Guidelines. The former kinds of research cannot be undertaken with Tri-Council funds or in institutions receiving Tri-Council funds.

The notes accompanying the update announcement state that human iPS cell research involving in vivo grafting experiments to test teratoma formation are exempt from SCOC review, provided that the investigators notify SCOC in writing that the animals will not be used for reproductive purposes.

Lastly, a significant editorial revision is the deletion of the word “great” from the following statement contained in the Foreward to the Guidelines: “Stem cell research holds great potential to treat human disease and prevent suffering.” This is a welcome revision that responds to calls from bioethicists and biotechnology law experts for responsible promotion of stem cell research. A lot has been written about biotechnology hype, and it is refreshing to see some acknowledgment of that literature in policymaking. 

July 08, 2010

Personalized medicine is not only a goal, but part of the process, too

The concept of personalized medicine is an intuitive one: knowing what treatment to provide a patient based on their own individual case of a disease. Molecular techniques and various flavours of “-omics” provide high precision in determining the status and types of many diseases, as well as our susceptibility to them. One key application of personalized medicine is to predict individual responses to chemotherapy prior to initiation – thereby reducing the number of patients on ineffective treatments while also contributing to the overall efficiency of health systems.

A dramatic example is provided by Avastin (bevacizumab), an anti-VEGF monoclonal antibody which costs up to $100,000 per year of treatment but where fewer than half of patients show a significant response. In Canada, most provincial health plans cover the cost of treatment, but in British Columbia, Avastin is currently funded on a case by case basis by the BC Cancer Agency. Though decisions depend on individual patient characteristics, they also depend on the availability of funding for the drug. This latter requirement generated enough contention that it was recently the focus in a Canadian television investigative report aired earlier this year. Better predictors of patient response to treatment regimes, particularly expensive ones, would reduce the dependence of treatment decisions on resources and potentially clarify motives behind health plan funding policies. In the case of Avastin, BG Medicine began investigating for early biomarkers to test prospective patients for positive response in 2007, but as of 2010 a straightforward test remains undiscovered. Presumably there are plenty of similar opportunities for development of future tests for drug response, particularly when medications are expensive to deploy.

Paradoxically, the concept that predictive tests can actually make significant contributions during pharmaceutical development is being realized.

In a recent Science Translational Medicine commentary, Dr. Joseph Nevins from the Duke Institute for Genome Sciences and Policy uses Herceptin (trastuzumab) as an example to concisely describe the problem created by the lack of predictive tests:

“Trastuzumab’s target, the HER2 growth factor receptor, is overexpressed in only about 20% of breast cancers, and of these, only about 30% respond to the drug. Thus, if trastuzumab had been developed in an unselected population of patients with breast cancer, its effectiveness would probably not have been detectable.”

The article explains that the difficulty in selecting populations responding well above thresholds of statistical significance results in larger clinical trials being organized at Phase II and III stages, with all their associated expenses and logistical challenges, delaying progression through the drug development cycle.

Most significantly, the use of unenriched populations can cause clinical results to under-represent a particular compounds’ effectiveness if an approach to personalize treatment based on molecular subgroups could be pursued. Survival improvements can be identified in subgroups retrospectively: for example, using the presence of EGFR mutations to identify enhanced response to gefitinib in patients with lung cancer, and KRAS wild type status to predict response to cetuximab in patients with colorectal cancer. Nevertheless, in extreme cases the lack of personalized medicine approaches during initial stages of development can mask the true activity of drugs and contribute to the abandonment of many promising treatments that would have otherwise performed well.

July 06, 2010

Can collaboration and commercialization co-exist?

by Tania Bubela

Increasingly, commercialization is a key requirement for securing project funding and support for scientific research. The field of stem cell research is no exception. But does this emphasis on commercialization, which necessarily involves issues of ownership and secrecy, come at the expense of another largely-encouraged element of scientific research, namely academic collaboration? This is a question we posed in a recent study, the findings of which were published on July 2 in Cell Stem Cell.

Using bibliometrics and network analysis to visualize academic collaboration patterns, we examined the impact of patenting behavior and involvement in startup companies on the number of co-authors of individual principal investigators (PIs) within Canada’s Stem Cell Network (SCN). We found that PIs involved in startup companies had about five times as many patents as those not involved. There was a negative relationship between the number of patents garnered and the degree of academic collaboration of SCN PIs. In other words, scientists with the lion’s share of patents typically had fewer academic co-authors and were less connected within the overall co-authorship network for stem cell research.

Above this key conclusion, our research showed some very positive facts about SCN. For one thing, most science researchers at SCN exhibited a high degree of collaboration (up to an impressive 828 co-authors in one case), within Canada and with international scientists—and many developed strong international profiles as a result. This is most evident in the fact that 14 of the 100 most highly-cited researchers in our sample of over 160,000 scientific publications related to the field of stem cell research were SCN PIs.

But what does our finding about the apparent competition between commercialization on the one hand, and collaboration on the other mean? Overall, it suggests that public funding to organizations such as SCN needs to balance incentives for patentable research with those offered for collaborative research. This is most important in the field of stem cell research where the development of marketable products and therapies is highly dependent on innovative, exciting multi-disciplinary, collaborative, international and largely academic research.