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7 posts from May 2011

May 31, 2011

iPSCs: A tool for understanding ‘A Beautiful Mind’?

By Angela C. H. McDonald

A young brilliant mathematician seen by his colleagues as agitated, socially withdrawn, emotionally flat and paranoid is approached by a Department of Defense agent who requests his assistance with code breaking. Following acceptance of this job, the young professor believes he is being followed and is eventually chased through his university campus, captured and sedated. When the young professor comes to, he is in a psychiatric hospital and forced to realize that his secret work for the Department of Defense is one of his schizophrenic delusions. This is the story of John Nash portrayed in the film A Beautiful Mind. Like many individuals suffering from schizophrenia (1 in every 100 Canadians), John Nash struggles throughout his life with an array of symptoms including delusions and hallucinations. 

Can induced pluripotent stem cells (iPSCs) help us understand the underlying mechanism of this devastating and complex condition?  Maybe.

Scientists have proposed the use of iPSCs for modeling human disease however; many question the usefulness of iPSCs for modeling complex neurological diseases such as schizophrenia. Last month a team of researchers led by Fred Gage at the Salk Institute published in Nature the first example of modeling a complex neurological disease in a dish.

Skin fibroblasts from schizophrenia patients were obtained from a cell bank and reprogrammed into iPSCs. Patient-derived iPSCs were differentiated into neurons to study the cellular and molecular mechanisms of schizophrenia. The researchers found that patient-derived neurons were electrophysiologically equivalent to control neurons and the levels of a number of synaptic maturation markers were unaffected. However, schizophrenia neurons did show a decrease in the number or neuronal projections, decreased neuronal connectivity and alterations in global gene expression. Over 550 genes were aberrantly expressed in schizophrenia neurons, 25 per cent of which have been previously linked to the disease.

iPSC-derived schizophrenia neurons were treated with five antipsychotic drugs in an attempt to improve neuronal connectivity in vitro. The drugs were administered for the final three weeks of neuronal differentiation. Loxapine, an antipsychotic commonly used to treat schizophrenia was the only antipsychotic drug that significantly increased neuronal connectivity in all patient iPSC derived-neurons.

Interestingly, this is not the first study to investigate the molecular mechanisms of schizophrenia in vitro. A small number of studies have been performed on cultured fibroblasts from skin biopsies of schizophrenia patients. One study identified a cell proliferation defect in patient fibroblasts. While studying patient fibroblasts may provide some insight into disease mechanisms many scientists stress the importance of studying the appropriate cell type in vitro. For example, in the Nature paper noted above, Fred Gage’s group reported increased NRG1 (a protein thought to be involved in schizophrenia) expression in schizophrenia neurons but not SCZD fibroblasts, which they suggest, demonstrates the importance of studying the relevant cell type.  

I recently attended a Stem Cell Journal Club session at the Hospital for Sick Children where this paper was presented. Stem cell and neurobiologists in attendance raised a number of concerns about this study includingthe difficulty of modeling a complex systems disease that is thought to be a dynamic process, leading to the dysfunction of many pathways in the brain. How much insight will researchers have into this disease if they are studying only a few types of neurons in a dish? Even though many scientists are skeptical, we can’t disregard that almost all insight into the molecular mechanism of schizophrenia in human patients has come from the study of postmortem brain tissue. iPSCs are the only source of live human neurons available to researchersfor studying this devastating disease and for this reason, scientists should continue to use and optimize neurons from iPSCs.

 

May 19, 2011

Pull your heads out of the sand: Young scientists need to be policy aware

by David Kent

OstrichXSmall In an article I wrote last month on Nature magazine’s "The Future of the PhD" series, I highlighted a thought from Steven Running (Forest Ecologist extraordinaire) who compared today’s PhD student to those going through the system with him in the 1970s:

“The modern PhD student needs to be much more policy aware, because society has many environmental problems to solve, and not much time.”

While Professor Running was mostly speaking about climate change policy and his own research area, his point about being equipped to handle the attention of the public is well taken, especially in this age of hyper-information exchange. Today’s graduate students and young investigators need to be policy aware and the field of stem cells is a great example where the highly successful laboratory heads often find themselves in policy advising and public relations situations.

Continue reading "Pull your heads out of the sand: Young scientists need to be policy aware" »

May 17, 2011

Stem cell technology development gets cold shoulder from European Advocate General

by Paul Krzyzanowski

Protecting inventions arising from publicly funded research is a polarizing issue for many scientists and the general public. One perspective views all the fruits of publicly-funded research as public domain, while another believes that same knowledge must be turned into products by entrepreneurship and private sector investment. It’s a tricky dilemma with no clear answer. In the stem cell research field, problems of ethics complicate matters further, particularly when it comes to human embryonic stem cells. 

In Europe, the Advocate General M. Yves Bot recently released a recommendation for a legal ruling that may result in severe restrictions on patentability of inventions using human stem cells.

Naturally, the research field opposes such restrictions on research and the implementation of knowledge. An open letter was recently published in Nature (Also available here for Open Access) and the ISSCR has also made a statement on this matter. For those interested, the European Advocate General’s nearly 8000-word Opinion Statement is available online, in addition to the European Court of Justice’s press release.

Continue reading "Stem cell technology development gets cold shoulder from European Advocate General" »

May 11, 2011

Science 2.0: Time to throw open the laboratory doors?

by Michelle Ly

Almost three years ago, Scientific American asked if we were entering an age of Science 2.0.  Would science now be conducted in the open access realm –- freely publishing data, drafts and even whole papers? The economic cost of academic publishing has long been considered unsustainable. As well, the lack of freely accessible papers and results is a frequently heard criticism of academic research. Animal rights groups, for example, often use the perceived absence of transparency in science to cast doubt upon ethical practices involving animal testing. 

Open access has the support of many prominent scientists. This support has certainly increased over the years with diverse voices such as stem cell pioneer and cancer researcher James Till and microbiologist Jonathan Eisen joining the fray. But have we ended up in the Science 2.0 that Scientific American speculated?  While some blogs and open access journals have flourished, the majority of published data still ends up in subscription-based journals. 

One area of biology which has consistently embraced open access models is the field of bioinformatics.  Open access tools for genome analysis, molecular modeling and data visualization are common and frequently used. Recently, researchers from the RWTH Aachen University and Kiel University in Germany, together with The Scripps Research Institute in San Diego, California, published results detailing a new method for testing stem cells.  he procedure, called PluriTest, is freely available online and may satisfy the needs of both grant-starved researchers and animal rights activists alike. 

The current standard for proving pluripotency in a new cell line is through the generation of human cell derived teratomas in immunodeficient mice. Teratomas are solid tumors which contain a mixture of histologically distinct tissue types. Pluripotency is confirmed through tissue collection and subsequent histological analysis of the teratoma to determine if the cell line was able to form tissues of all three embryonic germ layers -– ectoderm, mesoderm and endoderm.   

Despite its widespread use, teratoma assays are not standardized, raising questions and concerns about the assay’s effectiveness as a stem cell quality control and regulatory tool. As well, the procedure spans 6-8 weeks between cell implantation and histological analysis, which may be unrealistic for use in large scale production.

In contrast, PluritTest uses a pattern recognition algorithm which is able to distinguish between pluripotent and non-pluripotent cell lines without the need for animal models. The algorithm relies on a large database of gene expression patterns from known human stem cell lines and returns results in about ten minutes. One of the authors, Dr. Franz-Josef Muller, describes the standardized verification process of PluriTest as a way for researchers to “forgo data from animal testing laboratories and simultaneously achieve more precise results”. As the use of stem cells in cell therapy and regenerative medicine increases, any method which reduces the cost of cell line production and testing ultimately benefits patients.     

Will it help further the open access cause? The original paper was, ironically, published behind a Nature paywall and lack of access may limit the number of PluriTest early adopters. However, it is encouraging to see the development of free tools in stem cell research and I am hopeful that more will follow.

 

May 05, 2011

Researchers hit the bull's EYE

By Angela C.H. McDonald

Generating complex organ tissue from pluripotent stem cells is a major challenge in the field of regenerative medicine. Significant progress has been made in directing pluripotent stem cells to differentiate into specific cell types however; there have been few examples of the successful production of organ tissue in vitro. Last month, a group of researchers from Japan reported in Nature the remarkable generation of optic cup tissue from mouse embryonic stem cells in a dish.

NatureApril2011 Following 8-10 days of culture in defined retinal inducing conditions and in the presence of extracellular matrix proteins, embryonic stem cells differentiated to form three-dimensional structures that molecularly and morphologically resemble optic cup tissue in vivo. Using an embryonic stem cell line containing a fluorescent reporter gene expressed in the developing eye, researchers captured the elegant morphogenetic process of optic cup formation in a dish using live imaging. Stunning videos demonstrate the outpouching of embryonic stem cell aggregates and their subsequent morphological movements that result in an optic cup, recapitulating mammalian eye development. 

This new tool has developmental biologists excited about the possibility of elucidating molecular interactions that orchestrate eye development as well as the possibility of isolating stage-specific progenitor cells throughout optic cup development. 

But what does this research mean for patients suffering from degenerative eye disease?  The authors anticipate that application of this technology to human pluripotent stem cell lines could open up the possibility of generating artificial retinal tissue sheets for transplantation. 

Many eye diseases including age-related macular degeneration result from degeneration of retinal tissue. Following disease or injury, the human retina does not regenerate, leaving an individual with impaired vision. For patients suffering from degenerative eye disease, tissue transplantation is the only hope for regaining lost sight.  

There is reason to be optimistic about the potential of embryonic stem cell-derived retinal cells to treat eye disease. In fact, a number of groups around the world are working to move their stem cell technologies forward into clinical trials. However, stem cell therapy holds an array of challenges including the ability to coax transplanted cells into forming complex functional tissue layers. 

In April, Chinese and American researchers published their results following the transplantation of rod photoreceptors derived from swine induced pluripotent stem cells into swine retina in the journal Stem Cells. While the survival of a small number of injected cells and their subsequent differentiation into a mature morphology is exciting, there was no functional improvement in electrophysiological response to light. In contrast, transplantation of fetal retinal tissue into human patients can restore some visual acuity however ethical and supply issues hamper the use of fetal transplants as a viable therapeutic option. Optic cup tissue generated from pluripotent stem cells in vitro is an intriguing alternative.

While the generation of optic cup tissue in a dish from mouse embryonic stem cells is exciting, much more work needs to be done before we can think about therapeutic applications, beginning with the transfer of this technology to human pluripotent stem cells.

Why should regenerative medicine efforts focus in part on eye regeneration? Well for starters, one million Canadians have some form of age-related macular degeneration. According to the Canadian National Institute for the Blind, more Canadians have age-related macular degeneration than breast cancer, prostate cancer, Parkinson’s or Alzheimer’s disease combined. The economic impact of eye disease is staggering -– the National Coalition for Vision Health reports the cost of vision loss in 2007 as $15.8 billion, which includes direct health care costs as well as the indirect costs of lost productivity, welfare and other expenses. By 2032, this figure is expected to double, making a need for therapies even more pressing.   

 

May 04, 2011

Controversial stem cell clinic closed

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May 02, 2011

US Appeal Court reinstates Obama’s funding policy on stem cell research

by Ubaka Ogbogu

A few months ago I wrote about a temporary injunction (ban) issued by United States federal district court judge Royce C. Lamberth on federal funding for research on human embryonic stem cell lines derived from supernumerary IVF embryos. Subsequently, at the request of the federal government, a U.S. appeal court suspended the injunction pending a full review of the case. On April 29, 2011, the same appeal court permanently overturned the injunction and in accordance with customary legal process, sent the case back to the Judge Lamberth for a full hearing. This means that unlike the initial injunction, which was ordered based on a preliminary hearing of the case, Judge Lamberth is obliged to hear and decide the case on its merits following full submissions of facts and arguments by the parties. Thus, while the federal government may continue to fund the affected research, the case is far from over. Also, any decision issued following a full hearing of the case can be appealed.   

As I argued in my previous posts, and as is obvious from the alternating judgments and the possibility of further appeals, the court system is not the proper venue for shaping and setting science policy. A more stable approach would be for the U.S. Congress to settle the matter definitively by promulgating comprehensive policies regarding hESC research. This is the approach taken by the Canadian government, and despite a recent successful court challenge against aspects of Canada’s embryo research legislation, a fairly stable, albeit (in my opinion) unsatisfactory, policy regime remains.