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#SBS10 report: iPS disease models coming of age for neurology |  |
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Posted by Dr. Gunn April 14th, 2010 .
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I went to a morning session on stem cells on day 2 of the Society for Biomolecular Science meeting in Phoenix, a meeting focused on advancements in drug discovery and screening technology. After this, it’s all epigenetics.
Stephen Haggarty, Director of the Stanley Center Department of Chemical Neurology spoke on stem cells as genetically accurate disease models. The idea here is that you can take cells from a patient (and relatives) and use the clever trick first reported by Yamanaka et al. to convert skin fibroblast cells into stem cells, called induced pluripotent stem cells, or iPS cells. What this gets you is a genetically identical population of cells to do experiments or drug screening on. Since they all share the genetic mutation or mutations that are responsible for the disease affecting the patient, they’ll give you an early indication of how the drug would affect the patient. The challenge here is getting a population of cells that actually act in the dish as they would in the patient, and Dr. Haggerty reports progress his group has made in this area.
Ever since Yamanaka’s paper came out, the promise of the technique was to create patient specific stem cells for either rejection-free transplants or drug screening, yet we’re only just starting to see cell lines become available for use in this way. There are many issues related to the technique of inducing the stemness that causes cells to behave in ways that isn’t true to the disease, and the degree to which one cell within a tissue differs from neighboring cells in the same diseased tissue varies are problems that are only just beginning to be addressed. However, using a heritable and common neurological disorder, Fragile X syndrome, in which the genes involved are known, he’s derived some patient specific cells which act like the disease cells do in the body. Using fibroblasts from the Coriell repository, a repository of cells including those from diseased individuals, they derived some iPS cell lines that accurately behave as do cells isolated from a diseased individual and therefore make a good disease model. This approach could still run into complications from the effects of the stem cell induction process, but it seems fairly promising.
Work on a more complex genetic disorder, Bipolar disorder, is ongoing.
‘Technical note: Lithium for bipolar disorder is an old therapy, but Li also inhibits GSK3beta, activating Wnt and promoting cell division and other stem cell properties, so expect some interesting hits to be found in this area.
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SBS Day Two: A Holistic Approach To Drug Discovery #sbs10 |  |
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Posted by Mary Canady April 14th, 2010 .
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I’m blogging from the Society for Biomolecular Sciences conference in Phoenix, the organizers were kind enough to offer two of us complimentary passes. I was surprised that the sessions were separated into disease area, technique, or ‘phenomenon’ (e.g., epigenetics) which seemed a bit curious as well, as I had expected the different types of assay technologies would have been the basis (e.g. HTS, Cell-based). It will be interesting to see how this changes if SBS merges with ALA. Nevertheless, I’ve been spending most of my time in the oncology session, and have been looking for trends to share with you, as that is usually the most valuable thing I take away from conferences.
Over the years, I’ve noticed the evolution of different themes each year at drug discovery conferences. In the kinase area alone, I’ve been going to conferences from before the kinome was sequenced, to the era of differing theories of the efficacy of specific targeting, to today’s somewhat routine screening and questions regarding what will be the ‘next big thing’ (but have we figured them out yet?) I think a major theme of this meeting, and something I’ve seen evolving over the past few years, is the idea that a holistic approach to drug discovery, whereby high-throughput screening is seen as part of the process and not the dominant technology.
Peter Simpson of AstraZeneca talked about the need for quality assays across the spectrum, from eliminating error through acoustic liquid delivery, microfluidic methods, and an standardized ‘uber’ kinase assay to utilizing biophysical and fragment-based technologies to round out the information used for lead discovery and optimization. Indeed, a more holistic approach seems to be the norm, perhaps a response to the tightening of belts we’ve all experienced in this economy.
Part of this holistic approach is the the parallel utilization of cell-based assays, which are becoming an essential and more reliable part of the drug discovery process. Perusing the exhibit floor underlines this theme–I didn’t have to walk far to find many great examples of companies pushing the boundaries to improve cell-based assay technologies. SRU Biosystems launched BIND Scanner, a label-free technology and an instrument/software combination which specializes in analyzing data from samples with low cell numbers, such as primary and stem cells. Perkin Elmer has introduced Operetta, ‘bench-top high content screening.’ Fluxion is a South San Francisco company, has married microfluidics with standard 96-well plates to simulate more physiological conditions for live cell assays. Corning continues to make strides with its Epic label-free system, and has a few interesting posters. On the reagents side, Cellular Dynamics is a Madison, Wisconsin based company based on the research and IP from James Thompson of UW, and they aim to create many types of cells for screening utilizing induced pluripotent stem (iPS). Indeed, the confluence of the increased availability of such reagents and improved instrumentation makes this an exciting time for drug discovery.
As a (former?) scientist, one thing really nags me however. From what I’ve seen, most of the cell-based assays still give a binary answer. In other words, the cell reacts to stimuli or doesn’t, and this is plugged into the ‘old’ HTS-type thinking–hit or no hit (correct me if I’m wrong). I can’t help but think that the next wave, after the growing sophistication of the cell-based technologies, will be another wave of informatics/image analysis, whereby cellular responses are deconvoluted further, yielding more important information from these assays.
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