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#SBS10 report: iPS disease models coming of age for neurology

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 Meeting report shows strong growth of Pubchem database #SBS10

Posted by Dr. Gunn April 14th, 2010 .
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I’m blogging this week from the 2010 Society for Biomolecular Science meeting with my colleague Mary Canady.  I’ll be covering the scientific sessions and sharing interesting developments in drug discovery and screening technologies. You can also follow the #SBS10 hashtag on twitter for updates.

On Tuesday, Steve Bryant from NIH gave a report on the increasing utility of the NIH Pubchem database for pharma drug screening programs.  The Pubchem database, named after Pubmed, the go-to resource for life science research abstracts, is an open repository for structure and activity information about molecules which have drug potential. The database is being developed under the Genbank model, wherein researchers are encouraged to upload the results of screening runs so that this information can be linked to in publications and accessible to others.

As a resource, Pubchem has seen strong adoption by researchers in industry and academia.  To give a quick snapshot, the number of contributing organizations have grown 5-fold over the past 5 years. 60000 users submit data daily, with the number unique substances now numbering around 70 million.  For each of these compounds, information on bioactivity is also being collected. Over 90 million activities are associated with these compounds, and the rate of increase of this bioassay data is on the steep part of the exponential growth curve, meaning that number I just wrote is already wrong. While the bioassay information currently requires direct upload, there are plans to derive additional data from published literature.

Following Steve’s report, Josh Bittker gave a brief summary of how the Broad Institute is using Pubchem. They have a reporting mandate as part of a grant and are developing a pipeline for automatically submitting machine readable assay results to Pubchem.  As part of this automatic reporting, there’s an automatic embargo on the data for 1 year.

Simone Graeber then gave an update on an EU effort along the lines of Pubchem.  They go a little further than just a database, developing their own library of 0.5 million compounds, with a 17000 compound subset derived from this covering much of the “activity space” of the larger set and more usable by smaller groups without the resources to screen the whole larger library.  You may be wondering, as someone in the audience did, why they’re developing their own database instead of submitting to Pubchem. Apparently they included some proprietary compounds in their library and there are legal issues complicating the assay result reporting.

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SBS Day Two: A Holistic Approach To Drug Discovery #sbs10

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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SDBN Channels: Contribute, Interact, Learn

Posted by Mary Canady April 13th, 2010 .
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One thing I’ve learned from starting businesses/groups, is that your grand plans don’t always happen right away, but that they are eventually realized. We started the ‘main’ SDBN group on LinkedIn in order to give members a place to interact and connect, but it has limitations. Here, on the SDBN blog, we can do whatever we want, and the site is built upon WordPress which is infinitely customizable–we can allow anyone to blog here, add forums, etc. The result? We can help to grow San Diego Biotech in new, exciting ways!

We polled you late last year to find out what you’re interested in hearing about in 2010. We’re continuing to provide events that meet these expectations, and we want the conversations to not be limited to the actual event. Towards this end, we’re developing ‘SDBN Channels’ which will focus on topics important for San Diego Biotech. We’ll feature local blogs and bloggers, and if you’ve never blogged before, we’ll provide some tutorials (there’s a Channel for that!) to get you started (sign up here). Each Channel can also be a place to highlight local companies and products (contact us to learn more>.

Our first two channels will be Drug Discovery and Drug Development. We’re kicking off the Drug Discovery Channel with blog posts from the Society for Biomolecular Sciences conference in Phoenix, they were nice enough to give us some free passes for blogging (a benefit for you to blog!). Our May events will center around Drug Development, so we’ll launch that channel soon. Check out the table below, and feel free to comment if you don’t see what you want!

Channel Launch
Drug Discovery April 2010
Drug Development May 2010
Biotechnology May 2010
Blogging 101 May 2010
Translational Research June 2010
Research Tools TBD
Careers TBD
Medical Devices TBD

What’s next? Forums for each channel. Live streamed and recorded events. Other ideas? Leave them below!

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Blog About Drug Discovery for SDBN at SBS in Phoenix, Get in Free!

Posted by Mary Canady March 2nd, 2010 .
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Drug discovery is obviously a very hot topic for the San Diego biotech industry as we excel at it on so many levels. Many consider the Society for Biomolecular Sciences (SBS) annual conference to be the premier conference for drug discovery, and we are lucky that it will be held a short drive/flight away in Phoenix, Arizona this year April 11-15.

The conference organizers are also offering us a handful of FREE passes for those who would like to cover the conference through posts on the SDBN blog. Bloggers will still have to pay for travel and accommodations, but will benefit from learning the latest science, gaining recognition, and many networking opportunities. Also, SBS will provide blogging updates to attendees, giving you even more exposure.

How do you qualify and sign up? We’ll take applications until March 19th, please fill out the form. We might not be able to give passes to all who sign up, but we’ll also be starting blogging ‘channels’ on the SDBN website soon, including drug discovery and the other top interests from the 2010 poll. Stay tuned!

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