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#EB10 Conference Report: Lee Hood – A Systems Biology approach to prion disease

Posted by Dr. Gunn April 26th, 2010 .
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This is a post from the 2010 Experimental Biology meeting in Anaheim, part of the SDBN conference reporting channel.

Leroy Hood probably doesn’t need any introduction here, but for those who don’t know, he’s a leader in using a systems biology to address large, complex medical problems. One such problem is prion disease, a disorder caused by a proteinaceous infectious agent which results in neurodegenerative symptoms as the proteins accumulate in the brain. After decreasing in recent years subsequent to the slaughter of 4.4 million potentially prion-bearing cattle in the UK and establishment of new industry practices, deaths due to prion disease are now as high as they were at their height in 2003.

As prion proteins accumulate and physiology is disturbed, there’s a change in gene expression of over 7400 genes. using 8 mouse strains, Dr. Hood used subtractive biology techniques to narrow the list of relevant genes to 333. Of this number, 2/3 were already known to be involved from previous work. An additional 100+ genes discovered were newly implicated. To study the dynamics of accumulation co-occurring with prion accumulation, Hood developed a massive dataset consisting of transcriptme analysis, histopathological studies, and tissue distribution studied, combining these data with known protein interaction data and clinical signs of disease. This massive analysis identified the accumulation networks and revealed the dynamics of the process as it happens over 20 weeks. In the human, prion disease can gestate for 4 years, so 20 weeks is a reasonable time for a mouse model.
One of the neatest things to come out of this work was a a means of predicting the cell type involved, based on the differential expression of the genes. All the novel prion-associated genes were correctly predicted this way. From within this dataset, they further identified 15 proteins found in the blood which track the clinical course of the disease. Instead of a definitive diagnosis only being possible upon autopsy, now the disease state can be monitored via blood markers, resulting in much easier monitoring of at risk populations and a far safer food supply.
Dr. Hood took a few moments to mention that he’s founded a company, Integrated Diagnostics, which is undertaking some fascinating projects. Among these are creation of a human proteome atlas, which will yield a quantitative assay for every known human protein, and a microfluidic chip platform with some impressive stats. He said the chip would be able to assay 50 proteins in 5 minutes using a volume of 300nL of serum (not whole blood, I assume) at attomolar sensitivities. With that level of sensitivity, they’re well within clinically significant ranges for most proteins.
To do this, they invented a novel protein capture technique that used a combination of low-affinity 6mers and click chemistry to create highly stable chips with antibody-like specificity. he cited 5 years until their availability.
In 10 years, he expects genome sequencing to be routinely done as part of medical practice, costing no more than a couple hundred dollars (as the inventer of automated DNA sequencing, I’d believe him). What this would allow, for example, is capturing of an individuals MHC locus during allergy testing and identification of specific auto-antibodies.

Update: The slides for this talk (PDF) are now available, as gave the same presentation at the SAGE Congress.

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San Diego Biotechnology Network Partner Event May 27th: Rondaxe Drug Development Symposium

Posted by Mary Canady April 22nd, 2010 .
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san diego drug development workshopDrug development is an area that, according to our 2010 poll, you are interested in, and in previous meetings we’ve discussed that San Diego biotech could grow if we would better complement our drug discovery capabilities with drug development. The SDBN was approached by Rondaxe, a drug development services company, with an idea for an event which will highlight companies they work with from outside the San Diego region. The event will be held May 27th, from 9:00 a.m. to 2:15 p.m., and a light breakfast and lunch will be provided. Please join us, the full description and agenda follows, and you can register here.
In coordination with one major consulting firm and one important CRO in the Pharma arena (Rondaxe and TD2), Helsinn Advanced Synthesis is organizing a drug development symposium. Three major companies involved in API Manufacturing, CMC Services/Consulting and Clinical Development will give a short technical and educational presentation related to their expertise.
The symposium will also offer the opportunity to share your ideas with other participants. At the end of this event, the organizers cordially invite you to join them for lunch.

Rondaxe Drug Development Workshop

Synopsis

Helsinn Advanced Synthesis: The choice of the right CMO to avoid pitfalls by successfully transferring your API / HPAI process. Implementing a roadmap to avoid potential problems and extra costs.

TD 2: Integrates world-class preclinical, clinical and regulatory expertise with “-omic” science and provides unique drug development strategies and services aimed at minimizing the risk for clients in the oncology drug development industry.

Rondaxe: De-risking CMC through experience, project and knowledge management; utilizing virtual business development expertise to maximize value realization

Program

9:00 AM Check-in, Continental Breakfast Helsinn_logo





rondaxe





td2

10:15 AM Welcome Speech
Pierre Vitaloni, Manager Business Development Helsinn Advanced Synthesis
10:30 AM Helsinn: Supply chain challenges for the Biotech / Pharma Industry
Dr. Waldo Mossi, Senior Director
Sandra Moro, Deputy Director Business Development
11:15 AM TD2: Innovation and Precision – The future of oncology clinical development
Linda Vocila, Director of Clinical Operations
12:15 PM Rondaxe: Improving value realization with de-risked CMC and virtual business development
Jeffrey Evans, Rondaxe Managing Member
12:40 PM Rondaxe: How to stay compliant in the currently changing regulatory environment
Karl Hofmann, Rondaxe Quality, President
1:00 PM Participants’ Discussion & Closing Speech
1:15 PM Lunch

Event Details

Who: Biotechnology professionals in the greater San Diego area
What: San Diego Biotechnology Network Partner Event May 27th Rondaxe Drug Development Symposium
When: Thursday, May 27th, 9:00-2:15 p.m.
Where: Tango Del Rey, 3567 Del Rey Street, San Diego 92109 (Directions below)
Cost: $20/$15 Academic, +$5 at the door (cash/check only)
Contact: http://sdbn.org/contact
For more information about the event: http://sdbn.org/may

Directions: From the North: South on Interstate 5, Exit Balboa Ave, Straight to 4th Traffic Light then left on Bunker Hill St. Building directly ahead 3 blks. From the South: North on Interstate 5, Exit Grand/ Garnet Ave, Straight to 3rd Traffic Light then right on Bunker Hill St. Building directly ahead 3 blks. Park on the street or in the structure just past Tango del Rey.

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#SBS10 Day 3 – Smart mice and blowing House, M.D.’s mind: Drug discovery in epigenetics

Posted by Dr. Gunn April 14th, 2010 .
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At the afternoon session of the Society for Biomolecular Science in Phoenix, it’s all about epigenetics, the study of heritable changes that don’t involve changes in genetic sequence.  Epigenetics explains why identical twins turn out a little different and even clones won’t be exactly identical.

Manfred Jung from Freiberg kicked off the session giving an overview of recent developments in epigenetics and presented what would become the central theme of the afternoon: Here are some diseases which haven’t received the amount of attention they deserve, here are some enzymes and proteins that cause the diseases when there’s something wrong with them, here’s how to target those enzymes. Go get ‘em, boys! (more…)

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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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