Chattanooga Research Institute Presentation

Computational BiologyPhilip E. Bourne PhD
pbourne@ucsd.edu
http://www.sdsc.edu/pb
02/07/2011
Computational Biology Summit Chattanooga
Thanks to Howard Asher for some slides

Agenda
Computational Biology
What is it?
What are some success stories to date
What pitfalls can be avoided based on the experiences of others
What opportunities does it afford the region from a research, education and hence economic perspective?
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Biology has moved from being an observational to an analytical science
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Biology covers vast scales
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Comparative Genomics
Neural Circuits
Biochemical pathways
underlying drug addiction
Adaptive fast walking
Object recognition
Biologics

What drove these research directions?
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Technologies producing digital Information
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Its not just about numbers its about complexity
Number of released entries
Year
Courtesy of the RCSB Protein Data Bank

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June 26, 2000 was a milestone with the mapping of the human genome
British Prime Minister Tony Blair
Announced by then US president Bill Clinton
and the British Prime Minister Tony Blair
U.S. President Bill Clinton listens to British Prime Minister Tony Blair as Celera President J Craig Venter looks on during a joint teleconference announcement in the East Room of the White House, June 26, 2000. Venter's company Celera Genomics Corporation participated in a publicly financed Human Genome Project with private efforts and have both completed the first rough map of the human genome, the working blueprint for human beings. The discovery is seen as one of history's great scientific milestones.
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Today informatics ≥ 2 x data ≅3 months

Subdisciplines of “matics”
Electronic HR
Decision support
Drug dosing
Pharmacokinetics
Pharmacy Information
Systems
Pharmacy
Informatics
Biomedical
Informatics
Algorithms
Genomics
Proteomics
Systems
Bioinformatics
Note: These are only representative examples

Agenda
What is it?
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Metagenomics
New type of genomics
New data (and lots of it) and new types of data
17M new (predicted proteins!) 4-5 x growth in just few months and much more coming
New challenges and exacerbation of old challenges

Metagenomics: early results
More then 99.5% of DNA in every environment studied represent unknown organisms
Most genes represent distant homologs of known genes, but there are thousands of new families
Environments being studied:
Water (ocean, lakes)
Air
Soil
Human body (gut, oral cavity, human microbiome)

Metagenomics new discoveriesEnvironmental (red) vs. Currently Known PTPases (blue)
1
2
3
4
Higher eukaryotes

Personalized medicine

Personalized medicine
Right Therapeutic—Right Dose—Right Time—Right Place—Right Person
& Understanding of genetic contributions to disease and to its treatment…
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Your health—optimized to you
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Drug discovery – the sad truth
We know very little about how the major drugs we take work
We know even less about their side effects
Drug discovery seems not to have moved into the omics era
The cost and time of bringing a drug to market is huge ~ $1 Bn
The cost of failure is even higher e.g., Vioxx ~ $5 Bn
Fatal diseases are neglected because they do not make money
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Why the failure?
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Polypharmacology - One Drug Binds to Multiple Targets
Tykerb – Breast cancer
Gleevac – Leukemia, GI cancers
Nexavar – Kidney and liver cancer
Staurosporine – natural product – alkaloid – uses many e.g., antifungal antihypertensive
Collins and Workman 2006 Nature Chemical Biology 2 689-700

Why the failure?What can be done about it?
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High-throughput computational drug discovery can Be applied on three axes
Target
One to Multiple Targets
Bioinformatics
Cheminfomatics
Drug
Docking
HTS
Associative Transfer of Indications
Disease

Consider one example of using the corpus as a whole from our own research – high throughput hypothesis generation for use in drug discovery
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The TB-Drugome
Determine the TB structural proteome
Determine all known drug binding sites from the PDB
Determine which of the sites found in 2 exist in 1
Call the result the TB-drugome
Kinnings et al 2010 PLoS Comp Biol 6(11): e1000976
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2. Determine all Known Drug Binding Sites in the PDB
Searched the PDB for protein crystal structures bound with FDA-approved drugs
268 drugs bound in a total of 931 binding sites
No. of drugs
Acarbose
Darunavir
Alitretinoin
Conjugated estrogens
Chenodiol
Methotrexate
No. of drug binding sites
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Map 2 onto 1 – The TB-Drugome
http://funsite.sdsc.edu/drugome/TB/
Similarities between the binding sites of M.tb proteins (blue),
and binding sites containing approved drugs (red).

From a Drug Repositioning Perspective
Similarities between drug binding sites and TB proteins are found for 61/268 drugs
41 of these drugs could potentially inhibit more than one TB protein
conjugated estrogens &
methotrexate
No. of drugs
chenodiol
levothyroxine
testosterone
raloxifene
alitretinoin
ritonavir
No. of potential TB targets
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Top 5 Most Highly Connected Drugs
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Agenda
What is it?
02/07/2011

SDSC Abbreviated Timeline
1985
1990
2005
2010
1995
2000
Cray-XMP48
220 Mflops
Cray T3E
1 Tflops
Cray C90
5 Gflops
http://www.sdsc.edu/News%20Items/PR101510_25years.html

SDSC Lessons Learned
There is a tension between engineering and science – you need people at the interface
People and the services they provide are what make the difference
Fundamental shift from computer speed to data storage
The future is open with provenance
Beware the cloud
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SDSC lessons learned
More focus on education
More focus on integration with surrounding communities
More focus on outreach
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Agenda
What is it?
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From the Art of Medicine to the Science of Health…
2010 the Tipping Point
ArtTransformation Science
Art of
Medicine
at the
organ level
Science of
Health
at the
molecular level
2020
2000
2010
Genomic Era
Data Information Knowledge Wisdom

How to take advantage of this change?Pick important problems and become a source of valuable data and human resources for solving those problems

Depositor locations
Depositions since 2000
Download locations
RCSB PDB
PDBe
PDBj
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How to take advantage of this change?Enable the use of those data and resources in ways that the next generation will build upon

www.scivee.tv

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Enjoy the ah ha moments

Acknowledgements
Funding Agencies:
NSF, NIGMS, DOE, NLM, NCI,
NCRR, NIBIB, NINDS, NIDDK
44
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pbourne@ucsd.edu
Questions?
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What is the Protein Data Bank (PDB)?
The single community owned worldwide repository on the structures of publically accessible biological macromolecules
A resource used by ~ 200,000 individuals per month
A resource distributing equivalent to ¼ the National Library of Congress each month
02/07/2011

Chattanooga Research Institute Presentation

by Philip Bourne on Feb 07, 2011

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Chattanooga Research Institute Presentation — Presentation Transcript