A presentation made to Chattanooga officials about the importance of computational biology to the future of health care and what it might mean to the Chattanooga Research Institute (CRI).

1. 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

3. 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? 02/07/2011 Computational Biology Summit Chattanooga

4. Biology has moved from being an observational to an analytical science 02/07/2011 Computational Biology Summit Chattanooga

5. Biology covers vast scales 02/07/2011 Computational Biology Summit Chattanooga

6. 02/07/2011 Computational Biology Summit Chattanooga Comparative Genomics Neural Circuits Biochemical pathways underlying drug addiction Adaptive fast walking Object recognition Biologics

7. What drove these research directions? 02/07/2011 Computational Biology Summit Chattanooga

8. Technologies producing digital Information 02/07/2011 Computational Biology Summit Chattanooga

9. Its not just about numbers its about complexity Number of released entries Year Courtesy of the RCSB Protein Data Bank

10. 02/07/2011 Computational Biology Summit Chattanooga

11. 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. 02/07/2011

12. Today informatics ≥ 2 x data ≅3 months

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

14. 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? 02/07/2011 Computational Biology Summit Chattanooga

15. 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

16. 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)

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

18. Personalized medicine

19. Personalized medicine Right Therapeutic—Right Dose—Right Time—Right Place—Right Person & Understanding of genetic contributions to disease and to its treatment… 02/07/2011 Computational Biology Summit Chattanooga

20. Your health—optimized to you 02/07/2011 Computational Biology Summit Chattanooga

21. 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 02/07/2011 Computational Biology Summit Chattanooga

22. Why the failure? 02/07/2011 Computational Biology Summit Chattanooga

24. Gleevac – Leukemia, GI cancers

25. Nexavar – Kidney and liver cancer

26. Staurosporine – natural product – alkaloid – uses many e.g., antifungal antihypertensiveCollins and Workman 2006 Nature Chemical Biology 2 689-700

27. Why the failure?What can be done about it? 02/07/2011 Computational Biology Summit Chattanooga

28. 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

29. Consider one example of using the corpus as a whole from our own research – high throughput hypothesis generation for use in drug discovery 02/07/2011 Computational Biology Summit Chattanooga

30. 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 Computational Biology Summit Chattanooga 02/07/2011

31. 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 02/07/2011 Computational Biology Summit Chattanooga

32. 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).

33. 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 02/07/2011

34. Top 5 Most Highly Connected Drugs 02/07/2011 Computational Biology Summit Chattanooga

35. 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? 02/07/2011 Computational Biology Summit Chattanooga

36. 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

37. 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 02/07/2011 Computational Biology Summit Chattanooga

38. SDSC lessons learned More focus on education More focus on integration with surrounding communities More focus on outreach 02/07/2011 Computational Biology Summit Chattanooga

39. 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? 02/07/2011 Computational Biology Summit Chattanooga

40. 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

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

42. Depositor locations Depositions since 2000 Download locations RCSB PDB PDBe PDBj 02/07/2011 Computational Biology Summit Chattanooga

43. How to take advantage of this change?Enable the use of those data and resources in ways that the next generation will build upon

44. www.scivee.tv

45. 02/07/2011 Computational Biology Summit Chattanooga

46. Enjoy the ah ha moments

47. Acknowledgements Funding Agencies: NSF, NIGMS, DOE, NLM, NCI, NCRR, NIBIB, NINDS, NIDDK 44 02/07/2011 Computational Biology Summit Chattanooga

48. pbourne@ucsd.edu Questions? 02/07/2011 Computational Biology Summit Chattanooga

49. 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 Computational Biology Summit Chattanooga