- 1. One Scientific Career(Computers in Biology) Philip E. Bourne
PhD [email_address] http://www.sdsc.edu/pb
http://www.sdsc.edu/~bourne
2. The Life of One Scientist The Early Years So That You Might
Not Make the Same Mistakes
- My high school teacher Mr. Wilson said I would be a failure at
chemistry
- The opportunity to live in different places shaped my life
3. 40+ Years Later
4. BSc (Hon) It was About Then I Began to Understand Myself But
I Still Made Mistakes 5. PhD The Molecular Basis of Cancer
Treatment
- I thought I was at the center of the scientific universe
- I later discovered I was actually in deep space
6. I Love ComputersCirca 1974
- Your head will tell you stuff
- Your heart will tell you something different
7. Postdoctoral Work The Molecular Basis of How the Body
Works
- Regrets: never learnt another language
8. Studying Iron Metabolism 9. Some Things Stay with You Your
Whole Life 10. I Got Involved in Open Source Software
- Look for the signs that will shape your later life
11. Senior Scientist Columbia University New York
- Driven not by career but wanting to live in New York City
12. The IT Years
- Thought more about money than science
- Paid the price in later years only now catching up
- Stated another way science is for the long haul and it is about
establishing a reputation
- May have wasted the most productive years
2007 Ten Simple Rules for Doing Your Best Research, According to
Hamming PLoS Comp. Biol., 3(10): e213 13. The Authoring Years
14.
- Make the most of every day
15. Got Involved with the The Human Genome Was Only Possible by
Applying Computers to Problems in Biology
- Realized what was coming and leveraged the possibilities
- Built on existing strengths
16. Came to UCSD to Apply Computers to Big Biological
Problems
- Possibly the best place in the world to do computational
biology
17. 18. The Growth of Data is A Major Driver in Biology Number
of released entries Year 19. The PDB was a Big Plus
- Money talks even in academia
- Satisfied my needs that engineer again
- Used it to leverage my research
20. Today - Big Research Questions in the Lab
- Can we improve how science is disseminated and
comprehended?
- What is the ancestry of the protein structure universe and what
can we learn from it?
- Are there alternative ways to represent proteins from which we
can learn something new?
- What really happens when we take a drug?
- Can we contribute to the treatment of neglected {tropical}
diseases?
August 14, 2009 21.
- 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 theomicsera
- 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
Motivation Skaggs School of Pharmacy 22. Why Dont We Have More
and Better Drugs?
- Gleevac Leukemia, GI cancers
- Nexavar Kidney and liver cancer
- Staurosporine natural product alkaloid uses many e.g.,
antifungal antihypertensive
Collins and Workman 2006Nature Chemical Biology2 689-700 23.
Implications
- Ehrlichs philosophy of magic bullets targeting individual
chemoreceptors has not been realized
- Stated another way The notion of one drug, one target, one
disease is a little nave in a complex system
24. What Do These Off-targets Tell Us?
-
- A possible explanation for a side-effect of a drug already on
the market
-
- A possible repositioning of a drug to treat a completely
different condition
-
- A multi-target strategy to attack a pathogen
25. Need to Start with a 3D Drug-Receptor Complex - The PDB
Contains Many Examples Computational Methodology Generic Name Other
Name Treatment PDBid Lipitor Atorvastatin High cholesterol 1HWK,
1HW8 Testosterone Testosterone Osteoporosis 1AFS, 1I9J .. Taxol
Paclitaxel Cancer 1JFF, 2HXF, 2HXH Viagra Sildenafil citrate ED,
pulmonary arterial hypertension 1TBF, 1UDT, 1XOS.. Digoxin Lanoxin
Congestive heart failure 1IGJ 26. A Reverse Engineering Approach
toDrug Discovery Across Gene Families Characterize ligand
bindingsite of primary target(Geometric Potential) Identify
off-targets by ligandbinding site similarity (Sequence order
independentprofile-profile alignment) Extract known drugsor
inhibitors of theprimary and/or off-targets Search for similar
small molecules Dock molecules to bothprimary and off-targets
Statistics analysisof docking scorecorrelations Xie and Bourne
2009Bioinformatics 25(12) 305-312 27. The Problem
withTuberculosis
- One third of global population infected
- 1.7 million deaths per year
- 95% of deaths in developing countries
- Anti-TB drugs hardly changed in 40 years
- MDR-TB and XDR-TB pose a threat to human health worldwide
- Development of novel, effective, and inexpensive drugs is an
urgent priority
28. Summary of the TB Story
- Entacapone and tolcapone shown to have potential for
repositioning
- Direct mechanism of action avoidsM. tuberculosisresistance
mechanisms
- Possess excellent safety profiles with few side effects already
on the market
- Assay of direct binding of entacapone and tolcapone to InhA
reveals a possible lead with no chemical relationship to existing
drugs
Kinnings et al. 2009PLoS Comp Biol5(7) e1000423 29. SMAP p-value
< 1e-5 drugs TB proteins p < 1e-7 p < 1e-6 p < 1e-5 30.
31. Motivation 32. 33. There Have Been a Few Ah Hah Moments 34.
Current Career Goals
- Crowd source the twenty first century printing press
- Make a significant contribution to peoples lives as a result of
work on a neglected disease
35. A Few of Lifes Lessons
- Manage by doing not by saying
- Treat people well you will feel good and it pays off
- Every day ask yourself if you are content if the answer is no
do something else
36. Life Is About Balance 37. More Information
- Podcast on off-targeting -http://www.scivee.tv/node/15685
- Google PLoS Collections 10 Rules
- Great Motorcycle Journeys of the World -
http://www.travelblog.org/Bloggers/OFL/