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Nifty Fifty Presentation 2010
 

Nifty Fifty Presentation 2010

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A presentation to high school students at Chula Vista High School, San Diego as part of nifty-fifty where scientists go into the high schools and try and excite students to a career in science. These ...

A presentation to high school students at Chula Vista High School, San Diego as part of nifty-fifty where scientists go into the high schools and try and excite students to a career in science. These slides describe my own particular career path.

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  • Tuberculosis, which is caused by the bacterial pathogen Mycobacterium tuberculosis , is a leading cause of mortality among the infectious diseases. It has been estimated by the World Health Organization (WHO) that almost one-third of the world's population , around 2 billion people, is infected with the disease. Every year, more than 8 million people develop an active form of the disease, which claims the lives of nearly 2 million. This translates to over 4,900 deaths per day , and more than 95% of these are in developing countries. Despite the current global situation, antitubercular drugs have remained largely unchanged over the last four decades. The widespread use of these agents has provided a strong selective pressure for M.tuberculosis, thus encouraging the emergence of resistant strains. Multidrug resistant (MDR) tuberculosis is defined as resistance to the first-line drugs isoniazid and rifampin . The effective treatment of MDR tuberculosis necessitates long-term use of second-line drug combinations , an unfortunate consequence of which is the emergence of further drug resistance. Enter extensively drug resistant (XDR) tuberculosis - M.tuberculosis strains that are resistant to both isoniazid plus rifampin, as well as key second-line drugs . Since the only remaining drug classes exhibit such low potency and high toxicity , XDR tuberculosis is extremely difficult to treat. The rise of XDR tuberculosis around the world imposes a great threat on human health , therefore reinforcing the development of new antitubercular agents as an urgent priority. Very few Mtb proteins explored as drug targets
  • Purple circular nodes are TB proteins and green rectangular nodes are drugs Binding site similarity is indicated by connecting lines (‘edges’) between the TB proteins and drugs - proteins that are predicted to have similar binding sites are connected Edges are colored according to SMAP p-value i.e. the significance of the match (green<=1e-7) The thickness of the edges corresponds to the number binding sites of a particular drug that match the TB protein, expressed as a proportion of the total no. of different binding sites of that drug Dashed lines indicate that although all drug binding sites were matched, there was only one binding site for that drug anyway

Nifty Fifty Presentation 2010 Nifty Fifty Presentation 2010 Presentation Transcript

  • One Scientific Career (Computers in Biology) Philip E. Bourne PhD [email_address] http://www.sdsc.edu/pb http://www.sdsc.edu/~bourne
  • 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
    • My PhD is in chemistry
    • The opportunity to live in different places shaped my life
  • 40+ Years Later
    • Good friends are forever
  • BSc (Hon) It was About Then I Began to Understand Myself – But I Still Made Mistakes
  • 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
  • I Love Computers Circa 1974
    • Your head will tell you stuff
    • Your heart will tell you something different
    • Follow your heart
  • Postdoctoral Work – The Molecular Basis of How the Body Works
    • Regrets: never learnt another language
  • Studying Iron Metabolism
  • Some Things Stay with You Your Whole Life
  • I Got Involved in Open Source Software
    • Look for the signs that will shape your later life
  • Senior Scientist – Columbia University New York
    • Driven not by career but wanting to live in New York City
  • The IT Years
    • Thought more about money than science
    • Paid the price in later years – only now catching up
    • Do I have regrets? - Nah
    • 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
  • The Authoring Years
    • Make the most of every day
  • 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
    • Was prepared to move
    • Picked the best place
  • Came to UCSD to Apply Computers to Big Biological Problems
    • Possibly the best place in the world to do computational biology
  •  
  • The Growth of Data is A Major Driver in Biology Number of released entries Year
  • The PDB was a Big Plus
    • Money talks even in academia
    • Satisfied my needs – that engineer again
    • High visibility
    • Used it to leverage my research
  • 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
    • 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
    Motivation Skaggs School of Pharmacy
  • Why Don’t We Have More and Better Drugs?
    • 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
  • Implications
    • Ehrlich’s 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 naïve in a complex system
  • What Do These Off-targets Tell Us?
    • Potentially many things:
      • Nothing
      • How to optimize a NCE
      • 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
      • The reason a drug failed
      • A multi-target strategy to attack a pathogen
  • 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
  • A Reverse Engineering Approach to Drug Discovery Across Gene Families Characterize ligand binding site of primary target (Geometric Potential) Identify off-targets by ligand binding site similarity (Sequence order independent profile-profile alignment) Extract known drugs or inhibitors of the primary and/or off-targets Search for similar small molecules Dock molecules to both primary and off-targets Statistics analysis of docking score correlations … Xie and Bourne 2009 Bioinformatics 25(12) 305-312
  • The Problem with Tuberculosis
    • 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
  • Summary of the TB Story
    • Entacapone and tolcapone shown to have potential for repositioning
    • Direct mechanism of action avoids M. tuberculosis resistance mechanisms
    • Possess excellent safety profiles with few side effects – already on the market
    • In vivo support
    • Assay of direct binding of entacapone and tolcapone to InhA reveals a possible lead with no chemical relationship to existing drugs
    Kinnings et al. 2009 PLoS Comp Biol 5(7) e1000423
  • SMAP p-value < 1e-5 drugs TB proteins p < 1e-7 p < 1e-6 p < 1e-5
  •  
  • Motivation
  •  
  • There Have Been a Few Ah Hah Moments
  • 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
    • Inspire young minds
  • A Few of Life’s 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
  • Life Is About Balance
  • 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/