Kerry Blanchard Shanghai Biof


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Kerry Blanchard, May 11, 2012. Shanghai Bioforum Translational Medicine, Session S4, Shanghai, China

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Kerry Blanchard Shanghai Biof

  1. 1. Problems  with  Transla1on Kerry  L.  Blanchard,  PhD,  MD
  2. 2. 坐井观天
  3. 3. My  transla1on  +  Google坐井观天 = Sit  Well  Look  Sky
  4. 4. The  Context   A  li&le  frog  lived  in  the  well  and   thought  the  whole  world  was  the   well.  He  thinks  he  is  the  smartest   frog  in  the  world.  Later  on  the  frog   receives  a  visit  from  a  li&le  bird   who  has  flown  to  the  well  from  a   long  distance.  The  frog  realizes   how  blind  he  had  been,  and  the   fact  that  there’s  a  whole  new   world  out  there  yet  to  discover.   The  frog,  ‘opens’  his  eyes  to  the   reality  of  his  trapped  situaDon.   4  
  5. 5. 坐 井 观 天 Zuo  Jing  Guan  Tian To  have  tunnel  visionBig  fish  in  a  liJle  pond 大 鱼 小 池
  6. 6. Something  a  li&le  bit  scary Zuo  Jing  Guan  Tian 昨鲸管田Yesterday  a  whale  managed  a  field
  7. 7. The  Story •  Two  observers  see  the  same  data    •  Each  observer  has  a  different  impression  •  Both  impressions  have  elements  of  truth  •  Both  impressions  have  elements  of  untruth  •  Neither  is  correct The voyage of discovery is not in seeking new landscapes but in having new eyes…Marcel Proust 7  
  8. 8. Lessons•  Language  is  a  set  of  symbols  •  Symbols  describe  our  percep1on  of  reality  •  Transla1on  changes  one  language  to  another  •  Deciphering  symbols  is  mechanical  •  Meaning  is  oRen  lost  in  transla1on  •  Understanding  reality  requires  context   Like many intellectuals, he was incapable of saying a simple thing in a simple way…Marcel Proust
  9. 9. What is “translation”?Interpreting? Chinese to EnglishConverting? RNA information to protein structureDecoding? Target to biology to drug to diseaseNonrotational displacement? “a no-spin zone” To render in another language 9
  10. 10. What is translational research?Translational research is theholistic rendering of theinteractions betweenpatients, diseases, targetsand drugs. 10
  11. 11. Why we need translational research:Complexities in drug developmentTarget/pathway biology is complexDrugs have multiple mechanismsDisease definition is imprecisePatients with the same disease aredifferent Clinical samples define clinical relevance 11
  12. 12. Disease classification is impreciseLack of known recognized etiologic agent or eventConfusion of syndromes with diseaseLack of “gold standard” diagnostic criteriaExistence of common final pathophysiologic mechanisms•  Congestive heart failure•  Chronic renal failure•  Cirrhosis•  Chronic obstructive pulmonary disease 12
  13. 13. Patients with the same disease aredifferentGenetic background•  Disease modification•  Drug metabolism•  ToxicityMedical background•  Concomitant diseasesEnvironmental background•  Concomitant drugs•  Exposures, e.g tobacco, alcohol, illicit drug use 13
  14. 14. Translational Research is not:Profiling of compounds in animals or patientsLooking for responders to a drugFinding diseases for a drugMindless sequencing or chippingTissue banking 14
  15. 15. Translation Research can:Clinical Benefits:•  Reduce the diversity within a clinical syndrome•  Eliminate patients who can’t respond to a drug•  Optimize the risk/benefit ratio•  Provide appropriate surrogate biomarkers for drug activityDiscovery Benefits:•  Link a disease with an important biologic process•  Help find drugs for diseases We must never be afraid to go too far, for truth lies beyond…Marcel Proust 15
  16. 16. Frequency in tumor samples to date Breast 6/61 (8%) Colon 3/51 (6%) Ovary 1/50 (2%)E17K(G>A) The mutation is: E17K = Charge Reversal • Somatic • Heterozygous • Recurring
  17. 17. AKT1 E17K LearningsSentry glutamate hypothesisPathologic membrane localization•  Plasma membrane localization in absence of PIP3•  80X increase in binding to PIP2; 100X more PIP2 than PIP3•  AKT activation in the absence of PI3K activityPatient segregation by PI3K/AKT/mTOR status•  Response to particular drugs•  Where in the PI3K/AKT/mTOR pathway•  Disease natural historySomatic mutation in non-cancer diseases•  Proteus syndrome (AKT1)•  Beckwith Wiedemann syndrome with hemihypertrophy (AKT2)•  Hemispheric Developmental Brain Malformations (AKT3) 17
  18. 18. PHDi 18  
  19. 19. N Engl J Med. 2011 Aug 18;365(7):611-9. Neuron 74, 41–48, April 12, 2012 Science. 2011 Oct 28;334(6055):474.
  20. 20. The quest fordisease-modifying drugs Drugs Targets Pathways Disease Patients Biomarkers 20