Problems  with  Transla1on �

Kerry  L.  Blanchard,  PhD,  MD �

坐井观天�

坐井观天� Sit  Well  Look  Sky�= �

My  transla1on  +  Google�

The  Context  

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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.  

坐 井 观 天�

To  have  tunnel  vision �

Zuo  Jing  Guan  Tian �

Big  fish  in  a  liJle  pond �

大 鱼 小 池�

Zuo  Jing  Guan  Tian �

昨鲸管田�

Yesterday  a  whale  managed  a  field �

Something  a  li&le  bit  scary�

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

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The voyage of discovery is not in seeking new landscapes but in having new eyes…Marcel Proust

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

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What is “translation”?

Interpreting? Chinese to English

Converting? RNA information to protein structure

Decoding? Target to biology to drug to disease

Nonrotational displacement? “a no-spin zone”

To render in another language

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What is translational research?

Translational research is the holistic rendering of the interactions between patients, diseases, targets and drugs.

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Why we need translational research: Complexities in drug development

Target/pathway biology is complex

Drugs have multiple mechanisms

Disease definition is imprecise

Patients with the same disease are different

Clinical samples define clinical relevance

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Disease classification is imprecise

Lack of known recognized etiologic agent or event

Confusion of syndromes with disease

Lack of “gold standard” diagnostic criteria

Existence of common final pathophysiologic mechanisms •  Congestive heart failure •  Chronic renal failure •  Cirrhosis •  Chronic obstructive pulmonary disease

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Patients with the same disease are different

Genetic background •  Disease modification •  Drug metabolism •  Toxicity

Medical background •  Concomitant diseases

Environmental background •  Concomitant drugs •  Exposures, e.g tobacco, alcohol, illicit drug use

Translational Research is not:

Profiling of compounds in animals or patients

Looking for responders to a drug

Finding diseases for a drug

Mindless sequencing or chipping

Tissue banking

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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 activity

Discovery Benefits: •  Link a disease with an important biologic process •  Help find drugs for diseases

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We must never be afraid to go too far, for truth lies beyond…Marcel Proust

E17K (G>A)

Frequency in tumor samples to date

Breast 6/61 (8%) Colon 3/51 (6%) Ovary 1/50 (2%)

The mutation is: • Somatic • Heterozygous • Recurring

E17K = Charge Reversal

AKT1 E17K Learnings Sentry glutamate hypothesis

Pathologic 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 activity

Patient segregation by PI3K/AKT/mTOR status •  Response to particular drugs •  Where in the PI3K/AKT/mTOR pathway •  Disease natural history

Somatic mutation in non-cancer diseases •  Proteus syndrome (AKT1) •  Beckwith Wiedemann syndrome with hemihypertrophy (AKT2) •  Hemispheric Developmental Brain Malformations (AKT3)

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PHDi

Neuron 74, 41–48, April 12, 2012

Science. 2011 Oct 28;334(6055):474.

N Engl J Med. 2011 Aug 18;365(7):611-9.

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The quest for disease-modifying drugs

Targets Disease Patients Pathways

Drugs

Biomarkers