kerry blanchard shanghai biof
DESCRIPTION
Kerry Blanchard, May 11, 2012. Shanghai Bioforum Translational Medicine, Session S4, Shanghai, ChinaTRANSCRIPT
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