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

1. Problems
with
Transla1on
Kerry
L.
Blanchard,
PhD,
MD

2. 坐井观天

3. My
transla1on
+
Google
坐井观天 = Sit
Well
Look
Sky

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. 坐 井 观 天
Zuo
Jing
Guan
Tian
To
have
tunnel
vision
Big
fish
in
a
liJle
pond
大 鱼 小 池

6. Something
a
li&le
bit
scary
Zuo
Jing
Guan
Tian
昨鲸管田
Yesterday
a
whale
managed
a
field

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. 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. 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
9

10. What is translational research?
Translational research is the
holistic rendering of the
interactions between
patients, diseases, targets
and drugs.
10

11. 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
11

12. 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
12

13. 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
13

14. 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
14

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 activity
Discovery 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. 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. 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)
17

18. PHDi
18

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. The quest for
disease-modifying drugs
Drugs
Targets Pathways Disease Patients
Biomarkers
20