Thomas R' Insel, M'D'

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Translational Neuroscience Then, Now, Imagine
October 6, 2009
Thomas R. Insel, M.D. Director, NIMH
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Translational Neuroscience 1989
Beckman Institute Groundbreaking 1986
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Translational Neuroscience 1989
Brain structure static studies of microscopic
anatomy and gross anatomy
Brain function single unit physiology and
EEG/ERP
Brain development early regional changes in
protein and anatomy
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Translational Neuroscience 1989 - 2009

• From singular to plural

Omics, Physiology, Computational science

• From static to dynamic

Imaging nm cm, real time, in vivo

• From descriptive to mechanistic

Manipulating genes, proteins, and circuits
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From singular to plural Discovery Neuroscience
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Mapping Connections in the Brain Diffusion
Signal Imaging
Source Wedeen et al, 2008
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From static to dynamic Functional Imaging
Source Marcus Raichle, Washington University
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Modules in the brain Naming animals and tools
N 7
Chao et al., Cerebral Cortex, 2002
Tools hammer saw shovel
Animate camel dog face
R
z - 8
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From static to dynamic Observing Plasticity
Nature Reviews Neuroscience Sept 2009
2-photon imaging yields real-time visualization
of changing neural architecture in behaving
rodents
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From descriptive to mechanistic Manipulating
circuits in the brain
Optogenetics Using light activated channels for
manipulating neuronal circuits
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From Description to Mechanism 2009
Molecule Cell System Individual Social
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Sequencing Output (currently 1-2 Gb per machine
per day)
Single molecule?
Short-read sequencers
Microwell pyrosequencing
Second-generation capillary sequencer
Automated slab gel
Manual slab gel
First-generation capillary
1980
1985
1990
1995
2000
2005
2010
Future
Year
MR Stratton et al. Nature 458, 719-724 (2009)
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Democratization of Genomics
454
Illumina
ABI SOLiD
ABI 3730XL
. . . .
Cost of human genome (30x cov)
1B 1990 - 2003
100K Sept, 2009 30K
by late 2010
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Translational Neuroscience 1989 - 2009

• From singular to plural

• From static to dynamic

• From descriptive to mechanistic

Changing the Culture
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The Question for 2009 2029
How will discoveries in brain science become
breakthroughs for improving health?
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Burden of Disease (DALYs)
U.S., Canada, and Western Europe 15-44 years old
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Burden of Disease by Specific Illness
DALYsUnited States, Canada, and Western
Europe15-44 years old
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Mental IllnessWhy the high morbidity?

• Prevalent (6 U.S. - serious)

Disabling (largest population on SSI, SSDI)
Chronic disorders of young people (50 report
onset lt age 15)
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Mental Disorders Mortality

• Over 30,000 suicides per year (in the U.S.)
• - 90 related to mental illness

• For context
• 18,000 homicides
• 20,000 AIDS deaths
• only 3 forms of cancer gt 30,000

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Public Health ImpactEarly Mortality in
Individuals with Major Mental Illness (MMI)

• Data from outpatient
• and inpatient clients
• diagnosed with MMI
• Average age at time of death 56 years
• Increased cardiovascular and pulmonary disease

Adapted from Colton and Manderscheid, 2006, Prev
Chronic Dis
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Economic Burden of Mental Illness
Direct and indirect components of the economic
burden of serious mental disorders, excluding
incarceration, homelessness, comorbid conditions
and early mortality. ( in billions) 1992
2002 Health Care
Expenditures 62.91 100.12 Loss of
earning 76.71 193.23 Disability
(SSI SSDI) 16.41 24.34
Totals 156.0 B 317.6 B
Insel, Am J Psychiatry, 2008
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Disruptive Innovations In Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental disorders.
Mental disorders result from complex genetic risk
plus experiential factors.
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Mental disorders as brain disorders
PNAS, 2007
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Mental disorders as brain disorders
PNAS, 2007
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Brain differences associated with depression
Area 25 altered metabolism and 39 (bipolar)
and 48 (unipolar) reduced grey matter volume
Cg25
Drevets et al., Nature, 1997
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(No Transcript)
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Defining Depression Circuits Response Pathways
Cognition (attention-appraisal-action)
Par40
PM6
hc
PF9/46
Mood state
thal
mF9/10
na-vst
Self-awareness insight
pACC24
amg
mb-vta
oF11
Salience Motivation
sACC25
hth
a-ins
bstem
Interoception (drive-autonomic-circadian)
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Disruptive Innovations In Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental disorders.
Mental disorders result from complex genetic risk
plus experiential factors.
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Mental Disorders are Developmental
Schizophrenia
Drug Abuse and Addiction
10 13 Years
Eating Disorders
Obsessive-Compulsive Disorders
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Development What is it?
Systems Neural proliferation and
regression Synaptic organization Myelin deposition
Source J Giedd, NIMH
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A Developmental Brain Model for Schizophrenia
Normal Development
of Cortical Synapses
10 15 20 25
Age
Based on McGlashan and Hoffman (2000)
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Disruptive Innovations In Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental disorders.
Mental disorders result from complex genetic risk
plus experiential factors.
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High Heritability of Mental Disorders
Insel, JCI, 2009
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The Genomics Revolution

• Human Genome Project (2003)
• Mapped 3 billion bases of DNA in human genome

CTAGGCTTAAGCGGACCTGCTCTAGGTCAGTC.
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Manolio, Brooks, Collins, J Clin Invest 2008
1181590-625.
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Genome Wide Association Studiesin Mental
Disorders, Common Variants

• Schizophrenia
• Bipolar Disorder
• ADHD
• Autism
• Major Depressive Disorder
• OCD
• Treatment Response (antidepressants,
  antipsychotics)

- HLA genes, ZN804A
Ank3, CaCNA1C
CNTNAP2, CDH9, CDH10
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Complex Genetics of Mental Disorders
Penetrance
High
Unusual in Complex Disease
22q11.2 16p11.1 1q21.1 15q13.3
Intermediate
Low-frequency variants with intermediate
penetrance
Modest
Low
Frequency of DNA variation in population
Very rare
Rare
Uncommon
Common
0.001 0.01 0.10
McCarthy et al., Nat Rev Genetics 2008
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Pathways to Translation
Meyer-Lindenberg Weinberger, Nature Rev
Neurosci, 2007
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Translating Neuroscience to Health
Strategic prevention Cure Therapeutics
Biodiagnostics Treatment of core pathology
Diagnosis by symptoms Treatment of episode
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Dr. Beckmans Seven Rules for Success
1. Maintain absolute integrity at all times.
2. Always do your best Never do anything
half-heartedly
3. Never do anything to harm others.
4. Never do anything for which youll be ashamed
later.
5. Always strive for excellence theres no
substitute.
6. Practice moderation in all things including
moderation.
7. Dont take yourself too seriously.
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Paving the Way for Prevention, Recovery, and Cure
www.nimh.nih.gov