NeuroDevNet
What is Development?
Thomas R. Insel, M.D.
Director, NIMH
September, 2012
[Disclosures - None]
What is development?
The coordinated and reciprocal unfolding of
biological and psychological processes over time.
Time
Individual
Generational
Evolutionary
$0
Sep-01
Dec-01
Mar-02
Jun-02
Sep-02
Dec-02
Mar-03
Jun-03
Sep-03
Dec-03
Mar-04
Jun-04
Sep-04
Dec-04
Mar-05
Jun-05
Sep-05
Dec-05
Mar-06
Jun-06
Sep-06
Dec-06
Mar-07
Jun-07
Sep-07
Dec-07
Mar-08
Jun-08
Sep-08
Dec-08
Mar-09
Jun-09
Sep-09
Dec-09
Mar-10
Jun-10
Sep-10
Dec-10
Mar-11
Sequencing Costs Drop Faster than Moore’s Law
Cost per Megabase of DNA Sequence
$10,000
$1,000
$100
28,500X
$10
$1
Moore’s Law
Cost per Mb
Development: Embracing Complexity
Mom
Central Dogma of Biology
DNA
Dad
RNA
Protein
Genome–Transcriptome-Proteome
Every cell has the same DNA, but each
cell type has different RNA “expressed”
and different proteins produced.
Development = Process of differentiation.
Embracing Complexity: Transcriptomics
11/11
90% of genes vary across
development
Fetal brain: 60%
expressed differently; 83%
processed differently
Figure 1c. Global spatiotemporal dynamics of gene
expression.
Same cell but different
transcriptome during
development
Embracing Complexity: Transcriptomics
AJHG
Feb 12, 2012
108 subs from fetal to elderly
14,500 genes; 27,000 CpG loci
PFC – marked change from
fetal to postnatal
Brain Cloud
Somatic Mutations
12/11
18,000 insertions
unique to human
brain
Genome is dynamic
and unstable following
fertilization
8
De Novo Variation
(et al.)
Unexpected High Variation in Human Genome
Complete Sequencing in the 1000 Genomes Project
185 genomes from “healthy” subjects
Approx 100 LoF variants per genome
Approx 20 homozygous LoF variants (KOs) per genome
Identified >1,000 KOs of human genes,
most with no functional annotation
DNA is not Destiny
• DNA sequence is not fixed.
Variation can be tissue specific.
• Development is resilient.
Each of us is a “knockout” for
several genes.
• Genetic ≠ Inherited. It’s not (all)
your parent’s (or grandparent’s)
fault.
Development: Revising the Central Dogma
Mom
Dad
Developmental Biology
DNA
Infant’s
germline DNA
not a perfect
replication of
parents
RNA
Brain’s DNA
not a perfect
replication of
germline DNA
Protein
RNA and protein
depend on age
Embracing Complexity – Parental Imprinting
Science 2010
Mom
DNA – parental origin matters,
Dad according to brain area, age,
and sex of offspring
What is development?
Development = Process of
differentiation
Experience
Epigenomics
Changes in gene expression in the absence of changes in
DNA sequence.
Some experience-dependent
Some age-dependent
Some sex-dependent
Mechanisms and Duration - TBD
Multigenerational Transmission of Traits
Biological Psychiatry 2010
Biological Psychiatry 2011
Epigenetic Transgenerational Effects
Nature Rev Genetics March 2012
Epigenetic marks survive “erasure” during fertilization
metastable epialleles
environmentally sensitive
Diffusible elements: RNA species transferred during fertilization
Developmental Microbiomics
We are not alone: 90% of “our” DNA is not human DNA
Asthma
Allergies
Type 1 Diabetes
CNS?
Developmental Microbiomics
We are not alone: 90% of “our” DNA is not human DNA
Summary
What is development?
The coordinated and reciprocal unfolding of
biological and psychological processes.
Summary
What is development?
DNA contains many types of variation, some of which is not
“inherited”, some potentially specific to brain, and some
modified by epigenetic marks during critical periods
RNA highly variable across time, especially in brain where
expression may depend on parent of origin as well as
experience
Human development occurs in a microbial ecosystem.
Summary
I have no doubt that in reality the
future will be vastly more surprising
than anything I can imagine. Now my
own suspicion is that the Universe is
not only queerer than we suppose, but
queerer than we can suppose.
JBS Haldane
Possible Worlds and other papers, p 227
1927
Paving the Way for Prevention, Recovery, and Cure
www.nimh.nih.gov