Biological Embedding:
Implications for
Neurodevelopment
Clyde Hertzman, MD
Human Early Learning Partnership
University of British Columbia, Vancouver
Gradient in all Cause Mortality:
UK Whitehall Study
CHD Mortality - UK Whitehall Study
SEP Gradients in Health: Social
Determinants to Early Development
• ubiquitous in wealthy and majority world countries
by income, education, or occupation
• cuts across a wide range of disease processes
• not explained by traditional risk factors
• replicates itself on new conditions as they emerge
• occurs among males and females
• begins life as gradient in ‘developmental health’
with life course persistence and ‘flattening up’
Percent vulnerable and SES
Canada
0
0
31.9
29.1
23.1
0
0
Canada
13.7
very poor
poor
31.9
not poor
% vulnerable
well-off
29.1
23.1
0
13.7
0
0
very poor
poor
not poor
% vulnerable
well-off
Percent vulnerable and SES
60
Canada
50
Kosovo
56.3
40
43.2
40
30
30.8
20
10
0
60
Australia
Q1
Q2
Q3
Q4
% vulnerable
Mexico
50
40
35.3
30
27.6
26.3
27.3
24
23.9
20
18.7
17.5
10
16.1
11.2
Bottom 10%
10-25%
25-50%
50-75%
% vulnerable
75-90%
0
Top 90%
Very poor
Poor
% vulnerable
Not poor
Rich
Life Course Problems Related to
Early Life
2nd
Decade
• School Failure
3rd/4th
Decade
• Obesity
5th/6th
Decade
Old Age
• Coronary Heart • Premature
Disease
Aging
• Teen Pregnancy • Elevated Blood
Pressure
• Diabetes
• Criminality
• Depression
• Memory Loss
Biological Embedding
Biological embedding occurs when
• experience gets under the skin and alters human
biodevelopment;
• systematic differences in experience in different
social environments lead to different
biodevelopmental states;
• the differences are stable and long-term;
they influence health, well-being, learning, and/or
behaviour over the life course.
Archeology of Biological Embedding
Experience/Behavior
Neural Circuitry
Cell/Synapse
Gene Function
Surficial Archeology
Experience/Behavior
(early development in context)
Neural Circuitry
Cell/Synapse
Gene Function
Sensitive Periods in Early Brain
Development
Pre-school years
High
School years
Numbers
Peer social skills
Symbol
Language
Habitual ways of responding
Emotional control
Vision
Hearing
Low
0
1
2
3
4
Years
5
6
7
Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.)
The Early Development
Instrument
What Does the EDI Measure?
All Children
Included in Age 5
School Entry Year
‘Shallow’ Archeology
Experience/Behavior
Neural Circuitry
Cell/Synapse
Gene Function
Shallow Archeology
• HPA axis --- cortisol
• ANS system --- epinephrine/ne
• Prefrontal cortex
• Social affiliation --amygdala/locus cereleus
• Immune function -- the ‘peripheral
brain’
SES Differences in Prefrontal
Cortex Activity by School Age
Deep Archeology
‘Social Epigenesis’ and other
processes that can influence
gene expression
Molecular level
Start RNA
Promoter
CH3
Coding sequence
Stop
plmrs
Transcription
mRNA
Translation
protein
What’s new about this?
It does not only occur during basic
fetal development, when cells are
specializing……it can continue after
birth and be influenced by the
broader environment!
Biological Embedding:
Epigenetic Marks of Early Life
Early Life
15-40 yrs
1958 British Birth Cohort Study
(Int J Epid, March 2012)
40 adult males selected from SES extremes in both
childhood and adulthood
• Genome-wide methylation analysis from blood DNA
at 45 years of age
• 20,000 gene promoter regions
•
Methylation levels for 1,252 promoters associated with childhood
SEP
Methylation levels for 1,141 promoters associated with childhood
abuse
But only approx. 80 promoters associated with maternal smoking
during pregnancy!
Wisconsin Study of Families and Work
Essex, Boyce, Hertzman & Kobor, 2011
Infancy
Preschool
N = 570
N = 109
Stress:
•depression symptoms
•expressed anger
•parenting stress
•role overload
•financial stress
Epigenetic profiling:
•Buccal epithelial cells
•Illumina microarray
•~28,000 CpG sites in
~14,000 gene promoters
Epigenetic vestiges of early
developmental adversity
• Differential methylation of
multiple CpG sites by parental
stress in infancy and preschool
• Mothers’ stressors in infancy
more related to differences in
methylation for both girls and
boys
• Fathers’ stressors in preschool
associated with methylation
differences primarily for girls
• A pattern commensurate with
prior knowledge of maternal v
paternal and gender-specific
influences on development
Since 2010, 34 life course studies
have included measurements of
DNA methylation
Ng et al. Genome Biology 2012,
(Ng et al, Genoome Biology 2012; 13:246)
Journal Articles Referring to Biological Embedding*
* Databases
searched by M. Wiens -- Ebsco, Google Scholar, PubMed, Scirus, and Web of
Knowledge -- August 2012
**2012 includes Jan-July only (part-year)
Milestones in Biological Embedding 1
• 2004: Meaney/Szyf paradigm first cited as animal
evidence of biological embedding
• 2006: first human GxE interaction (childhood
maltreatment by MAOA) to be cited as evidence
of biological embedding
• 2006: biological embedding first used to account
for development origins of adult disease
• 2006: biological embedding linked to racial health
disparities in North America
Milestones in Biological Embedding 2
• 2008: biological embedding first used to account for
why parents’ social standing is associated with neural
development in brains of children
• 2008: biological embedding first used to account for
the childhood SES/CHD risk relationship
• 2008: biological embedding first used to justify
investment in the early years as human capital
investment
• 2010: biological embedding first used to ‘explain’ life
course influences of ACE’s
Milestones in Biological Embedding 3
• 2010: biological embedding first used as central
organizing concept in ‘stress’ study (of
inflammation)
• 2011: biological embedding first demonstrated in
human epigenetics
• 2011: biological embedding used to account for
SES differences in telomere length
• 2012: biological embedding first used to account
for validity of allostatic load
2011: Biological Embedding becomes
Conventional Wisdom
“A scientific consensus is emerging that the origins of
adult disease are often found among developmental
and biological disruptions occurring during the early
years of life. These early experiences can affect adult
health in two ways – either by cumulative damage
over time or by the biological embedding of
adversities during sensitive developmental
periods……..”
(Leckman JF, March JS. Editorial: Developmental neuroscience
comes of age. J Child Psychol Psychiatr. 2011;52(4):333-8.)
Merci!
www.earlylearning.ubc.ca