Developmental programmingDevelopmental programming or how your parentsor how your parents’’ environment environment
before you were born impacts on your and your before you were born impacts on your and your childrenschildrens’’ risk of diseaserisk of disease
Jonathan Seckl
Scottish CuisineScottish Cuisine and diseaseand disease
"Without stress, there would be no life" Hans Selye
GlucocorticoidsGlucocorticoids•
Mobilise fuel–
Glucose
– Fatty acids
– Proteins
• Increase blood pressure
• Euphoria
• Inhibit–
inflammation
– immune responses
– wound healing
– digestion
– growth/bone formation
– reproduction
– detailed learning and memory
cortisol
2
O
C = O
CH OH
O HH O
Cortisol
....
Cushing’s Disease
• High blood pressure• diabetes• high blood cholesterol• abdominal obesity• stretch marks• bruising• osteoporosis• muscle weakness• infertility• depression• memory loss
XX
Nature and nurtureNature and nurture
But
Identical twins reared apart from birth (same genes, different environment)……
have the same concordance of many diseases (schizophrenia, diabetes, etc) as those reared together (same genes, same environment).
This suggests that the environmental factors that underlie the differences between identical twins operate BEFORE or at birth.
Birth weight and adult diseaseBirth weight and adult disease
8.5 lbs (~4 kg)8.5 lbs (~4 kg) 5.5 lbs (~2.4 kg)5.5 lbs (~2.4 kg)
Ethel Margaret BurnsideEthel Margaret Burnside HertfordshireHertfordshire’’s s ‘‘Lady Inspector of MidwivesLady Inspector of Midwives’’ (1911(1911--30)30)
Birth weight and adult diseaseBirth weight and adult disease
Barker et al, 1990, BMJ, 301:259
Low birth weight and risk of T2D/MSLow birth weight and risk of T2D/MS
Hales et al, BMJ 1991; Barker et al, Diabetologia 1993; Whincup et al, JAMA 2008
Systematic review Systematic review
• 30 reports, 152000 subjects
• Pooled OR 0.75/kg (CI 0.70-0.81)
• Not reduced by adjusting:
– adult BMI
– SE status
Type 2 diabetes Metabolic syndrome
10
5
20
10
<5.5 -6.5 -7.5 -8.5 -9.5 >9.5
Odd
s ra
tio
<5.5 -6.5 -7.5 -8.5 -9.5 >9.5Birth weight (lbs) Birth weight (lbs)
from the Hertfordshire cohort study: Thompson et al BJPsych 2001
Birth weight and depression aged 68 yearsBirth weight and depression aged 68 years
Odds ratio
P=0.02
0
0.5
1
1.5
2
2.5
3
3.5
<6.5 6.5-7.5 7.5-8.5 >8.5
<5.5<5.5 --6.56.5 --7.57.5 --8.58.5 --9.59.5 >9.5>9.5
400400
200200
300300
plasmaplasmacortisolcortisolnmol/lnmol/l
Birth weight (lbs)Birth weight (lbs)
P=0.001P=0.001n=423n=423
Plasma Plasma cortisolcortisol in 64y old men correlates negatively in 64y old men correlates negatively
with birth weightwith birth weight
Phillips et al, Phillips et al, JCE&MJCE&M, 1998, 1998
Birth weight and adult diseaseBirth weight and adult disease
8.7 lbs4 kg
5.3 lbs2.4 kg
low birth weight
• hypertension• type 2 diabetes• hyperlipidaemia• metabolic syndome• coronary heart disease• osteoporosis• depression, anxiety, psychosis
• Increased overall mortality
• Butterflies hatched during different seasons were coloured differently
• Season-dependent colouration mimicked by larval incubation temperature
summer winter
Weissman 1893
The environment and regulation of The environment and regulation of development development
• The phenomenon is widespread (ubiquitous)
• It is adaptive– In a famine-striken warzone the ‘small baby’ phenotype
appears beneficial (low birth weight, rapid growth, higher BP, waryness, early puberty, etc)
• A tiny improvement in individual survival over evolutionary time would maintain the processes
• Associations with disease reflect contemporary concerns and miss the underlying biology
• We do not (yet) understand most of the ‘rules’– low b. wt is a blunt marker of ‘something challenging happened’
Developmental programming is Developmental programming is notnot about about diseasedisease
Mechanisms linking to adult diseaseMechanisms linking to adult disease
Possible mechanisms• genetics
8.7 lbs (4 kg) 5.3 lbs (2.4 kg)
Mechanisms linking to adult diseaseMechanisms linking to adult disease
8.7 lbs (4 kg) 5.3 lbs (2.4 kg)
Possible mechanisms• genetics• Socio-economic class
Mechanisms linking to adult diseaseMechanisms linking to adult diseasePossible mechanisms• genetics• socio-economic class• maternal malnutrition
8.7 lbs (4 kg) 5.3 lbs (2.4 kg)
PrePre--natal starvationnatal starvation……Dutch Hunger Winter 1945 and Chinese Famine 1959Dutch Hunger Winter 1945 and Chinese Famine 1959--6161
offspring show:-• small reduction in birth weight• increased schizophrenia• addiction and depression• increased diabetes• increased blood pressure• more heart disease• higher cortisol
levels
‘We Were So Hungry We Ate Tulips’
Father Leo Zonneveld
Mechanisms linking to adult diseaseMechanisms linking to adult disease
Possible mechanisms• genetics• social class• maternal malnutrition
2
O
C = O
CH OH
O
8.7 lbs (4 kg) 5.3 lbs (2.4 kg)
• glucocorticoids• reduce birth weight
• alter organ maturation• cause hypertension,
diabetes, depression, etc• Sex steroids ‘programme’
Prenatal glucocorticoid excess ‘programmes’ higher BP and glucose in adult offspring
systolic BP
120
130
140
150
160*
*
female male
controldexamethasone
mmHg
insglu
no inject saline dexwk 1
dexwk 2
dexwk 3
0
1
2
3 *
Single dose of Single dose of betamethasonebetamethasone ‘‘programmesprogrammes’’ insulin insulin resistance 30 years later: resistance 30 years later: Lancet 28Lancet 28thth May 2005May 2005
11-HSD-2
VOL 341: FEB 6, 1993 355
Dysfunction of placental glucocorticoid
barrier: link between fetal
environment and adult hypertension?
CHRISTOPHER R. W. EDWARDS RAFN BENEDIKTSSON ROBERT S. LINDSAY
JONATHAN R. SECKLBirthweight is associated with the subsequent development of common
disorders of adult life, especially hypertensior;:' maternal malnutrition has been suggested as the cause. We suggest an alternative aetiology- increased fetal exposure to maternal glucocorticoids. This hypothesis is supported by our findings that in rats decreased activity of the enzyme that acts as a placental barrier to maternal glucocorticoids (11~-hydroxysteroid dehydrogenase) is associated with low birthweight Furthermore, increased exposure of the fetus to exogenous glucocorticoids leads to low birthweight and subsequent hypertension in the offspring. Glucocorticoids acting during critical periods of prenatal development may, like other steroid hormones, exert organisational effects or imprint patterns of response that persist throughout life. Thus, the lifetime risk of common disorders may be partly determined by the intrauterine environmentLancet 1993; 341: 355-57.
whereas weight at 12 months correlates closely with weight subsequently. to This fInding suggests that in both animals and man there are local maternal factors, quite distinct from the maternal and paternal genes affecting the infant's ultimate size, which limit the growth of the fetus. Physical limitation of uterine space is not an important factor in rabbits,9 although the evidence in man is less clear.5 Whatever these maternal factors are, there could be catch-up growth after birth. It is interesting that adolescents with the highest blood pressures are those who grow fastest as children.ll
There are clear geographical differences in the incidence of cardiovascular disease in the UK; the correlation between these variations and blood pressure,12 suggests that there are important environmental determinants of blood pressure. Maternal smoking can affect fetal growth, but not placental weight.14 Moreover, smoking is associated with proportional reductions in birthweight and length, 15for any birthweight, head circumference increased with placental weight, but body length decreased. The Preston investigators5 suggested that there might be diversion of blood away from the trunk
Placental 11Placental 11--HSD2 activityHSD2 activity
ratrat humanhumanDeficiency of the placental cortisol barrier and reduced birth weight
placental 11β-HSD2
*
362 US babies
Huh et al, BMC Med 2008Quartile of E/(E+F) ratio
*
80
84
88
92
96
100
50
54
58
62Diastolic BPmmHg
Systolic BPmmHg
Placental 11Placental 11ββ--HSD2 predicts BP at 3yrsHSD2 predicts BP at 3yrs
1111ßß--HSD inhibition programmes increased HSD inhibition programmes increased blood pressure and glucoseblood pressure and glucose
112200
113300
114400
115500 *
00
11
22
33
44
55
66
55
66
77
88
99
controlCBX
12012090906060303000 minmin
**
* **
control CBX control CBX
birth weightbirth weight blood pressureblood pressure blood glucoseblood glucose6 months
Lindsay et al, Lindsay et al, HypertensionHypertension, 1996, 1996Lindsay et al, Lindsay et al, DiabetologiaDiabetologia, 1996, 1996
Pla
cen
tal
11
β-H
SD
2
•• cortcort•• other placentalother placental
and maternal and maternal factorsfactors
dietdiet stressstress diseasedisease
PlacentalGC barrier
0
5
10
15
20
25
30
35
22% 18% 9%
Placental 11Placental 11ββ--HSD2 deficiency: key to developmental HSD2 deficiency: key to developmental programming?programming?
Langley-Evans et al, 1996
Protein restriction
**
*
**
Mairesse et al, 2007
stress
con stress
Maternal anxiety, reduced placental 11β-HSD2 and increased fetal cortisol
Glover, O’Donnell et al, Psychoneuroendocrinol, 2009; 2011
Pla
cen
tal 1
1β-
HS
D2
Pla
cen
tal 1
1β-
HS
D2
Maternal anxiety scoreMaternal anxiety score
Feta
lco
rtis
ol
Maternal cortisol
A Finnish favouriteA Finnish favourite
Glycyrrhiza glabra
Maternal licorice consumption reduces offspring cognition and increases ADHD
0.0153.2 (8.7)49.1 (9.1)Total behavior problems
0.0353.6 (8.8)50.1 (8.4)Externalizing symptoms
0.1352.7 (9.5)50.4 (9.9)Internalizing symptoms
Child Behavior Checklist
0.049.3 (3.4)10.4 (3.1)Narrative memoryDevelopmental Neuropsychological Assessment
0.2399 (14.9)102 (12.3)Beery Development Visual-Motor Integration
0.4610.3 (3.6)10.8 (3.1)Symbol search
0.049.8 (3.1)10.9 (2.9)Block design
0.0110.2 (3.3)11.6 (3.1)Similarities
0.0210.4 (2.8)11.6 (3.0)Vocabulary
Wechsler Intelligence Scale for Children III
M (SD)M (SD)
N = 62N = 202
High
> 500 mg/week
Zero-low
0-249
P value
Maternal consumption of glycyrrhizin
Räikkönen et al, Am J Epid 2010
Effects persist after adjusting for……child’s sex, age, length of gestation, birth weight, head circumference, birth order, mother’s age, occupational status, smoking, alcohol consumption, psychological stress during pregnancy,
mode of delivery, gestational diabetes, gestational hypertension and preeclampsia
0.0425.9 %15.4 %Attention Deficit Hyperactivity Disorder
How to programme a tissue?How to programme a tissue?
• alter cell number– proliferation– apoptosis
• alter gene expression– chromatin
• histones (acetylation, methylation)• DNA methylation
– transcription factors
1Z 21Bmmmmmm
Prenatal challenges programme the Prenatal challenges programme the glucocorticoidglucocorticoid receptor, but in a cellreceptor, but in a cell--specific mannerspecific manner
Nyirenda et al, JCI, 1998; Cleasby et al, Endo, 2003
**
visceral
1.0
0.5
subcutperivenous periportal0
100
200
300
400 **
adiposeliver
DG CA1 CA2 CA3
hippocampus
* *
Levitt et al, Neuroendocrinol, 1996
11 14 1111715 16 2
17 2-9
16 2-9
19 2-9
liver hippoc thymus
+++ +++ +++
- ++ -
++ - -
- - ++
AP2 NGFIA
n >11
11018
11 2-9
19
McCormick et al, Mol Endo, 2000
>30kb
The GR gene contains multiple alternate, tissueThe GR gene contains multiple alternate, tissue--specific specific 1st 1st exonsexons
5HT
PKAcAMPCa++
GR geneGR gene11 14 1111715 16 211018 19
AP2 NGFIAP2 NGFI--AA
17 2-9
17 2-9
17 2-9
prenatal GCexcess
5HT regulates hippocampal
GR gene transcription
How can early life events affect someone for the rest
of their lifespan?
epigeneticsepigenetics
epigenetics
EpigeneticsEpigenetics -- the differences in geneticallythe differences in genetically--identical identical individuals grown in different wombs individuals grown in different wombs
CopycatCopycat CopycatCopycat’’s s ‘‘mummum’’
Weaver et al, Nature Neurosci 2004
CpG
C-m
eth
yla
tio
n(%
)
Early life environment determines the epigenetic state Early life environment determines the epigenetic state ((methylationmethylation) of the GR 1) of the GR 1 77 promoterpromoter
16 17
17
NGFI-A
5’ CpG 3’ CpG 100
80
60
40
20
0
**
E20 P1 P6 P21 P90 E20 P1 P6 P21 P90C-m
eth
yla
tio
n(%
)
100
80
60
40
20
0
* *
Age (dy)
Lower total DNA methylation with low SES
McGuinness et al, Int J Epidemiol 2012
no
n-m
an
ual
man
ual
3535--44 y44 y 4545--54 y54 y 5555--64 y64 y
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
man
ual
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
man
ual
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
no
n-m
an
ual
man
ual
3535--44 y44 y 4545--54 y54 y 5555--64 y64 y3535--44 y44 y 4545--54 y54 y
The excitement of steroid metabolism
Children exposed to the Holocaust
Lower Lower glucocorticoidglucocorticoid metabolism in Holocaust survivorsmetabolism in Holocaust survivors
0.99 ±
0.08**1.23 ±
0.0811ß-HSD2 ratio
7.4 ±
1.48.0 ±
1.55-red ratio
5.6 ±
0.7**17 ±
45-red ratio
1600 ±
3001900 ±
4005-THF
2500 ±
400**5600 ±
6005-THF
6500 ±
600*11000 ±
1200Total glucocorticoids
Controls (n=22) Holocaust survivors (n=51)
Yehuda et al, J Psychiatr Res 2009
Younger at trauma - greater decrease in metabolism
Steroid metabolism
Age at trauma ‘exposure’5 10 15 20 years
‘normal’ range
0
9.11 study9.11 study -- 1 yr old offspring 1 yr old offspring cortisolcortisol
altered: altered:
only after 3only after 3rdrd trimester exposuretrimester exposure
First Trimester
0
1
2
3
4
5
6
7
8
Log
Saliv
ary
Cor
tisol
(nm
/uL)
Second Trimester
012345678
Third Trimester
012345678
am pm am pm am pm
YehudaYehuda et al, et al, JCE&MJCE&M, 2005, 2005
cortisol cortisone
5-dihydrocortisol
5-reductase
11β-HSD2
INTRACRINE EFFECTSINTRACRINE EFFECTS2 enzymes are reduced permanently in youngest exposed to Holocau2 enzymes are reduced permanently in youngest exposed to Holocaustst
Both seem plausible early life adaptations to starvation/stress
Increased fuelGlucoseCholesterol and fats
Increased BPSalt retentionBlood pressure
Programmed for deprivation… (famine, physical challenge)….
then born to EXCESS and STRESS
Obesity Trends* Among U.S. Adults BRFSS, 1985
Obesity Trends* Among U.S. Adults BRFSS, 1990
Obesity Trends* Among U.S. Adults BRFSS, 1995
Obesity Trends* Among U.S. Adults BRFSS, 2000
Obesity Trends* Among U.S. Adults BRFSS, 2005
>30%
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. Adults BRFSS, 2010
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
PTSD after Holocaust PTSD after Holocaust traumatisationtraumatisation associates associates with with ‘‘metabolic syndromemetabolic syndrome’’
020406080
100120140160180200
Controls Holocaust survivorsPTSD+
Perc
ent w
ith sy
mpt
omBMI>25Atherosclerosis and/or HyperlipidemiaDiabetesHypertension
‘‘IntergenerationalIntergenerational’’ effectseffects
Birth weightBirth weight Glucose homeostasisGlucose homeostasis
Intergenerational effects of prenatal stressIntergenerational effects of prenatal stress
F1F100
1010
2020
**
00
11
22
33
44
55
66
gg
F1F1 F2F2
**
*
F2F2
**
Drake et al, Am J Drake et al, Am J PhysiolPhysiol 20052005
EpigeneticsEpigenetics??
*†
02468
1012141618
F2 veh F2 dex F2 veh/dex F2 dex/veh
*
*†*†
02468
1012141618
F2 veh F2 dex F2 veh/dex F2 dex/veh
*
*†*†
02468
1012141618
F2 veh F2 dex F2 veh/dex F2 dex/veh
*
*†
Liver glucose production
veh vehdex dexMother as fetusFather as fetus
Drake et al, Am J Drake et al, Am J PhysiolPhysiol 20052005
Fetal liver F1
F2
Veh/VehDex/DexDex/Veh MATERNALVeh/Dex PATERNAL
0.5
1
1.5
2
Igf2 Cdkn1c GR
mR
NA
**
**
0
0.5
1
1.5
2
2.5
Igf2 cdkn1c(Grb10)
GR
*
*
Phlda2
Phlda2
* *
The changes differ in the first and second generationsThe changes differ in the first and second generations
Drake et al, Epigenetics, 2011
*
Epigenetic effects also differ in the first and second Epigenetic effects also differ in the first and second
generationsgenerations
% m
ethy
latio
n
0
10
20
30
40
50
60
DMR2
saldex
**
Drake et al, Epigenetics 2011
0
30
40
50
60
ICR
*
F1=DMR2 F2=ICR
*
P0 P1 P2 P3
H19DMR1DMR0 DMR2 ICR
PaternalMaternal
15-30% methylation
difference in Beckwith-Weidermann
and Silver-Russell syndromes
Overkalix
You are what your grandparents ate?You are what your grandparents ate?
Pembrey et al, Eur J Hum Gen, 2006
Gra
nd
son
’s m
ort
ali
tyR
ela
tive r
isk
Gra
nd
dau
gh
ter’
s m
ort
ali
tyR
ela
tive r
isk
2.0
1.0
0.5
2.0
1.0
0.5
GrandparentGrandparent’’ssNutrition in Nutrition in childhoodchildhood
PoorPoorGoodGood
0 2 4 6 8 10 12 14 16 18 20Paternal Grandmother’s age
0 2 4 6 8 10 12 14 16 18 20Paternal Grandfather’s age
And unto the next generation?And unto the next generation?
This suggests that parental PTSD is a ‘vulnerability factor’ for offspring PTSD
•• 50% Holocaust survivors have PTSD 50% Holocaust survivors have PTSD (5(5--10% normal population)10% normal population)
•• 30% of survivors30% of survivors’’ children have PTSDchildren have PTSD
•• These children do not appear to have These children do not appear to have experienced more major traumaexperienced more major trauma
•• Holocaust exposure predicts offspring Holocaust exposure predicts offspring depression, ..but survivor PTSD depression, ..but survivor PTSD predicts offspring PTSDpredicts offspring PTSD
PlasmaCortisol(ug/dl)14
6
4
06 12 18 24 h
ControlsNo parental PTSDPaternal PTSDMaternal PTSD
You are shaped by your motherYou are shaped by your mother’’s stress:s stress:maternal PTSD & her healthy offspringmaternal PTSD & her healthy offspring’’s s cortisolcortisol
12
10
8 **
Yehuda et al, Arch Gen Psych 2008
Maternal PTSD also impacts steroid enzymes in her Maternal PTSD also impacts steroid enzymes in her childrenchildren
No ParentExposed
No ParentsPTSD
Father PTSD
MotherPTSD
Both Parents PTSD
0
0.2
0.4
0.6
0.8
1
Rat
io E
/F
11β-HSD2
0
1000
2000
3000
4000
5000
6000
No Parentalexposure
No ParentsPTSD
Father PTSD
MotherPTSD
Both ParentsPTSD
5-reductase
Yehuda et al, unpublished
9.11 study9.11 study lower 5lower 5--reductase reductase predictspredicts PTSDPTSD
Yehuda et al, Yehuda et al, PsychoneuroendocrinologyPsychoneuroendocrinology 20092009
0
1
2
3
4
5
11-HSD 11-HSD2
Non-recoverers
Recoverers
0
0.04
0.08
0.12
5
reductase 5
reductase
11β-HSDs A ring reductases
*
So what can be done?So what can be done?
The 1960s MotherwellThe 1960s Motherwell dietdietIMPORTANT. This is a special diet for expectant mothers. If you
ADD to it or TAKE from it, it is no longer special
1. Meat – One pound of red meat should be eaten every day of gestation. Quantity is more important than quality.
2. Green vegetables – try to eat twice daily. Do not eat peas, beans, turnip, parsnip, carrot or beetroot
3. Sweets – should be limited to ½ pound of boiled sweets per week. Do not eat chocolate
4. Do not eat potatoes or chips, breads, rolls, scones, cakes or biscuits of any kind
5. Do not eat milk puddings, cereals, macaroni, spaghetti and ice cream
If you persevere with this diet for three weeks it becomes natural and easy…………
The advantages of success in controlling your diet……come only if you are successful, not just trying
HF inHF in pregnancy:pregnancy:
increased cortisol in 30y offspringincreased cortisol in 30y offspring
Maternal meat & fish intake(portions /week)
trend p<0.05
350
400
450
500
550
Plasma cortisol(nmol/l)
<11 12 -15 16 -
21 >21
Reynolds et al, JCEM 2007
Biomarkers and stratified therapy?Biomarkers and stratified therapy?
Reynolds, Drake et al, unpublished
0 2 4 6 8 10 12 14 16 18 20 22 24
Meat portions in late pregnancy
-1
0
1
2
3
4
5
6
Glu
coco
rtico
id re
cept
or m
ethy
latio
n (%
)
r=0.53, p=0.003
Adult GR 1Adult GR 177
and maternal dietand maternal diet
Meat portions in late pregnancy
0 4 8 12 16 20
GR
17
mR
NA
(%
)
Metformin reversesMetformin reversesincreased liver GRincreased liver GR
*
control
GR
mR
NA
Cleasby et al, Endo, 2003
metformin
Give methyl donors (Give methyl donors (folate, choline, Vit B12, betainefolate, choline, Vit B12, betaine))
Leptin reverses low protein effects on placental Leptin reverses low protein effects on placental 1111ββ--HSD2 and birth wtHSD2 and birth wt
0
5
10
15
20
25
**
% C
onve
rsio
n B
to A
Placental 11β-HSD2 activity
Saline Saline Saline Saline LeptinLeptinChow Chow LP LP LPLP
0.0
1.0
2.0
3.0
4.0
5.0
Feta
l wt (
g)
**
Saline Saline Saline Saline LeptinLeptinChow Chow LP LP LPLP
Fetal wt
Stocker et al, Int J Ob, 2004
SummarySummary
• A variety of environmental factors ‘programme’ the offspring for the lifespan
• The outcomes of different maternal challenges are rather similar
• Maternal stress and its glucocorticoid hormone mediators is a powerful programming influence
• Placental 11β-HSD2 affords one link between maternal, placental and fetal environments
• Epigenetic alterations are likely to underpin some of these effects
• The brain is particularly vulnerable to fetal programming
• Programmed changes in glucocorticoid metabolism may impact vulnerability to mood disorders, notably PTSD
• Effects persist into a second generation
• Not everything is written in your genes and epigenes
And the Future?And the Future?
• We don’t yet know how important these early life impacts are, nevertheless..
• Epigenetic marks may measure individual exposure and risk
• They are relatively stable, unlike many blood tests and other measures in adult life
• Epigenetic changes are also potentially modifiable, unlike genetics
• If we can understand the ‘rules’ we may be able to target screening and ‘prevention’ to those at greatest risk
• We may also find ways to personalise therapy depending on the individual ‘cause’ of disease
• However, this biology has survived hundreds of millions of years of evolution because, on balance, it is beneficial to the individual, so interfering blindly may give unwanted consequences
Edinburgh
Amanda DrakeLizzy Cottrell
Caitlin WyrwollRafn Benediktsson
Robbie LindsayRoger Brown
Moffat NyirendaMark CleasbyLincoln Liu
Chris KenyonLeonie Welberg
Justin TangAnnick deVriesMegan HolmesKaren ChapmanJim McCormick
Dawn LivingstoneRebecca Reynolds
Ruth AndrewRichard Meehan
11ß-HSD KOsJohn Mullins
Janice PatersonYuri Kotelevtsev
Collaborations
Mt Sinai, New YorkRachael Yehuda
Linda Bierer
SouthamptonDavid BarkerDavid PhillipsKeith Godfrey
Simon Langley-EvansMark Hanson
BuckinghamClaire Stocker
Mike Cawthorne
McGillMichael Meaney
Josie DiorioIan WeaverMoshe Szyf
Collaborations
HelsinkiKatri RaikkonenJohan Eriksson
DallasDavid Russell
Mala Mahendroo
We canWe can’’t avoid early life stresst avoid early life stress
Strewth Bruce! Is that you?
Methyl donor (icv) methylates GR1Methyl donor (icv) methylates GR177
in adult hippocampus in adult hippocampus