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Radici profondeper l’adultodi domani
Vassilios Fanos
Terapia Intensiva Neonatale,Patologia Neonatale, e Nido
Azienda Mista eUniversità degli Studi di Cagliari
Agendafrom Eliot to Eliot
• Background• Barker: developmental programming• An endless story of trees• Who are the actors ot the scenario?• Programming in the different organs• U-shaped risk• 3 examples: brain, heart, kidney• 3 M and Maternal Milk: Metabolomics,
Microbiomics, Multipotent stem cells• Take-home messages• Conclusions: 10 P Pediatrics
In my beginning is my end…
Thomas S. Eliot. Four Quartets
In my beginning is my end…We had the experience but miss themeaning,And approach to meaning restores theexperienceIn a different form, beyond any meaning…The only wisdom we can hope to acquireIs the wisdom of humility:humility is endless.
Thomas S. Eliot. Four Quartets
What is life? (E. Schrödinger)
Le cinque grandi ideedella biologia e della medicina (P. Nurse)Cosa non buttare dalla mongolfiera
• Genoma• Cellula• Biochimica• Evoluzione• Biologia dei sistemi
(systems biology)
Geographic Information Systemof a Human Being:one health, so many omics
The new languages of Medicine (I)Metabolomics
Systems Biology
Systems Medicine
Networks Medicine
Omics Technologies
Data trained Medicine
Big data in Medicine
Resilience, antifragility, fragility
Olistic Medicine
Individualized Medicine
Key word: complexityThe whole is not equivalentto the sum of its parts (Aristotle)
The new languages of Medicine (II)Microbiomics
Microbiota
Olobionte
Networking batterico
Sociomicrobiologia batterica
Ecosistema corporeo
Co-evoluzione
Simbiotici
Sistema NEI (neuro-endocrino-
immunitario)
Batteri ed evoluzione del
cervello
Trapianto di microbiota
Perinatalprogramming
“The response by a developing
organism to a specific challenge
during a critical time window that
alters the trajectory of development
qualitatively and/or quantitatively with
resulting persistent effects on
phenotype»
Perinatalprogramming
“The response by a developing
organism to a specific challenge
during a critical time window that
alters the trajectory of development
qualitatively and/or quantitatively with
resulting persistent effects on
phenotype»
Perinatalprogramming
“The response by a developing
organism to a specific challenge
during a critical time window that
alters the trajectory of development
qualitatively and/or quantitatively with
resulting persistent effects on
phenotype»
Are the fetus and thenewborn father to theman?
CV DiseaseHypertensionDyslipidemiaObesity
PulmonaryDiseaseRenal Disease
DiabetesDepressionSchizophreniaAnti-SocialPersonalityDisorderAutism
First Trimester Second Trimester Third Trimester
Windows of vulnerability/Windows of opportunity
During the Dutch Famine of 1944–1945, energy intakedropped from 1,800 to 400–800 calories per day for about 5 months.
…an endless story of trees
Struttura dell'albero bronchiale: un albero senza foglie,rovesciato, con i rami vuoti internamente.
Santiago Ramon y Cayal (1852 – 1934) Spanish pathologist, histologist,neuroscientist and Nobel laureate, the father of modern neuroscience
“The totalarborization of aneuron representsthe graphic historyof conflicts sufferedduring thedevelopmental life”.
NOREGENERATION
….we have not yet unravelled themistery of what is our brain.
…looking to the patient, not tothe disease.
PRECISION MEDICINE
Barack Obama, interviewto Popular Science, 15February, 2016
Ecole Polytechnique Fèdèrale deLausanne, blue Brain Project 2008
Thirty millions connections betweenten thousand neurons.The different colors indicatedistinctive levels of electric activity
Jackson Pollock, Number 5, 1948
The brain is not a computer, it is a jungle of trees
Metanephric mesenchymeand Branching ureteric bud
The kidney: How does it make a tree?
The Mysterious Treeof a Newborn’s Life
Understanding the Placenta, the least understood human organAn innocent bystander?
By DENISE GRADY New York Times JULY 14, 2014
A print of a placenta was created by dipping the organ’s treelike branches in blueacrylic paint. The blood vessels that feed the branches were painted red before theblot was made.
Placenta is the first ofthe trees of theorganism: when it isstrongly involved inpathologies, especiallyat ≤ 26 weeks ofgestation, it probablydetermines a negativeinfluence on all theother trees.
Editorial (Curr Pharmac Design 2012)
Cells, The Tree, Drugs and The Tailor
Vassilios Fanos
•Hypoplasia: less cells•Dysplasia: less function
Reduction/inhibition of arborizationbrain connectionsbronchial treeureteric bud……….
Reduction of vascular arborization
What is a disease?
At high power (13,000X), interior of the liver mitochondria is presented, allowing a goodevaluation of cristae volume and architecture. Mocci C, J Pediatr Neonat Individual Med. 2014
At high power (13,000X), interior of the liver mitochondria is presented, allowing a goodevaluation of cristae volume and architecture. Mocci C, J Pediatr Neonat Individual Med. 2014
Uteroplacental insufficiency Reduction in energy supplyand oxygen activation of mitochondria in the fetus to satisfy
the cellular need of energy increased production of ROSand oxidative stress mitochondrial dysfunction long term
problems in all organs
Finestra di vulnerabilità
Identical twinsare notidentical!
SameGenome/DifferentEpigenome• Acetylome• Metylome• Microbiome• Virome• Fungome• Inflammasome• Metabolome• Phenome• Diseasome
TWINS
Food Microbiota
Metabolites Programming
Who are thenew actorsof thescenario?
Gut microbiotachanges duringpregnancy
ProteobacteriaActionobacteria
DiversityFecalibacterion
Koren O.Cell 2012
AVETE MAI VISTODEI TOPI PRIVI DIGERMI?
SONO ANIMALISERIAMENTEINCASINATI!
MARIA GLORIA DOMINGUEZ-BELLOMicrobiologa presso la New YorkUniversity
EnvironmentalHealthPerspective
7 July 2016,Vol. 124
La scatolanera dellagravidanza
Si stima che un lattante che ingerisce 800 ml di latte materno al giornopossa recepire, per questa via, fra i 100.000 e i 10.000.000 di batteri
Obesity?Autism?
From tyrosine via the gut bacteria
Abnormal metabolites arising from anaerobic bacteria of the gut(Clostridia spp.). Elevated in urine in previous studies on autism.Decrease after treatment with oral vancomycin: a valid biomarkerfor Clostridia spp.
Do each of these babies havedifferent adult health fates?
Urinary metabolomics reveals that low and high birthweights infants share elevated inositol concentrations at
birth
L. Barberini 1, A. Noto 6, C. Fattuoni 2, D. Grapov 5, A. Casanova 3, G. Fenu 4, M.Gaviano 4, R. Carboni 6, G. Ottonello 6, M. Crisafulli 6, V. Fanos 6, A. Dessì 6
Universities of Cagliari and California Davis (submittedBiomed Res Intern)
inositol
AUC=1
RISCHIO CARDIOVASCOLARE INSUFFICIENZA RENALECRONICA
DIABETE AUTISMO
October 2015
Segmento 2.
Sviluppo delcervello: come siforma una giungla
Abbot A,Nature 5February2015
Fetal Programming of the Human Brain: is there a Linkwith Insurgence of Neurodegenerative Disorders inAdulthood?
Author(s): G Faa, M A. Marcialis, A Ravarino, M Piras, M CPintus and V Fanos
Aluminum sources that infants may receive duringthe first 6 months of life
• Evitare di bere bevande acide (speciegassate) o the in contenitori di alluminio.
• Restringere l’assunzione di the e preferirel’aggiunta di latte (riduce labiodisponibilità) a quella del limone(aumenta assorbimento)
• Limitare l’uso di dentifrici e traspiranticontenenti alluminio.
• Evitare l’assunzione di caffè ottenuto conla moka in alluminio.
• Limitare il consumo di cibi cotti oconservati in contenitori di alluminio.
• Evitare formaggi o dolci contenentialluminio.
• Evitare l’assunzione di erbe ove non siaspecificato il livello di contaminazione daalluminio.
• Evitare, durante l’allattamento, l’uso diprodotti di bellezza contenenti alluminio.
• Scegliere le formule lattee con minorecontenuto di alluminio.
• Scegliere le acque minerali con minorecontenuto di alluminio per diluire leformule lattee.
• Porre grande attenzione alle formule disoia per l’elevato contenuto di alluminio.
• Porre grande attenzione alle terapieparenterali per l’elevato contenuto dialluminio.
• Evitare i farmaci contenenti alluminio, inparticolare gli antiacidi.
• Non rimandare la vaccinazione convaccini conteneti alluminio (la quantità èmodesta
I consigli perle mamme ingravidanza!
FANNI D, FANOS V, …FAA G. WORLD J PEDIATRICS 2014
Ethanol exposure during pregnancy causes apoptosis ofPurkinje cells and cerebellar granule cells.
Messaggio da portare a casa: alcol zero!!!
Luo J, Cerebellum 2012, 31, 543-549
SMOKE
Fanos V et al. BMC Embryo Today, submitted
Perinatal Heart Programming:Long-Term Consequences
Author(s): A. Faa, R. Ambu, G.Faa and V. Fanos 2014
The Cagliari Experience
Long term problems in young adults born ELBWBassareo PP, Fanos V et al. Int J Cardiov Epidemiol 2012, Int J Cardiol 2011, JMFNM
2009, 2010, Acta Pediatrica 2010, JDOHaD 2015
R = - 0,67
350
400
450
500
24 25 26 27 28 29 30 31 32
Gestational age (weeks)
QTc
(mse
c)
Significant QT interval prolongation and long QT inyoung adult ex preterm newborns with extremely lowbirth weight
Pier Paolo Bassareo1, Vassilios Fanos2, Melania Puddu2 , Christian Cadeddu1,Marta Balzarini1, Giuseppe Mercuro (JMFNM 2010)
Differences in the two groups related to the alterations in the arginine andproline metabolism, in the purine and pyrimidine metabolism in thehystidine, beta-alanine metabolism and with the urea cycle(Fanos V. et al Clinical Biochemistry 2011 , mod)
Metabolomics in adult patients (mean age 20 years)born at Term born ELBW
20years
BarkerhypothesisAltered embryonic/fetal developmentresults in lowbirthweight andpredisposes for adultdiseases (renal,metabolic,cardiovascular)
EventsPrenatalperturbation
Reducednephronnumber
Reduction intotal filtrationsurface area
Hypertensionand renaldisease
BrennerhypothesisLow nephronsnumber predisposesto adult hypertension
genes
Main ModifiersPerinatalProgramming
Extreme prematurity
Low birth weight
Nutritional setting
Catch-up growth
Obstructive andrefluxing nephropathy
Nephrotoxic drugs
Puddu M,Fanos V.Am J Nephrol 2009
What Perinatologist do not know …
•Preterm infant: window of 6 wks of postnatal renal maturation
ex. 24 wks: maturation until 30 wks stop
•Preterm infant with acute kidney failure: window of 4 wks ofpostnatal renal maturation
ex. 24 wks: maturation until 28 wks stop
• If IUGR: maturation window further reducted
Reduction final number of nephrons
Variability in total nephron number for single kidney at birth
CLINICAL SIGNIFICANCE (basal value + postnatal kidney injury)
200.000 900.000 2.500.000
IUGR
NSAIDs
THE BLUE STRIP WIDTH
Immunoistochimica tissutaleMarcatori in corso di studioCollaborazione Prof. G. Faa
• WT1• MUC1• CD10• CD44• Proteina mTOR• BCL2• BCL1• Kim1• Timosina beta 4• Timosina beta 10• hCTR1• Glypican 3• Galectina• …….
Neonatal Physiological Rigenerative Medicine ?
3 MMammasarda cheallatta incostumetipico
FORMULA
PRETERMBREAST MILK
NMR (acqueous phase): Principal Component Analysis (PCA)Tallin 2012, Proceedings 20th European Workshop on Neonatology,
J Perin Med June 2012, JMFNM 2012
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
-260 -240 -220 -200 -180 -160 -140 -120 -100 -80 -60 -40 -20 0 40 60 80 100 120 140 160 180 200 220 240 260
F
B
D
E1
C
A
Human MilkFormula Milk
Maltose, Myo-inositol, Lactose, Glucose, GalactoseAlanine, Valine, Leucine, Isoleucine, Glutammate
Citric, Lactic, Fumaric acid, Creatine, Phospho/creatine, Creatinine, Taurine
Using the best formula for the patient, when mother’s milk is notavailablese non è disponibile il latte materno
Milk ofmothers whodelivered apreterm baby
LGAIUGRAGA
ATBIRTH
BreastfeedingFormula milk
7° DAY
2016
AGA IUGRLGA
FormulaBreastfeeding
CD 44 good marker of stemness
CD 133 positive only in the first 3 days
Ki67 marker of asymmetric division
Couldmetabolomicsbe useful forstudying stemcells in brestmilk?Correlationwith presenceandpercentageof stem cells
BREASTMILK STEM CELL TRANSFERFROM MOTHER TO NEONATAL ORGANS
Maternal stem cells may:Migrate across the intestinal
BarrierDifferentiateAssimilate and integrate
with newborn tissues
Hassiotou F. Faseb Journal 2014, 28
FROM BREAST MILK TO BRAIN
+
Twigger A-J J Hum Lact, 2013
Le cellulestaminali del lattematerno
Programmazione della salute e dellamalattia da parte del latte materno
Prof G. Faa Cagliari
FROM BREAST MILK TO BRAIN
Hosseini SM Neurol Res Int 2014
Differentiation of breast-milkstem cells to neural stem cellsand neurons
Neurons
Oligodendrocytes
Astrocytes
Metabolomica liquidocellule staminali
In collaborazione con l’Università di Atene:Prof.ssa Malamitsi-Puchner
(dati non pubblicati)
Cellule CD44 +
IUGR= 20 volte maggiori
Radici Profonde…Messaggi da portare a casa
• Periodi critici di vulnerabilità (“trasformare le finestre divulnerabilità in finestre di opportunità”).
• Il programming determina cambiamenti strutturali permanenti inorgani importanti (God save the brain...) e può modificare lasuscettibilità alle malattie
• La placenta svolge un ruolo chiave (“E’ la placenta un innocentbystander, un testimone innnocente? No, non lo è”).
• Il compenso che si verifica vuole farci raggiungere l’immortalità(“Per riprodurmi, son nato”) ma ha dei costi (“una tassa dapagare”).
• Gli effetti del programming sono transgenerazionali. Dalloslogan paradossale “devi sceglierti i genitori” al “devi sceglierti igenitori, i nonni e i bisnonni!”
Fanos V. Metabolomica e microbiomica. Hygeia Press 2015
Siamo tutti diversi
Straordinaria variabilità interindividuale basale che aumenta dopo unostimolo intenso (es. asfissia, sepsi, digiuno prolungato….)
Concetti di FRAGILITA’ E RESILIENZA
EARLY INTERVENTIONSCOULD PREVENT EARLY ONSET
•What to do?
PRENATAL• Prudent diet• Micronutrients• Avoid toxic substancesPOSTNATAL• Close monitoring• Appropriate lifestyle
- promote physical activity,- avoid secondary smoking,- prevent obesity)
• Dietary interventions- breastfeeding- avoid rapid growth periods- monitor newborns at risk
Godfrey KM, Gluckman PD, Hanson MA:Developmental origins of metabolic disease:
life course and intergenerational perspectives.Trends Endocrin Met 2010;21:199–205.
• Italian Edition, July 2015• English Edition, ELSEVIER 1st
September 2016
I have a dream
PEDIATRICS of 10 P
• Personalized• Prospective• Predictive• Preventive• Precise• Participated• Patient-centered• Psycocognitive• Postgenomic• Public
In my beginning is my end…
Four Quartets
Thomas S. Eliot
In my beginning is my end…
Four Quartets
…Pray for us nowand at the hour of our birth.
Animula
Thomas S. Eliot
Graziedell’attenzione
Are we born with innate knowledge,ideas and virtues?
YES
PLATO
THEPERFORMATIONTHEORY
GENETIC VIEW
NO
ARISTOTELE
THE BLANK SLATE
EPIGENETIC VIEW
Are we born with innate knowledge,ideas and virtues?
YES
PLATO
THEPERFORMATIONTHEORY
GENETIC VIEW1/3
NO
ARISTOTELE
THE BLANK SLATE
EPIGENETIC VIEW2/3
Acknowledgmentsand permanentcollaborations
Luigi Atzori, Luigi BarberiniScienze Neur. e Cardiovascolari,University of Cagliari
Melania Puddu, Giovanni Ottonello,Antonio Noto, Angelica DessìNICU Cagliari
Emanuela Locci, Flaminia Marincola,Paola Scano Dip. Scienze Chimiche,University of Cagliari Dmitry Grapov, California, USA
Michele MussapSan Martino Hospital, Univ. of Genoa
Giuseppe Buonocore, Univ. of Siena
Julian Griffin Aalim WeljieDepartment of Biochemistry Metabolomics Research Centre
University of Cambridge Univ. of Calgary
95 collaborations with 19 countriesin 5 continents
95 collaborations with 19 countriesin 5 continents
Genetica Ambiente
AlimentazioneBoth undernutritionand overnutrition
are MALNUTRITION
Lezioni di Pediatria, Università di Verona, 1981Prof. Dino Gaburro
Il primo pastoè come ilprimo respiro
4 DECEMBER 2015
ITALIAN SOCIETYDOHaD
VASSILIOS FANOS (CHIEF)
IRENE CETINSERGIO BERNASCONIGIAN CARLO DI RENZOLUCA RAMENGHIVASSILIOS FANOSBENITO CAPPUCCINILUCIA MIGLIOREERNESTO BURGIOGIAN PAOLO DONZELLIFEDERICO MECACCI
4 DICEMBRE 2015
GRUPPO COSTITUENTEDOHAD SOCIETY ITALY
VASSILIOS FANOS(RESPONSABILE) [email protected]
IRENE CETINSERGIO BERNASCONIGIAN CARLO DI RENZOLUCA RAMENGHIVASSILIOS FANOSBENITO CAPPUCCINILUCIA MIGLIOREERNESTO BURGIOGIAN PAOLO DONZELLIFEDERICO MECACCI
STRUCTURE ANDFUNCTION
In my beginning is my end…We had the experience but miss themeaning,And approach to meaning restores theexperienceIn a different form, beyond any meaning…The only wisdom we can hope to acquireIs the wisdom of humility:humility is endless.
Thomas S. Eliot. Four Quartets
Group 1 (spontaneous) related togroup 3 (cesarean) at birth.Higher0.62 (s) ppm1.24 (sb) ppm suberic acid1.27 (sb) ppm sebacic acid1.63 (s) ppm alpha-amino adipic acid (to confirm)2.72 (s) ppm dimethylamine2.06 (sb) ppm Glycoprotein signal2.08 (sb) ppm Glyco protein signal2.38 (s) oxaloacetate2.43 (s) beta-keto-adipic acid
Lower3.208 (s) Choline3.02, 1.73(m), Lysine4.08 (m) Myoinositol7.84 Hippurate8.45 Formate7.09, 7.91 (s) Histidine
Geographic Information Systemof a Human Being
The new languages of MedicineMicrobiomics
Microbiota
Olobionte
Networking batterico
Sociomicrobiologia batterica
Ecosistema corporeo
Co-evoluzione
Simbiotici
Sistema NEI (neuro-endocrino-
immunitario)
Batteri ed evoluzione del
cervello
Trapianto di microbiota
3? ?
Leonardo da Vinci studies of the fetus on the womb:circa 1510-1513
8th International Workshop on Neonatology, Cagliari 24-27 October 2012
Differences in the two groups related to the alterations inthe arginine and proline metabolism, in the purine andpyrimidine metabolism in the hystidine, beta-alaninemetabolism and with the urea cycle(Fanos V. et al Clinical Biochemistry 2011 , mod)
Metabolomics in adult patients (mean age 24 years)born at Term born ELBW
24years
Who do we think we are?
• Cellule organismo
• Microbiota
• Viroma
• Fungoma
• Chimerismo
Diverse mammals, including humans, have been found to carrydistinct genomes in their cells. What does such genetic chimerismmean for health and disease?
In my beginning is my end…
Four Quartets
Thomas S. Eliot
What is life? (E. Schrödinger)
Le cinque grandi ideedella biologia e della medicina (P. Nurse)
What is life? (E. Schrödinger)
Le cinque grandi ideedella biologia e della medicina (P. Nurse)
Cover of the April10, 2014 issue ofNature
This is what weare: lots and lots of
connections
“cells that firetogether, wire
together”
PLS-DA of IUGR vs control (at birth)
Controls
IUGR
In collaboration withUtrecht and PaduaUniversities andAlessandria Hospital
ControlNewborn
IUGRNewborn
6 VIP: creatinine, creatine, myoinositol,betaine, succinate, sarcosine.
1H-NMR urine samples