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Education Course 1 : Frontiers in Developmental Bi-ology
Embryo and Tumors : The Relevance of Teratology
Tumor : ~ invasion Embryo : road map “two cell ~ message sent by inducer”
BC1750 함무라비 – cyclopia
1553 Paracelsus
1941 Greg – Congenital rubella syndrome
1959 Minamata bay
1960 Teratology Society founded 1961 Thalidomide episode
1970 ~ Gene-Enviromental cause
Effects of the Microbiome on embryonic and postembryonic development
Microbiome? Oral streptococcus, vaginal lactobacillus, genital herpes sim-plex, varicella zoster, Cervical HPV etc.
Microbiome is structured predominantly based on diet
rather than habitus
Diet can partially rescue a dysbiotic microbiome
Maternal diet can persistently affect the developing microbiome
Dietary alterations determine if an organism is
commensal(symbiotic) or pathogenic(dysbiotic)
What does this mean for disease treatment?
- Dietary changes as a means for treating pathogenic bacteria?
How does bacterial metabolism based on dietary alterations
influence our metabolism and disease?
Genomic approaches to understanding Normal and
Abnormal Brain development: From Human to Ani-
mal models and Back Holoprosencephay as an ex-
ample
Midline defect of the developing forebrain and
face
Prevalence : 1 in 250 early embryo
1 in 10,000 live born infants
~ 1 in 100,000 children >1 year
Phenotype : extremely variable
HPE start? Human : Cyclopia take place before lateral move-ment of optic primordia at day 18 HPE : Environamental causes
Most common teratogen : PGDM 1% risk
Alcohol, retinoic acid
Cholesterol lowering agent
Heritable causes
Cytogenetic abnormalities (25-50%) Trisomy 13
Microdeletions (10-20%)
Single gene mutations : syndromic and non-syndromic
Clinical presentation
Neurologic : developmental delay, epilepsy, hypotonia,
spasticity
Endocrine : DI, GH deficiency, adrenal hypoplasia, hypogo-
nadism
Oromotor dysfunction : feeding and swallowing difficulties
require gastrostomy tubes
Dysautomatic dysfunction : instability of BT, heart and
breath rateGenetic counseling
Challenges : phenotypic variablity, genetic heterogene-
ity, high
risk of recurrence(13%)
The Role of Cilia in Development
The Role of Cilia in Development
The Role of Cilia in Development
The Role of Cilia in Development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
The Role of Nutrition in Embryo & Fetal develop-ment
Maternal nutritional status is a key modula-tor of embryonic and fetal development
Session 2: Mechanism of Abnormal Embryonic Development
Oxidative stress in Abnormal Embryonic and Fetal Brain Development
Session 2: Mechanism of Abnormal Embryonic Development
Oxidative stress in Abnormal Embryonic and Fetal Brain Development
Epigenetic Marks in Germ cells and Embryos
Epigenetic marks
1. DNA methylation
2. Histone modifications
3. Non-coding RNAs(miRNA,,,)
There is increasing evidence that changes in DNA methy-lation,
histone modifications and non-coding RNA transfer heri-table
information to the offspring.
Epigenetic modifications have been identified as factors in a variety of human diseases.
They are likely to play a key role in mediating the adverse effects of a number of environmental exposures on devel-opment.
Cellular signal transduction path-ways
Cellular signal transduction path-ways
Cellular signal transduction path-ways
Cellular signal transduction path-ways
Cellular signal transduction path-ways
Signal transduction pathways mediate an organ-ism’s
response to its internal and external environment
Many embryotoxic compounds disrupt normal sig-nal
transduction pathways
Disruption of signaling pathways can alter transcription factors and change gene expression, or can interfere with other cellular process
Signaling pathways are complex and interact in networks
Main points
Gene Regulatory Networks(GRN)
Types of biological networks :
• Transcription factor-binding networks
• Protein-protein interaction networks
• Protein phosphorylation networks
• Metabolic interaction networks
• Genetic & small molecule interaction networks
GRN?
“The body plan of an animal, and hence its exact mode of development, is a property of its species and is thus encoded in the genome.
Embryonic development is an enormous informa-tional transaction, in which DNA sequence data gen-erate and guide the system-wide spatial develop-ment of specific cellular functions…
GRN provide system level explanations of develop-mental and physiologic functions in the terms of the genomic regulatory code.”
GRNs offer a mechanistic view of how the embryonic body plan is formed through lineage specification, differentiation, and morphogenesis”
Josef Warkany Lecture : KNUDSON TB – Developmental system biologist (EPA)
Teratology V2.0 : Building a Path Forward
Birth defect, gene, gene-evironment, re-search, understanding, fund
Push the boundaries : Complex embryogenesis Big data : developmental pathway, process, toxicities
Computational system biology :
simpler : predictive and mechanistic understanding of teratogenesis
Systems Medicine and Proactive P4 Medicine :
A revolution in Healthcare
Ex)Prion accumulation- Glial activation - Synaptic degeneration- Neu-ronal cell death Lung mass - lung cancer/ benign D/Dx
Personal health data, Genome, Biomarkers(proteins)--- Big data--- System biology
Well-ness
Wellness
Disease
Time
P4 : Predictive, preventive, personalized , participa-tory
Digital medicine for individual pa-tient
Business plan Emerging wellness
industry(Microsoft)
Hood L. : John’s H University, System biologist
Special lecture
March of Dimes Symposium
Advances in Early Diagnosis of Birth Defects and Adverse Perinatal Outcomes
Smart skin sensors and Analytics in the Cloud to Advance the Frontiers of Wearable Health
Dr. Coleman : Flexible skin-mounted wireless electronics +Multi-modal analytical algorithms in Cloud
Big data ----+ small, relevant data ----+ clinician
Screening for Birth Defects and Teratogen risks
with
ultrasonography in Early Gestation
Prolonged Doppler imaging : potential embryonic effects Early US for validate Ix : Gestational dating…
Abortion 의심 시 7-10 일에 repeat
Slow heart rate – poor prognosis, but, range dramatically between 7-12wks.
Maternal obesity : 20% lower detection of fetal anomalies
Role of First Trimester Fetal Echocardiography in
the Identification of Birth DefectsEarly fetal echocardiogram : high risk group-
3 early markers of congenital heart anomaly :
Increase NT, abnormal ductus venosus flow, tricuspid regurgitation
additional markers : cystic hygroma, other anomalies
Ix of Echocardiogram: Retinoid, Lithium, Trimethadione , Paroxetine, Alcohol (by AIUM, ACOG 2013)<14 weeks : >75% of standard cardiac viewsSensitivity in 1st trimester : 10% in low risk population, >50% in high risk group For early reassurance Screening and diagnostic tools needs further evaluation
Simpson LL, Columbia University
Fetal MRI As an Adjunct to Second Trimester US
JOLLEY JA, U. of Washington, Seattle
Fetal MRI 도움 : CNS, facial anomalies, tumors, mass of neck and thorax
US 한계 : reverberation artifact, Poor position,
oligohydramniosis, obesity
<18 주 : little benefit
21-22 주 : useful adjunct
>3 기 : optimal
Epigenetic Mechanisms in Intellectual Developmental Disabilities
Epigenetic mechanism :
Alteration in chromatin structure– regulate gene expres-sion Do epigenetic mechanisms operate in behavioral memory formation?
1. Contextual fear conditioning triggers alterations in hippocampal
DNA methylation and histone post-translational modifications
2. Inhibitors of DNA methylation block both hippocampal long-term
presentation and associate learning in vivo
3. Remote contextual fear memory is associated with persisting
changes in DNA methylation in the Anterior Cingulate Cortex,
and DNA methyltransferase inhibition can reserve established
remote memory
4. Histone acetylation increases in memory formation, and histone
deacetylase(HDAC) inhibitors enhance both memory formation
and hippocampal long-term potentiation.
Epigenet-ics
Environmentally-induced Epigenetic Trans-genera-
tional Inheritance of Disease: Ancestral Ghost in Your
Genome Trans-generational effects of environmental toxicants
Sensitive period :
during embryonic gonadal sex determination –
germ line is undergoing epigenetic programming & DNA methylation
Endocrine disruptor( fungicide, vinclozolin, BPA, phthalate, DDT, dioxin
et al)
Increase adult onset disease : infertility, ovary disease, cancer, obesity
Trans-generational(F1, F2, F3 and F4 generation)
by permanent altered DNA methylation of the germ line
New paradigm in disease etiology that is relevant to other areas of biol-
ogy
such as evolution
Chromatin Remodeling , miRNAs, and Determination of
Neurogenic cell fate
miRNA : regulate gene expression by post-translationally repressing their target gene
Brain enriched miRNA : miR-9/9* and miR-124 (neurogenic proper-ties)
human skin fibroblasts - post-mitotic neuron
Hypothesis : transcription factors enriched in specific brain regions – guide the miRNA mediated neuronal conversion into specific neu-ronal subtype ex) transcription factors enriched in the striatum fibroblast – striatal neurons
Demonstrate : miR-9/9* - miR-124 and transcription factors to generate specific neuronal subtypes
FAS(Fetal Alcohol Syndrome) Jones KL
Retrospective look at 40 yrs of FAS
FASD : spectrum of defects by prenatal alcohol exposure
FAS : growth deficiency, microcephaly, characteristic facial abnormalities, neurodevelopmental defects
ARND(Alcohol related neurodevelopmental disorder) : mild end lack the pattern of structural and growth deficits Issue : intervention and prevention
DSM 5 Appendix
The Impact of Spina Bifida on Individuals, Families, and So-ciety
Whiteford ML, UK
SB : life time cost – 620,000$
America : folic acid fortification
Europe : 2ndary prevention by termination
1965 Hibaard Lancet
2007 CRC?
2011 No association with CRC
2014 Level of FA, Debate in house of Lords
Accelerating the pace of preventing Sina Bifida F and Anen-cephaly F
1991, unambiguous evidence of prevention of NTD
1998, 1.4ppm in USA, 1.5ppm in Canada
Thalidomide – 10,000 victims
NTD- 180,000 a year
TS & ETS : all governments require folic acid fortifica-tion.
Safety : 15mg safe by Goodman %Gilman 1996
2006
????????
2013
Accelerating the pace of preventing Sina Bifida F and Anen-cephaly F
[Teratogen update]
Teratology and public health: working together to make recommendations for pregnant women in the face of un-
certainty Weighing Risk & Benefit
Benefit of intervention 》 Potential risk of harm
1. Rubella vaccine developed (1969) --- adolescent vaccine(UK) Children vaccine(USA)
Prenatal test & postpartum vaccine(1984)2. Folic acid potential risk : mask of Vitamin B12 deficiency, Pregnancy loss, Twining, Colon cancer, Dementia 1992 recommendation: 400mcg/d 1998 Fortification : 27% reduction of NTD(US)
3. Influenza : 5% death in pregnant women with in-fluenza Prophylaxis : Pregnant vaccine protect : up to 6month Tx of influenza : Tamiflu + Acetaminophen
TH Shepard
감사합니다^^
