2. Education Course 1 : Frontiers in Developmental Biology
 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

3. Effects of the Microbiome on embryonic and
postembryonic development
Microbiome?
Oral streptococcus, vaginal lactobacillus, genital herpes simplex,
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?

5.  Genomic approaches to understanding Normal and Abnormal
Brain development: From Human to Animal models and Back
Holoprosencephay as an example
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

6. Phenotype : extremely variable

7. HPE start? Human :
Cyclopia take place before lateral movement
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

8. Clinical presentation
Neurologic : developmental delay, epilepsy, hypotonia, spasticity
Endocrine : DI, GH deficiency, adrenal hypoplasia, hypogonadism
Oromotor dysfunction : feeding and swallowing difficulties
require gastrostomy tubes
Dysautomatic dysfunction : instability of BT, heart and breath rate
Genetic counseling
Challenges : phenotypic variablity, genetic heterogeneity, high
risk of recurrence(13%)

9. The Role of Cilia in Development

10. The Role of Cilia in Development

11. The Role of Cilia in Development

12. The Role of Cilia in Development

13.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

14.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

15.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

16.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

17.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

18.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

19.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

20.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

21.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

22.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

23.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

24.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

25.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

26.  The Role of Nutrition in Embryo & Fetal development
Maternal nutritional status is a key modulator
of embryonic and fetal development

28. Session 2: Mechanism of Abnormal Embryonic Development
 Oxidative stress in Abnormal Embryonic and Fetal Brain
Development

29. Session 2: Mechanism of Abnormal Embryonic Development
 Oxidative stress in Abnormal Embryonic and Fetal Brain
Development

30.  Epigenetic Marks in Germ cells and Embryos
Epigenetic marks
1. DNA methylation
2. Histone modifications
3. Non-coding RNAs(miRNA,,,)

34.  There is increasing evidence that changes in DNA methylation,
histone modifications and non-coding RNA transfer heritable
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
development.

35. Cellular signal transduction pathways

36. Cellular signal transduction pathways

37. Cellular signal transduction pathways

38. Cellular signal transduction pathways

39. Cellular signal transduction pathways

40.  Signal transduction pathways mediate an organism’s
response to its internal and external environment
 Many embryotoxic compounds disrupt normal signal
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

41. 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

42. 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 informational
transaction, in which DNA sequence data generate and
guide the system-wide spatial development of specific
cellular functions…
GRN provide system level explanations of developmental
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”

44. Josef Warkany Lecture :
KNUDSON TB – Developmental system biologist (EPA)
Teratology V2.0 : Building a Path Forward
Birth defect, gene, gene-evironment, research,
understanding, fund
Push the boundaries :
Complex embryogenesis
Big data : developmental pathway, process, toxicities
Computational system biology :
simpler : predictive and mechanistic understanding
of teratogenesis

45. Systems Medicine and Proactive P4 Medicine :
A revolution in Healthcare
Ex)Prion accumulation- Glial activation - Synaptic degeneration- Neuronal cell death
Lung mass - lung cancer/ benign D/Dx
Personal health data, Genome, Biomarkers(proteins)--- Big data--- System biology
Wellness
Wellness
Disease
Time
P4 : Predictive, preventive, personalized , participatory
 Digital medicine for individual patient
 Business plan
 Emerging wellness industry(Microsoft)
Hood L. : John’s H University, System biologist
Special lecture

47. 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

49. 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 7-10일에 repeat
Slow heart rate – poor prognosis, but, range dramatically between
7-12wks.
Maternal obesity : 20% lower detection of fetal anomalies

53. Role of First Trimester Fetal Echocardiography in the
Identification of Birth Defects
Early 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 views
Sensitivity 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

57. 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
<18주 : little benefit
21-22주 : useful adjunct
>3기 : optimal

58. Epigenetic Mechanisms in Intellectual Developmental Disabilities
Epigenetic mechanism :
Alteration in chromatin structure– regulate gene expression
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.

59. Epigenetics
Environmentally-induced Epigenetic Trans-generational
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 biology
such as evolution

60. 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 properties)
human skin fibroblasts - post-mitotic neuron
Hypothesis :
transcription factors enriched in specific brain regions –
guide the miRNA mediated neuronal conversion into specific neuronal
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

61. 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

62. The Impact of Spina Bifida on Individuals, Families, and Society
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

63. Accelerating the pace of preventing Sina Bifida F and Anencephaly 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 fortification.
Safety : 15mg safe by Goodman %Gilman 1996
2006
????????
2013

64. Accelerating the pace of preventing Sina Bifida F and Anencephaly F

65. [Teratogen update]
Teratology and public health: working together to make
recommendations for pregnant women in the face of uncertainty
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 influenza
Prophylaxis : Pregnant vaccine protect : up to 6month
Tx of influenza : Tamiflu + Acetaminophen

67. TH Shepard
감사합니다^^