54th annual meeting of ts in seattle

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^^