1. science
2. medicine
3. genetics

The Birth,
Development and
Future Prospects for
Craniofacial Biology
Hal Slavkin, Professor & Dean Emeritus
Center for Craniofacial Molecular Biology, Herman Ostrow School of
Dentistry, University of Southern California, Los Angeles, California
(slavkin@usc.edu)
Opening General Session: Keynote Address
72nd Annual Meeting & Symposia of the American Cleft Palate-Craniofacial Association
Westin Mission Hills Golf Resort & Spa Hotel, Rancho Mirage, April 22nd, 2015
Dedicated to the Memory of Professor
Samuel Pruzansky (One of the
Midwives for Birth of a Discipline:
Craniofacial Biology)
•
Role Model
Mentor & Coach
Advocate
Leader
Listener
Inspirational
Friend for 16 years
•
•
•
•
•
•
•
•
Organized the First International Symposium on
Craniofacial Malformations in 1959
Coined the term “Craniofacial Biology”
Served as Chair for the First “Dental Study Section” at
NIDR, NIH
Founded the First Center for Craniofacial Anomalies at
the University of Illinois College of Medicine in 1967
First President of Craniofacial Biology Group at IADR
in 1968
Received the “Honors of the Association” in 1976 From
American Cleft Palate-Craniofacial Association
Published 190 Scientific Publications
Authored the Forward for my book “Developmental
Craniofacial Biology” (1979)
His Death in 1984
Three Examples of Innovative Craniofacial Clinical Scholars
Paul Tessier
Carl Witkop,Jr.
1st
Lab Chief, Genetics Branch, NIDR,
NIH (1950s);
Pioneer of enamel and dentin genetic
diseases and disorders (amelogenesis
& dentinogenesis imperfecta; AI &
DI)
French Surgeon who created major
transformations of craniofacial surgery;
consulted for NIDR in 1960s-1980s; provided
training for craniofacial surgeons such as Dr.
Henry Kawamoto; close friends with Drs.
Sam Pruzansky and John Converse
Robert Gorlin
Father of craniofacial
genetics of
dysmorphology
SELECTED EVENTS












Social Security Act included funds for the care of children with congenital birth
defects-1935
1st Cleft Palate Clinic- (Dr Herbert Cooper); 1st Craniofacial Team-1938 (creation of
Inter Professional Teams for Health Care)
NIDR created-1948 (with Cancer & Heart Institutes)
NIDR formed the very first genetics branch at NIH (1950)
Thalidomide Epidemic (10,000 babies) – October 1957
NIDR supports Gatlinburg Conference-December 1959
1st March of Dimes Conference on Birth Defects-1960
Dr Sam Pruzansky coins term “craniofacial biology” – 1968 (synthesis of
embryology, biochemistry, clinical specialties)
Japanese, USA, UK, France, Australia, Canada, Scandinavia Cleft lip and Cleft
Palate Centers for Clinical Services as well as Research Institutes created
NIDR becomes NIDCR in 1998; leads Surgeon General‟s Report on Oral Health in
America” (released May 2000)
Eurocleft led to WHO (2000) led to Americleft (2006) led to CLEFT-Q
Regenerative medicine & dentistry, clinical trials for ED, Gordon Conferences,
NIDCR FaceBase, Precision Health Care, 3-D Imaging, Nanotechnology, $1,000 for
patient‟s complete genome, and era of the microbiome in 21st Century
Dr Herb Cooper’s Interprofessional Team
at Lancaster, PA (1938)
Dr. Cooper with patient
Cooper Protocol for CL/CP
Composition of Craniofacial
Interprofessional Health Teams
( ~200 CF Teams in USA, Canada, Japan, Australia, Europe & Beyond)
Surgeon, Pediatrician, Neurologist,
Anesthesiologist, Physician Nurse Assistant,
Nurse, Pedodontist, Prosthodontist,
Orthodontist, Speech Therapist,
Audiologist/ENT, Geneticist, Craniofacial
Biologist, Clinical Psychologist, Social
Services, Physical Therapy for Feeding
Disorders, Psychologist, Psychiatry, Nutrition
and Education, Language, Occupational
Therapy & Dental Hygiene
Core Competencies for Interprofessional
Education & Clinic Care (May 2011)
American Association of Colleges of Nursing
American Association of Colleges of Pharmacy
American Association of Colleges of Osteopathic Medicine
American Dental Education Association
American Association of Medical Colleges
American Association of Public Health Colleges
Competency Domain 1. Values/Ethics of
Interprofessional Practice
Competency Domain 2. Roles/Responsibilities
Competency Domain 3. Interprofessional
Communication
Competency Domain 4. Teams and Teamwork
My journey
beginnings…
After high school, pursued dental
technician training at Fort Sam Houston, Texas,
and then dental and craniofacial technology at
Walter Reed Hospital, DC, and Forest Glen,
Maryland (severe facial burns unit - - -acquired
craniofacial anomalies)
Worked as dental tech (“crown &
bridge”) through undergrad & dent school (19581965)
After 1yr (Richard Greulich, Anatomy,
UCLA) & 2yrs (Lucien Bavetta, Biochemistry, USC)
postdoctoral fellowships, joined USC in 1968 &
served for 46 years on faculty (minus 5yrs as
director NIDCR and 4yrs various sabbatical leaves)
…my discovery of doing science as a
dental student (1963-1965)...

Slavkin, H.C., Canter, M.R. and Canter, S.R. (1966). An anatomic
study of the pterygomaxillary region in the craniums of infants and
children. Oral Surg. Oral Med. Oral Pathol. 21(2):225-235.
 Slavkin, H.C. (1965). Anatomical investigation of the greater palatine
foramen and canal. Alpha Omegan, 58:148-151.
 Slavkin, H.C. (1965). Dental amputation neuromas. JADA,
70:662-675.
 Greulich, R.C. and Slavkin, H.C. (1965). Amino acid utilization in
the synthesis of enamel and dentin matrices as visualized by
autoradiography. In: The Use of Radioautography in Investigating
Protein Synthesis (eds. C.P. Leblond and K.B. Warren), pp. 199-214.
New York: Academic Press.
 Canter, S.R., Slavkin, H.C. and Canter, M.R. (1964). Anatomical
study of pterygopalatine fossa and canal: Considerations applicable to
the anesthetization of the second division of the fifth cranial nerve. J.
Oral Surg., Anesth. Hosp. Dent. Svc. 22:318-323.
Creating Craniofacial
Teams & Celebrating
Professional &
Cultural Diversity
1938 - Present
“Craniofacial biology, as a life
science, is a single fabric of
interconnected facts and concepts in
which, as in all dynamic works, the
structure and strength of each portion
depends significantly on the condition
of the others.” S. Pruzansky 1968
The Burden of Congenital and
Acquired Craniofacial Anomalies




1 out of every 10 people in industrial countries present
craniofacial-oral-dental disease or disfigurements
1 million people in USA have severe congenital craniofacialoral-dental disfigurements (e.g. non-syndromic and syndromic
clefts, birth marks, hemangiomas, oligodontia, severe
malocclusions)
Acquired craniofacial-oral-dental diseases and disorders include
severe craniofacial facial burns, head and neck trauma, head &
neck cancers, hypertrophic scars, and severe acne with facial
scars impacting many millions of people
Total direct & indirect global health care costs are ~ $500 billion
per year
Types of Cl/CP
(in California 1:500 live births)
The burden of craniofacial conditions cause $95.9 billion per year in medical and
wage/household work costs (1999 dollars). A baby is born every hour with CL/CP
in USA, every minute world-wide, and often requires surgery, speech, hearing,
learning, orthodontics, dental, feeding needs, social services & psychosocial
health care needs
PHENOTYPE + GENOTYPE = PHENOMICS
from single nucleotide polymorphisms to patient,
family & population craniofacial phenotypes
Phenotype (Examples)







Cleft lip and/or Cleft palate (CLP)
Unilateral vs Bilateral, Ethnicity
Male vs. Female
Chromosomal, Mendelian, Complex, and
Teratogenic; Syndromic & Non-syndromic
CLP affects 1/700 live births with wide
variability across geography, racial & ethnic
groups, SES & environmental exposures
See http://www.ncbi.nlm.nih.gov/omim
See Michael Dixon, Mary Marazita, Terri
Beatty & Jeff Murray (2011) Cleft Lip and
Palate: Synthesizing Genetic and
Environmental Influences. Nature Review
Genetics 12(3):167-178.
Genomics (Examples)
TGFalpha, RARA, IRF6, MSX1,
FGFR1,FGFR2, TP63, PAX7,NOG
and Other Gene Networks (e.g.,
BMPs, TGF-beta (1-3), Wnts, Shh)
See Leslie and colleagues (2015)
Identification of functional variants for
cleft lip with or without cleft palate in or
near PAX7, FGFR2 and NOG by
targeted sequencing of GWAS loci.
Amer J Human Genetics 2/20/2015.
Craniofacial
Biology
Highlights
3.62 million sites in
0.32 seconds from
Google search
4/20/2015




















Vertebrate fossils show craniofacial birth defects
Aristotle and biological observations
Charles Darwin “On The Origin of Species” (1859) & “The Expression of the
Emotions of Man” (1872) first used term “craniofacial”; first pubMed citation
Thomas Huxley (1876) with evolutionary biology
Creation of National Association of Teachers of Speech in 1925
Synthesis of genetics, biochemistry, embryology to become “Evo-Devo”
Hans Spemann receives Nobel Prize in 1935 (studies in craniofacial biology)
Herbert Cooper creates first craniofacial team (1938)
World War II and ultrasound, antibiotics, anesthesiology and surgery
Vannevar Bush and creation of the NIH (cancer, dental, and heart) in 1948
NIDR creates “1st” Genetics Branch at entire NIH (1950)
NIDR first grants for craniofacial in 1957 to Lancaster
Landmark Conference December 6-9, 1959 called “Gatlinburg Conference” or
“Congenital Anomalies of the Face and Associated Structures”
(Pruzansky,editor)
Paul Tessier, John Converse, Peter Randal, Poul Fogh-Andersen (surgeons),
Bob Gorlin, Carl Witkop, F. Clark Fraser, Michael Cohen, Jr., Marilyn Jones
(genetics), Sam Pruzansky, R.Bruce Ross, Ross Long (orthodontist), Duane
Spriestersbach, Betty Jane McWilliams, & Don Warren all Exemplars of
Clinical Scholars (late 1960s – 1980s, and beyond)
Creation of American Speech-Language-Hearing Association (ASHA) in 1978
Basic, translational & clinical research in craniofacial diseases and disorders
Joseph Murray Plastic/Craniofacial Surgeon receives Nobel Prize in 1990
NIDR to NIDCR in 1998 (budget doubles) “50 Year Anniversary”
NIDCR sponsors “Face Base Initiative” 2004-present
Gordon Conferences “Craniofacial Morphogenesis and Tissue Engineering”
Precision craniofacial medicine and dentistry
An American Perspective

Head & Neck Trauma
Wars Advance Clinical Care

1938-Present
Birth, Development, and
Differentiation of Craniofacial
Teams

1950-Present
Thalidomide (teratology), March of Dimes,
NIH (NIDR & NIDCR, NICHD) & Birth
Defects
Increasing research budgets: NIH doubled
1995-2000; NIH again doubled 20002015 (~$31 billion in 2015)
Disruptive Technology = displaces established
technology or provides a product or service that
creates a completely new industry









Head & Neck Trauma from Wars and
Head & Neck Cancers
Craniofacial Teams
Inter-professional Education & Health
Care (GME in 1960s)
Basic, Translational & Clinical Research
(e.g. Pharmaceuticals, Medical Devices,
Speech-Language-Hearing, Clinical
Psychology and Preventive & Social
Services)
Gene-based diagnostics (saliva & blood)
Digital 3-D imaging & CAD-CAM
Haptics: Computer-assisted sensory
perceptions
“FaceBase” a NIDCR Resource
Voice-activated computer technology
NIH Plans Million-Person
MegaStudy 2015




Accelerate the development of treatments and
therapeutics tailored to individual patients;
Integrate phenotype and genotype datasets 
for each patient (phenomics); Increase
precision or personalized health care;

Increase preventive services; Reduce costs.
2004: Cost of sequencing one
human genome = $4 million
dollars and 2 years of time
2004: 1 million smart phones in
USA
2004: 25% health providers use
electronic records
2015: Cost of sequencing one
human genome = $1,000 and
less than a day of time
2015: 160 million smart phones
in USA
2015: >90% health providers
use electronic records
Strategic Plan of NIDCR 2014-2019
“Enable Precise and Personalized Craniofacial-OralDental Health Care”

Martha Somerman
DDS, PhD.
Director, NIDCR,
NIH
Expanding the foundation for personalized medicine:
implications and challenges for dentistry (Garcia, Kuska
& Somerman, 2013 in JDR “Clinical Reviews in Oral
Biology & Medicine 92(suppl 1):3-10s)

Personalized health care aims to individualize care
based on a person’s unique genetic (genotype),
environmental, and clinical profile (phenotype)
 The completion of the Human Genome Project
(2004), cost-effective whole genome-wide
sequencing methods and bioinformatics (2013),
enable clinicians to formulate decisions based upon
the patient’s genotype and phenotype (e.g. risk
assessment, diagnosis, treatment, prognosis)
 Now is the time for craniofacial-oral-dental health
professionals to prepare for the arrival of
personalized or precision health care
Changing Knowledge & Therapy
Understanding at cellular level
Pharmacogenomics
Genes
Diagnostics
Prevention
Proteins
Underlying Basic
Biologic Defect
Stem Cell
Therapy
Disease
Targeted Drug
Therapy
Gene
Therapy
Precision Medicine: Who Benefits from
Aspirin to Prevent Colorectal Cancer?

Several genetic variants
on chromosome 12,
within genes that
regulate prostaglandins,
play central role in risk
for colorectal cancers
(see H. Nan and
colleagues JAMA
313(11):1133-1142,
2015)
Changing Knowledge & Therapy
Understanding at cellular level
My cancer
Genes
Proteins
Disease
Pharmacogenomics
Diagnostics
Underlying Basic
Biologic Defect
Targeted Drug
Therapy
Prevention
Stem Cell
Therapy
Gene
Therapy
Personalized / Precision Health Care
Two Examples of Specific Mutations in
One Gene that Produce Different
Phenotypes
FGFR2 fibroblast growth factor receptor
2
BRACA1/2 tumor suppressor genes
Centers for Disease Control
and Prevention
Saving Lives. Protecting People. TMwww.cdc.gov
Breast and Ovarian Cancer and BRCA1/2 Genes
•
•
•
•
•
Most cases of breast and ovarian cancer that occur in the general population are
not the result of an inherited mutation in the BRCA1 or BRCA2 genes.
Only about 3 out of every 100 women who develop breast cancer will have a
BRCA1 or BRCA2 mutation
About 10 of every 100 women who develop ovarian cancer will have a BRCA1 or
BRCA2 mutation (variable SNP in sequence determines expression).
For women who have a BRCA1/2 mutation, the risk for early breast cancer and
ovarian cancer is greatly increased (SNP location in sequence).
In some families, breast cancer or ovarian cancer will occur due to inherited
mutations in genes other than BRCA1/2. However, this is uncommon.
Craniosynostosis Syndromes and FGFR2 Gene Mutations
• Different mutations (SNPs) in different locations within the DNA sequence of
FGFR2 gene produce different phenotypes - - -Crouzon, Pfeiffer, Apert and/or
Beare-Stevenson syndromes (“one gene produces different phenotypes”)
Precision Medicine and Type 2 Diabetes:
Lessons from Genetics to Epigenetics

Known genetic variability (common
SNPs) do not account either for current
epidemics of type 2 diabetes or for
family transmission of this disorder
 Rather, environmental factors illustrate
extraordinary impact on natural history
and/or epidemiology of type 2 diabetes
 Epigenetic mechanisms may explain
familial aggregation of type 2 diabetes;
certain epigenetic changes can be
transgenerationally transmitted
 Cytokines & other metabolites affect
DNA methylation and acetylation that
reprogram specific gene expression and
contribute to the type 2 phenotype
The Promise of Precision Medicine
The promise of precision
medicine is delivering the right
diagnosis and treatments, at the
right time, to the right person. It
is through this promise that we
are given one of the greatest
opportunities for new medical
breakthroughs that we have ever
seen.
Sylvia Mathews Burwell, HHS Secretary 3/20/15
Convergence between the Biological and Digital
Revolutions Meet Craniofacial Anomalies
From Fish to Philosopher: “Evo-Devo” Evolutionary & Developmental Biology
Reveal Highly Conserved Craniofacial “Blueprint”
Slavkin Birth of a Discipline: Craniofacial Biology, Aegis
Communications 2012
Highly Conserved Homeotic Genes Control
Craniofacial and Body Form (discovered in 1980s)
Slavkin Birth of a Discipline: Craniofacial Biology, Aegis
Communications 2012
“A Tipping Point:” Thalidomide Tragedy Informs Teratology &
Craniofacial Birth Defects (1950s – 1970s; Accutane in 1980s)
Slavkin Birth of a Discipline: Craniofacial Biology, Aegis
Communications 2012
From Chromosome Discovery (1842)
To Karyotyping (1930s-1970s)
To Genomics, To “The Post-Genomic Era”(2004)
To The Transcriptome, To Proteomics
To Metabolomics, To “The Diseaseome”
To Pharmacogenomics and Systems Approaches
To Biomimetics and Tissue Engineering
To Regeneration and Nano-bio-informatics
To Phenomics, Precision Medicine and Beyond…
Genesis of Craniofacial
(Multidisciplinary) Teams




Cooper HK. Crippled children? Am J Ortho & Oral Surg.
28:35-40, 1942
Cooper HK. Integration of services in the treatment of cleft
lip and palate. J Am Dent Assoc. 47:27-35, 1953.
IOM & NRC. Improving access to oral health care for
vulnerable and underserved populations. Washington, DC:
The National Academies Press, p.p. 114-115, 2011.
Fox LM, Stone PA. Examining the team process: developing
and sustaining effective craniofacial team care. In: Cleft Lip
and Palate (S Berkowitz, editor), Berlin; Springer-Verlag,
885-896, 2013.
Genetics as a Paradigm for Studies of Human
Craniofacial-Oral-Dental Diseases and
Disorders
“With the exception of trauma,
essentially all diseases and disorders
have a major genetic component (single
or multiple genes & gene-gene and gene
environment interactions).”
HC Slavkin (2001) The Human Genome, Implications
for Oral Health and Diseases, and Dental Education.
Journal of Dental Education 65(5):463-479.
HC Slavkin, M Navazesh & P Patel (2015) Basic
Principles of Human Genetics: A Primer for Oral
Medicine. In 12th Edition Burket‟s Oral Medicine
(edited Michael Glick), People‟s Medical Publishing
House – USA, Shelton, Connecticut pp.625-654.
From Nucleus to Genetic Variance Including
Mutations in One or More Genes
…ACGTATTGCTAAT
CGATTCGGCAT…
Genetic Code=Triplets
or Codons (CGG, ATA)
Slavkin Birth of a Discipline: Craniofacial Biology, Aegis
Communications 2012
SNPs (single nucleotide polymorphisms) are
tools to identify minor genetic variance
within genome-wide scans
Human Genomic Math: 21,000
genes & 19,000 pseudogenes
Human Genetic Variations,
and Variation in DNA Sequences
(less than 0.1% of Human Genome)
a
g
g
t
a
t
t
g
c
c
t
a
t
g
c
g
t
c
g
t
g
a
g
a
g
g
c
a
t
g
att
agt
ccc
tca
tat
ggg
ttt
tac
gct
tcc
tta
ttg
tgg
agt
agg
aaa
ggg
gga
tgg
tca
ctg
agc
taa
aca
gta
ctg
ctt
tta
aca
aca
g gag
a
a gag
t
g aag
g
g cgg
t
a caa
c
a tga
a
t cgg
t
a gct
c
c ttc
a
t aac
c
g ttg
t
g aaa
c
c aat
c
t gta
t
c tgg
g
g att
c
a aaa
g
a gca
g
t gtt
t
c ccc
a
t aaa
c
a aaa
g
c acc
g
a tga
a
c tct
c
g acc
t
c aag
g
t gct
c
g agc
a
a tta
a
ca
gt
ac
ac
at
ga
ag
ct
gc
cc
at
ct
tt
ca
ct
gt
gc
gc
tt
at
ac
ta
tt
aa
gt
ac
gg
gg
gt
gt
aat
ctt
cat
cag
ccc
gct
att
ctt
gat
agc
tta
tgt
cgt
ggc
agg
gat
aat
cta
atc
ctc
atg
taa
ctg
aac
cct
tgg
taa
cac
cat
tct
g aat
c
t gca
g
g cga
a
a caa
c
t ttg
c
g gtt
c
t agt
t
a cgg
t
t ttc
a
c att
t
t aga
a
t atc
g
g tga
g
g ttg
c
g aaa
g
t act
c
g gaa
a
t gga
t
t ggc
t
a tct
t
g ttg
a
g aat
c
g ggg
a
t tta
c
g aag
a
a gag
c
a ata
t
c ata
t
c aag
a
t gag
g
ca
tt
gg
tt
tt
ca
tc
ga
ta
tt
ag
tc
tc
cc
tg
ca
aa
ga
tt
gc
ac
tg
ag
at
at
gc
ag
aa
ca
aa
cag
agg
tcg
ttg
gat
aag
tat
aga
ggc
ggc
act
ctt
gct
ttc
atg
gaa
atg
tac
ccc
att
tct
gaa
gga
ggt
att
aag
cac
gaa
tgc
ggt
c agt
g
a gtt
c
c cct
t
a gaa
g
t cgc
t
a aaa
a
g gat
a
a tat
c
a tgg
a
c tca
t
t taa
a
t caa
c
c ctt
t
t ggg
t
a taa
g
a tat
g
a tga
t
t taa
c
t agc
t
g tct
t
c tgg
t
t aaa
t
t tgg
t
g aga
t
a att
t
a ctc
t
a ggg
t
a aat
t
c act
a
g gat
a
ca
ga
gg
ag
tg
tc
ct
ag
ct
tc
gc
ca
gc
ac
gt
tg
aa
ta
ac
gc
ag
ct
gg
ca
ca
ac
aa
ca
ag
ca
gag a aaa
a
gcc c aac
g
aaa a gcc
g
gat a cga
a
aca a tta
c
cta a atc
c
ttt t aat
t
ctt c cat
t
tat g ctt
c
aca t tga
g
tgt c agc
a
acc t gac
a
aag t gca
g
ttg g ttc
t
aca g aat
g
aaa a ttc
a
act t aga
a
gct c acc
g
taa t caa
a
gca t gcg
g
caa t aac
a
taa c gct
a
aat t att
t
gcc t ctc
t
aga t aaa
g
ttc t atg
a
gaa t tca
t
tC TTt ggt
aag a gac
g
cac t ggt
a
gg
gg
ag
ca
tc
at
tt
ga
ct
at
cg
aa
ct
ct
ca
ca
ca
tt
gg
gt
aa
ac
ga
tt
ag
at
tt
gt
at
gg
gtt
ccc
cgt
gcg
tga
taa
agg
ccc
ctt
gca
tgt
att
cct
gat
gag
atc
aac
ctt
aat
cac
aat
aga
gaa
cag
agg
gat
ctg
ttc
ctc
agg
g acg
g
t aca
g
t gct
t
c cgg
t
a aat
a
t gcc
c
g gag
a
g gta
a
t atg
t
g aga
t
t cag
t
t gtg
a
c agg
t
a gcc
t
a gtg
c
t gta
t
a gac
a
c tct
t
c acc
t
t cgc
g
a cgg
a
a gag
t
a gaa
c
t att
a
a cgt
a
t agg
t
t ttc
c
c ttg
a
c agt
a
t cac
a
gc
gg
cc
aa
tg
tt
tc
ac
tg
ga
at
aa
gg
tt
gg
ag
tg
ca
tc
aa
at
tg
aa
tc
tg
ga
ag
at
tt
ga
agg
gac
aaa
ttg
gaa
cgg
acc
aag
agg
ata
aaa
gga
cta
gcc
aag
gca
aaa
ggg
cgg
ttt
ttc
atg
caa
tca
ttg
gaa
ttt
gaa
gca
gca
c acc
c
c cag
c
c ttt
t
t cga
a
a gga
a
c gtg
a
a agc
a
g aga
g
a cct
a
g cat
t
a tag
a
c tgc
t
a ttg
c
c ttt
t
a tag
c
t atg
c
c tac
g
t ttt
c
a aat
a
c ctg
c
t tca
a
g aaa
g
a aaa
c
c tct
t
g cgt
g
c tga
g
t ctg
c
t aag
t
g aaa
g
a gat
a
a
c
t
c
a
t
a
a
g
g
t
a
g
t
t
c
t
t
a
g
a
t
t
t
t
g
g
agaatttca
at[T/C]gt
aagaggaca
a
t
3.2 billion letters of human DNA encoded within 21,009 genes
1 Base per 1,000 Shows Single Nucleotide Polymorphism (SNPs)
Regulation of Gene Expression through
Epigenetic Processes (Epigenome)
Gluckman P et al. N Engl J Med 2008;359:61-73
From Family Genetic Pedigree to Gene
Identification & Positional Gene Cloning
Phenomics: Decoding the Human Genome and
Assigning Phenotype with Specific Gene(s)
•TNFSF4: Heart
Attacks
•LCT: Lactose
Intolerance
•CLOCK: Evening
Preference
•SLC6A3:
Substance Abuse
•CHRNA6: Linked
to Tobacco
Addiction
•OCA2: Blue Eyes
Next Frontier
Integrating genome-wide transcriptome, DNA
methylation, and histone modification data with
gene network and phenotype analyses will
reveal the consequences of human disease- and
disorder-causing mutations and introduce
rational or precise drug design for many
conditions.
Who pays for health care in 2015?
The government pays for it
Annual Medicare Part A Surplus or Deficit
Billions
of Dollars
100
50
0
-50
-100
-150
-200
-250
-300
-350
Public Spending
-400
accounts for more
-450
than half all health
care spending 2010
2000
2020
2030
2040
Based on 2009 & 2013 Annual Report of the Board of Trustees of the Federal Hospital Insurance and Federal Supplementary Medical Insurance
Trust Funds and 2005 & 2013 GAO reports
Healthcare Becoming Unsustainable
National Health Expenditures as Percent of GDP (1960-2020)
$2.57
Trillion
19.8% GDP
%
GDP
Only 4 other countries have entire
economies bigger than what we spend
on healthcare
Source: Truffer, et al. Health Spending Projections Through 2019: The Recession’s Impact Continues. Health Affairs 2010;29:1-8
Major Challenge: US Declining Health
Is this the future for our children?
1/3 to ½ become obese
1/3 get type 2 diabetes
Earlier disabilities
Life expectancy  2-5 yrs
Key Components of Craniofacial Health Care
Cost
Access
Quality
Which do you want? Can we have all
three?
Craniofacial-Oral-Dental
Genomics! Will Clinicians Ride
the Wave or Watch From the
Beach? Now is the time!
A call for increased education in genetics for dental
health professionals. Collins & Tabak, 2004 JDE
Genetics and its implications for clinical practice and
education. Report of Panel 3 of the Macy Study. Genco,
Tabak, Tedesco et al, 2008 JDE
A view of the future: dentistry and oral health in
America. Garcia & Tabak, 2009 JADA
Larry Tabak and Francis Collins

A call for increased education in genetics for dental health professionals.
Collins & Tabak, 2004 JDE
“Education is about the future, not the past, and we are now
entering the era in which genetics and genomics will play a vital
role in both oral health research and dental practice.”
Calls To Action for “Personalized Craniofacial-Oral-Dental
Health” (2012-2015)
Personalized Medicine: Will Dentistry Ride the Wave or Watch from the Beach?
Kornman & Duff, 2012 JDR
Personalized Oral Health Care: Providing “ –omic” Answers to Oral Health Queries.
Glick, 2012 JADA
Evolution of the Scientific Basis for Dentistry and its Impact on Dental Education:
Past, Present, and Future. Slavkin, 2012 JDE
Patient Stratification for Preventive Care in Dentistry. Giannobile, Braun, Caplis, et al.
2013 JDR
Personalized Medicine Enters Dentistry: What Might This Mean for Clinical Practice?
Giannobile, Kornman & Williams. 2013 JADA
Revising the scope of practice for oral health professionals in health care: Enter
Genomics. The Santa Fe Group (Primary Author Slavkin). 2014 JADA
From phenotype to genotype: enter genomics and transformation of health
care. Slavkin. 2014 J Dent Res
Human genetics very successful at
explaining diseases caused by single
gene mutation (Mendelian Inheritance)
Genotype
Phenotype
Environment
Mendelian inheritance of “traits” is very much the exception, not the rule.
…but most “traits” or common diseases are
caused by a combination of multiple genes,
gene-gene and gene-environment
interactions, and epigenetics…
Genotype
Phenotype
Environment
Enter personalized health care to improve diagnosis, risk,
stratification of patients “at risk,” and treatment for specific diseases
and disorders
NextSeq 500 Desktop Sequencer
(from Illumina, San Diego)
• Faster (complete genome 8-12 hrs)
• Cheaper ($1,000 per human genome)
• Smarter (precise, efficient, accurate)
• DNA and RNA sequencing
• FDA approved in late 2013
• In 2015, now utilized in inherited disease
detection, genetic variance and risk assessments,
stratification of patients within large populations,
and cancer diagnostics for treatment/chemotherapy
selections
The Decreasing Cost of Genotype Information
Lu JT et al. N Engl J Med 2014;371:593-596.
Examples of the Regulatory Genes
that Control Craniofacial-OralDental Morphogenesis
•Anhydrotic Ectodermal Dysplasia: TNF-alpha
ligand (ectodysplasin-A1) and receptor genes
•A Novel Oligodontia: PAX9 transcription
factor gene
•Cleidocranial Dysplasia (supernumerary
teeth): CBFA-1 transcription factor gene
•Rieger Syndrome (tooth number, size and
shape): PitX2 transcription factor genes
• 700 genes identified in mice and 200 in
humans (see Inborn Errors of Development)
Phenotype of the X-linked Anhidrotic
Ectodermal Dysplasia (ED)
child
Can we correct single gene
mutations?

X-linked Anydrotic
Ectodermal Dysplasia
 Human defects include
sweat and lacrimal glands,
hair, nails and teeth
 Mouse animal models
 Dog animal models
 Define and measure
clinical phenotype features

Therapeutic Strategies
 Inject TNF-alpha (EDA)
during pregnancy
 Inject TNF-alpha (EDA) after
birth
 “Proof of Principle”
 FDA approvals
 Public/private partnerships
 First patient injected with
ED1200 protein in 2013; with
clinical trial in progress
Slavkin Birth of a Discipline: Craniofacial Biology, Aegis
Communications 2012
FROM DARWIN TO CLINICAL TRIALS
1875 - 2015
1990, Jonathan Zonana and Juha Kere discovered XLHED the gene
mutation for X-linked hypohidrotic (anhydrotic) ectodermal dysplasia.
2000-2009, Oliver Gaide and Pascal Schneider identified ED1200
protein and showed that this protein rescued mutant Tabby strain mice
with HED.
2006-2009, Margaret Casal rescued HED in a dog strain
2010, FDA approval EDIMER COMPANY begins „replacement
therapy‟ trials with National Foundation for Ectodermal Dysplasia
2012-2013 Studies to better define and quantitate phenotypes
2013 First ED infant injected with ED 1200
2015-present Clinical Trial continues
Biomimetics…(to
“mimic” biology) --design and
fabricate biological
processes and
biomaterials
Tissue Engineering
for Challenges of
Craniofacial-OralDental Birth
Defects, Head and
Neck Trauma, Head
and Neck Cancers
& Behavioral
Sciences
Applications
Mesenchymal Stem Cells
Biomimetic Approach for Nose Replacement: Stem Cells,
Scaffolds, Tissue Engineering and Biomaterials
Robert Langer MIT
Biomimetic Solutions for Nasal Carcinoma
Design and Fabricate Human Roots Using Stem
Cells
Porcelain
Crown
Dental
implant
Stem cell-mediated
Root/Perio-complex
regeneration
Bio-root
implant
Songtao Shi 2006
Reducing Scarring
After Surgery or Burn Injuries
Scarring is an unmet medical need:
• Correction of birth defects, e.g.
cleft lip and palate
• Reconstruction after injuries from
war fighting or accidents
• Repair of burn injuries
• Revision of
hypertrophic scars
and keloids
First in
man trial
targeted
for 2016
Small Business Phase II
Grant: Anti-scar Peptide
for Cleft Lip Repair
Small Business Phase I Progress included:
Grant: Anti-scar Peptide • Identification and characterization of
peptide
for Cleft Lip Repair
Exploratory Grant (2007):
A Novel Peptide Inspired
by Nature - Fibromodulin
•
•
•
•
•
In vitro work in cell cultures
Studies in small and large animal
models
Scarless Laboratories, Inc. formed
Pre-IND meeting with FDA
Pre-clinical package in progress
Advanced Head & Neck Cancer Treatments
Targeted
Drug
Encapsulated
Drugs
Photodynamic
Therapy
Modified
Virus
Monoclonal Antibody
with Radioisotope
Gene Therapy
Nanomolecular
“smart drug”
Craniosynostosis & Novel Innovations
New studies demonstrate that
perivascular mesenchymal stem
cells (MSCs) contribute to
endochondral as well as
intramembranous craniofacial bone
turnover. These Gli1+ cells are
located within suture mesenchyme
and give rise to bone formation
during development as well as in
response to injury in adults.
Ablation of Gli1+ cells results in
craniosynostosis.
H. Zhao and colleagues. Nature Cell
Biology 17:386-396, 2015.
The Next Frontier: Changing &
Emerging Opportunities
The Next Ten Years (2025)
• Science-Based Health Care (Biomedical & Behavioral)
• Major Revision of Health Care Professional Education as a Function
of Societal Needs (Interprofessional education & clinic care)
• Advocacy For Health Promotion, Risk Assessment & Disease
Prevention
• Improved Cost Effectiveness & Clinical Efficacy
• Human Genome-Wide Scans for less than $1,000 per person
• Cellular, Molecular, Tissue and Organ Regeneration
• Virtual Surgery and Nano-instrumentation
• Advanced Bio-imaging
• Therapeutics & Rehabilitation of “Aging Populations”
• Access to Quality, Integrated, Coordinated and Comprehensive
Health Care for all People at Reduced Costs in USA and beyond