for Defining Functional Foods Cindy D. Davis davisci@mail nih gov

Challenges and Opportunities Using
“omics” for Defining Functional
Foods
Cindy D. Davis
[email protected]
davisci@mail nih gov
Nutritional Science Research Group
Division of Cancer Prevention
National Cancer Institute
Bethesda, MD 20892
Ascorbic Acid
Folate
polyphenolics
Stanols & sterols
Indole-3-carbinol
Flavonoids
Carotenoids
anthocyanidins
Diet has been implicated in the incidence of 6 out of 10 of the
leading causes of death of Americans
Surgeon General’s Report
Difficult Problem: While unprecedented opportunities exist for the expanded use
of foods & components to achieve genetic potential, increase productivity and
reduce the risk of disease, which of the 25,000 food components is most important
and under what circumstances ?
1
 Tomatoes
 Spinach
 Broccoli
 Garlic
 Nuts
 Salmon
 Oats
 Blueberries
 Green tea
 Red wine
Time Magazine: January 21, 2002
Nutritional Preemption
(A Strategy for Health Promotion)
Concept that bioactive food
components can be introduced
at points of initiation &
progression for pathway leading
to an unhealthy or lethal
phenotype
R
National Academy of Sciences Defines
Functional Foods:
“encompass potentially healthful products,”
including “any modified food or food
ingredient that may provide a health benefit beyond the
traditional nutrients it contains.
Recent Report
Institute of Food
Technologists
IFT Experts Report
March 24, 2005
2
Numerous Dietary Components Can
Have Health Benefits
Essential Nutrients- Ca, Zn, Se, Folate, C, E
Non-Essential
Phytochemicals- Carotenoids, Flavonoids,
Indoles, Isothiocyanates, Allyl Sulfur
Zoochemicals - Conjugated linoleic acid
acid, n-3
n3
fatty acids
Fungochemicals - Several compounds in
mushrooms
Bacteriochemical - Those formed from food
fermentations and those resulting from intestinal
flora
Phytochemicals & Cancer Prevention
Surh, Nature Reviews 3: 768-780, 2003
Phytochemicals May Influence Genetic Events
Associated with Several Cancer Processes
3
The Literature Provides Mixed Conclusions.
Epidemiologic Studies of Dietary Soy Components and Breast
Cancer Risk
Asian Lee ‘92 (total soy protein)
Western
p < 0.001 Premenopausal
NS Postmenopausal
Hirose ‘95 (beancurd, miso)
Yuan ‘95 (tofu, soymilk)
NS Premenopausal
NS Postmenopausal
NS p = 0.44–
0.44–0.79 Shanghai, Tianjin
Wu ‘96 (tofu)
p < 0.01
0 01 Premenopausal
P
l
p < 0.05 Postmenopausal
Dai ‘01 (soy)
NS All Breast Cancer
S Just ER+/PR+
Ingram ‘97 (urinary isoflavones)
NS Diadzein
p = 0.009 Equol
den Tonkelaar ‘01 (urinary
phytoestrogens)
NS Postmenopausal
Keinan--Boker ‘02 (food content)
Keinan
NS Isoflavones
S Lignans
.1
.3
.6
.6
1.3
.6
.8
2.6
1.0
.7
1.0
1.3
.61
.6
.46
.66
.25 .44
.17
.1
.95
.78
.47
1.33
.27
.69
.46
.83
1.3
.79
.34
0
.58
.5
1.08
1.59
.98
1
1.5
Estimated Relative Risk
2
Image courtesy of Nature,
issue: Feb. 15, 2001
The Genetic Revolution is Providing New Insights into a Number of
Health Issues Including the Role of Diet in Cancer Prevention
What is Personalized Medicine?
 Using
information
about a person's
genetic makeup
to tailor
strategies for the
detection,
treatment, or
prevention of
disease.
4
Promises of Personalized Medicine
 Improve disease classification
  precision of therapies targeting molecular
mechanism(s) of disease
 Identify those at  risk for disease
 Target interventions to high-risk groups
 Motivate individuals to engage in preventive
health behaviors
 Facilitate informed decision-making for
behavior and lifestyle modifications
Burke W et al. Genetics in Medicine 8: 451-8, 2006
Personalized Medicine and Personalized Nutrition
Recent advances:
Herceptin is a Novel Pioneering Drug for
Personalized Medicine Approach Based on
Pharmacogenomics to block Her2-neu
expression.
Evidence Has Existed for Some
Time:
EGCG from Green Tea, Oleic Acid from
Olive Oil, n-3 fatty acids from Fish Oil and
Apigenin from parsley, thyme, and
peppermint may also significantly influence
HER2neu expression!
Genetic Variation
Most genes have small sequence differences
(polymorphisms) between individuals
Occur every 1350 bp on average
Some of these polymorphisms may affect:
How well the protein works
How the protein interacts with another protein or
substrate
The different gene forms containing
polymorphisms are called alleles
5
Can your genes tell you how to focus
your diet for cancer prevention?
~ 30,000 genes in human genome and roughly
five to eight million SNPs
Is It Logical to
Assume All
Individuals will
Respond
Identically??
6
Using the “Omics” of Nutrition to Identify
Responders from Non-Responders
N
u
t
r
i
g
e
n
o
m
i
c
s
Bioactive
Food
Components
Nutrigenetics
DNA
Nutritional
Epigenetics
RNA
Nutritional
Transcriptomics
Phenotype
Protein
Proteomics
Metabolomics
Metabolite
Nutrigenomics
A discipline that
investigates the effects
of dietary components
on the structure,
function and regulation
function,
of coding and noncoding DNA segments
of all genes present in
the genome of a given
species.
What is Nutrigenomics?
Nutrigenomics= the scientific study of the way specific genes respond
to given nutrients
Personalized Nutrition= application by individuals of their knowledge of
nutrigenomics to their everyday decisions about nutrition
Bioactive Food
Components
N
U
T
R
I
G
E
N
O
M
I
C
S
Nutrigenetics
g
DNA
RNA
Nutritional
Epigenetics
Nutritional
Transcriptomics
RNA
7
What is the evidence that nutrigenetics has
an impact on the relationship between diet
and cancer?
Genetic Variability Impacts Cancer Risk
and May Determine Response to Selenium
Effect of Glutathione Peroxidase Polymorphism on Lung Cancer Risk
hGPX1 Codon 198
Pro/Pro
Pro/Leu
Leu/Leu
P
Cases (n=315)
Controls (n=313) Odds Ratio
91 (29%)
157 (50%)
46 (21%)
Px2<0.0001
132 (42%)
1 00
1.00
135 (43%)
1.8
46 (15%)
2.3
Ptrend<0.001
Ratnasinghe et al. Cancer Res. 60: 6381-6383, 2000
The leucine-containing GPx allele is also more frequently associated
with breast, colon, and head and neck cancer.
Glutathione Peroxidase proteins differing by a
single amino acid at codon 198 respond
differently to increasing selenium
relative induction of G P X aactivity
6
5
4
198pro
198leu
3
2
1
0
0
30
60
90
120 150
Selenite(nM)
Hu and Diamond, Cancer Res. 15: 3347-51, 2003
8
What About Other Antioxidant Enzymes?
Manganese Superoxide Dismutase (MnSOD)
1. A major enzyme responsible for the detoxification
of reactive oxygen species in the mitochondria.
2. T → C substitution, resulting in a Val → Ala
change at the -9 position (Val-9Ala), alters the
secondary structure of the protein and has been
noted to affect transport of MnSOD into the
mitochondria.
Manganese Superoxide Dismutase Polymorphism
(Val-9Ala ) & Breast Cancer Risk
Odds Ratio
2
1.8
1.3
1
0
Val/Val
Ala/Ala
Val/Val
Ala/Ala
Postmenopausal
Cai et al. Breast Cancer Res. 2004; 6:647-55
Prostate Cancer Risk Modification by
MnSOD Genotype and Prediagnostic
Levels of Plasma Antioxidants
RR Prostatte Cancer
2
*
MnSOD Genotype
VV and VA
AA
1.6
1.2
0.8
*
0.4
0
1
2
3
4
Quartile Baseline Selenium
Li H, et al. Cancer Res. 2005 65:2498-504.
9
Polymorphism in Folate Metabolism Can Influence Health
5,10-methylenetetrahydrofolate reductase (MTHFR): 677 C to T
substitution, occurs in 5-20% of the population worldwide
MTHFR Genotype, Dietary Folate
and Colon Cancer Risk
ODDS Ratio
1
677CC
677TT
0.8
0.6
0.4
0.2
0
<273
> 388
Dietary Folate (mg/day)
Curtin et al., Cancer Epidemiology, Biomarkers, Prevention 13: 285-292, 2004
Polymorphisms in Many Folate-Metabolizing
Enzymes May be Linked to Cancer Risk
Ulrich et al. Cancer Epidemiol Biomarkers Prev 14: 2509-2516, 2005
10
Polymorphisms in the Vitamin D
Receptor Gene
Locations of five known polymorphisms within or near the human VDR gene
These polymorphisms may alter 1,25 Vitamin D function and thereby
affect cancer risk
Oakley-Girvan et al., Cancer Epidemiol Biomarkers Prev 13: 1325-30, 2004
Vitamin D Receptor Gene
Polymorphisms and Breast Cancer Risk
2
*
2
*
P<0.01
12
1.2
0.8
0.4
0
bb
Bb
BsmI polymorphism
BB
*
1.6
Odds Rattio
Odds Ratio
o
1.6
12
1.2
0.8
0.4
0
LL
LS
SS
Poly (A) Polymorphism
Guy et al. Clinical Cancer Research, 10: 5472-5481, 2004
VDR FokI Polymorphism Affects
Calcium Metabolism
Abrams et al. J. Bone Mineral Res. 20: 945-953, 2005
11
Dietary Calcium, VDR FokI
Genotype and Colon Cancer Risk
OR for Colon Cancer
3
*
2.5
*
2
Dietary Calcium
< 388 mg/day
>388 mg/day
15
1.5
P ffor ttrend=0.004
d 0 004
1
0.5
0
FF
Ff
ff
VDR Genotype
Wong et al. Carcinogenesis, 24: 1091-1095, 2003
Need to Consider Haplotypes in the VDR Gene
Uitterlinden et al. Gene 338: 143-156, 2004
Variations in The Human Genome
International HapMap Project- constructed a map of
patterns of SNPs occurring across populations in Africa,
Asia and the U.S. was completed in 2005
http://www.hapmap.org/
Scientists have identified about 3 million locations
where single-base DNA differences (SNPs) occur in
humans. This information is revolutionizing the process
of finding chromosomal locations for disease-associated
sequences and tracing human history.
12
Diet Can Modify Genetic
Susceptibility to Cancer
% of Animals with T
Tumors
100
Prostate Tumors in Lady
mice.
80
Antioxidants= vitamin E,
selenium and lycopene
60
40
20
*
*
0
Control
High Fat
Control + Anti
High Fat + Anti
Venkateswaran et al., Cancer Research 64: 5891-5896, 2004
Gene-Nutrient Interactions and Colon Cancer
p21+/+ AIN-76A Diet
100
p21+/- AIN-76A Diet
Percent survival
90
p21+/+ Western Diet
80
p21-/- AIN-76A Diet
p21+/- Western Diet
70
60
50
40
p21-/- Western Diet
30
20
10
0
0
4
8
12
Yang et al, Cancer Res. 61, 565, 2001
16 Weeks
20 24
28
32
36
One Size Does Not Fit All! Genetic Background May
Determine Who Will Respond to Bioactive Food
Components
13
Nutrigenetics Today!
•
Commercial Nutrition-Gene Test
– Genelex Sciona 19 genes including
MTHFR $395
–
Gene Care CVD nutritional genetic test (South
Africa) MTHFR (Hcyst), apoA1 (HDL)
+9 others $400
•
About 30, 000 Genes, 5-8 Million SNPs
http://www.gao.gov/new.items/d06977t.pdf
GAO Investigation:
Nutrigenetic Testing
Created fictitious consumers by
submitting for analysis 12 DNA
samples from a female and 2 samples
from an unrelated male
Submitted DNA from cheek swab to
analyze between 4-19 genes and
submitted questions about sex, age,
weight, and lifestyle
Fees ranged from $89 to $395
14
Genetic Testing Promises vs Reality!
 All predicted fictitious consumers were at risk for
developing a range of conditions
 Many predictions were medically unproven and/or
ambiguous  results with no meaningful
information
 Some recommend expensive supplements similar
to commonly available vitamins and antioxidants
($1200/yr vs $35/yr) and make unproven claims,
e.g. “DNA repair” and Cat’s Claw
 Some provided common sense health
recommendations instead of those based on unique
genetic profile
Because genotype contributes to phenotype….
If it were only this easy…
Future Directions for Nutrigenetics




Human genetic variation and HapMap
Affordable whole genome association studies
Better methods to measure dietary intake
More powerful study designs to assess G x E

Identification of clear nutritional benefits for
individuals
 More clearly identify the benefits
• Health claims
• Identification of non-traditional nutrients
 Improvements in the food supply
 Possible use of supplements that have clear benefits
15
Genes Are Only Part Of The Equation
Epigenetics Definition
• genetics: the study of heritable changes in
gene function that occur with a change in
q
the DNA sequence
• Epigenetics: the study of heritable changes
in gene function that occur without a change
in DNA sequence.
What is Epigenetics?
• Epigenetic abnormalities are involved in cancer,
genetic disorders, pediatric syndromes, and
contributing factors in autoimmune diseases and
aging
• Influence gene expression
• Two critical mechanisms:
– DNA methylation
– Histone posttranslational modification
16
DNA Methylation
• The covalent addition of methyl group to 5’
position of cytosine
– Largely confined to CpG dinucleotides
– CpG islands - regions of more than 500 bp with CG
content > 55%
– Islands found in promoter regions of genes
• Catalyzed by DNA methyltransferases
Epigenetic Regulation of Cancer
Epigenetics Regulates:
Regulating
Factors
Cell Cycle Control
DNA Damage
Apoptosis
Invasion
X-Chromosome Inactivation
Imprinting
Aging
g g
Dietary
Hormonal
Genetic
DNA Methyltransferases
Histone Methyltransferases
Histone Acetylases/Deacetylases
Global
Hypomethylation
Site Specific
Hypermethylation
Histone
Modifications
Verma M, Srivastava S. Lancet Oncol. (2002) 3:755-63.
Dietary Factors Known to
Influence DNA Methylation
Alcohol
Choline
Equol
Folate
Methionine
Tea Polyphenols
Vitamin B6
Zinc
Arsenic
Coumestrol
Fiber
Genistein
Selenium
Vitamin A
Vitamin B12
17
Bioactive Food Components in the
DNA Methylation Process
Nutrients
Polymorphisms
SAH
SAM
DNA Methyltransferase
CpG
Me-CpG
DNA Demethylation
Nutrients?
Tumor
LTR Hypomethylated
LTR Hypermethylated
Maternal
Supplements
zinc
i
methionine
betaine
choline,
folate
B12
Yellow Mouse
High risk cancer, diabetes,
obesity & reduced lifespan
Agouti Mouse
Lower risk of cancer, diabetes,
obesity and prolonged life
Cooney et al. J Nutr 132:2393S (2002)
Genistein Can Also Influence Agouti Phenotype
Viable yellow Agouti (Avy) Locus
Yellow Slightly Mottled Heavily PseudoMottled
Mottled agouti
Control Diet
Supplemented Diet
100
Cells Methylated (%
%)
100
40
Avy Offspring (% of Total)
Control Diet
Genistein Diet
p = 0.007
30
90
90
80
80
70
70
60
60
50
50
40
40
30
30
20
20
Pseudo-agouti
80%
Heavily Mottled
50%
Mottled
26%
20
Slightly Mottled
13%
10
10
10
0
0
Yellow
Slightly
Mottled
Mottled
Heavily
Mottled
Pseudoagouti
Yellow
7%
0
0
1
2
3
4
5
CpG Site in Avy PSIA
6
7
0
1
2
3
4
5
6
7
CpG Site in Avy PSIA
Dolinoy et al. Envir. Health Perspect. 114: 567-572, 2006
18
•DNA is packaged into chromatin
•Primary constituent of chromatin is the nucleosome (octamer of
4 histone proteins)
•Once thought to be merely a scaffold for DNA
•Now recognized as a major contributor to regulating DNA
processing
•Closed chromatin is a barrier to transcription, replication and
repair of DNA
Peterson and Laniel (2004) Curr Biol. 14:R546-51.
Chromatin Structure Influences Gene Expression
Gene “switched on”: open chromatin, unmethylated cytosines, acetylated histones
Gene “switched off”: closed chromatin, methylated cytosines, deacetylated histones
Histones Can Be Regulated by Isothiocyanates,
Allyl Sulfur, Genistein, and Butyrate
HDAC
Co-repressor
complex
Acetylated histones H3 and H4
associated with P21 and Bax
promoters
HDAC Inhibition
Molecular Target??
Transcription of P21 and Bax
mRNA
HDAC
Co-repressor
complex
acetyl groups added
p21 and Bax protein levels
increased
Cell cycle arrest Caspase activation
APOPTOSIS
19
HDAC Inhibition by SFN-rich Broccoli
Sprouts in Human Volunteers.
Dashwood RH, Ho E. Semin Cancer Biol. 2007 May 5; [Epub ahead of print]
Resveratrol improves health and survival
of mice on a high-calorie diet
Histone Modification by Dietary Factors
Inhibited by copper,
curcumin
INACTIVE CHROMATIN
ACTIVE CHROMATIN
Histones acetylated
HATs
HDACs
Type I & II:
inhibited by butyrate,
diallyl disulfide,
sulforaphane
Histones
unmodified
Type III:
require NAD+
Calorie restriction,
resveratrol
HMTs
Histones methylated
(H4-Lys20)
Methyl deficiency
DNMTs
DNA methylated
20
Genetic and Epigenetic Events Can Effect
DNA and Therefore Gene Expression
Transcriptomics
The study of the transcriptome, which is the
complete set of RNA transcripts produced by
the genome, and which link the genome,
proteome, and the cellular phenotype.
Key Variables:
Length and Timing of Exposure,
Effective Concentration
Petricoin, EF and Liotta LA, J. Nutr. 133:2476S-2484S, 2003
21
Transcriptomic Studies Are Providing Clues About
Molecular Targets for Specific Food Components
Selenium in LNCaP
Cells:
Androgen
Signaling
Proliferation/Cell cycle
Detoxification
Immune/stress
Apoptosis
Transcription
Signal Transduction
Cell Shape
Zhao et al., Molec. Biol. Cell 15: 506-519, 2004
Gene Expression Changes in Breast Cancer
Cell Lines Treated with Lycopene
A=apoptosis; B= cell cycle; C= receptors; D= oncogenes; E= DNA repair
Chalabi N et al. Pharmacogenomics 7:663-672, 2006
Transcriptomic Studies Are Providing Clues About
Molecular Targets for Phytochemicals
Resveratrol in LNCaP cells
Narayanan BA Current Cancer Drug Targets 6: 711-727, 2006
22
Isothiocyanates
Organosulfur compounds
Selenium
Isothiocyanates
HS
S
keap-1
SH
keap-1
S
nrf2
Cytoplasm
nrf2
nrf2
small
maf
Nucleus
ARE
“antioxidant responsive element”
Increased GST, QR
Transgenic and Knockout Models Key to
Identifying Sites of Action of Food Components
Microarray Analysis of Nrf-2 Knockout Mice fed Sulforaphane
The majority of up-regulated genes at the inducible and/or basal level are associated
with various metabolic reactions involved in detoxification of electrophiles and free
radicals.
Thimmulappa et al. Cancer Res. 62: 5196-5203, 2002
Transcriptomics: Differentially expressed genes in
human leukocytes after consumption of a high
protein or high carbohydrate breakfast
HC: Glycogen
metabolism genes
HP : Genes involved in
protein biosynthesis
Both: Immune
response and signal
transduction
van Erk MJ, et al. Am J Clin Nutr. (2006) 84:1233-41.
23
Proteomics
The systematic evaluation of changes in the
protein constituency of a cell to characterize
disease processes through protein pathways
that interconnect the extracellular
microenvironment with the control of gene
transcription.
Key Variables:
Length and Timing of Exposure,
Effective Concentration
Petricoin, EF and Liotta LA, J. Nutr. 133:2476S-2484S, 2003
Surface-Enhanced Laser Desorption/Ionization TimeOf-Flight Mass Spectrometry (SELDI-TOF)
Urol Oncol. 22:322-8, 2004
Proteomic Analysis of QuercetinTreated HT-29 Cells
2-D PAGE followed by mass spectrometry
More than 600 protein
spots resolved:
20 spots differed at
least 2-fold
2f
between
treated and control
cells
These proteins
included annexins,
detoxification
enzymes, cytoskeletal,
metabolism and gene
regulation
Wenzel et al. Proteomics, 4: 2160-2174, 2004
24
Proteomic Analysis of Breast
Cancer and Normal Breast Tissue
Scattergram
2-Dimensional difference gel electrophoresis
Red= higher expression in breast cancer
Green= higher expression in normal
Yellow= similar expression
LC/LN= low cancer, low normal
LC/HN=low cancer, high normal
HC/LN= high cancer, low normal
HC/HN= high cancer, high normal
Somiari et al, Proteomics 3: 1863-1873, 2003
Pioneering New Technologies:
Proteomics
Identify abnormal protein structures
and show how shape affects biology
and response to diet
Determine if and how bioactive food
components influence 3-D proteins
Use to assess the influence of
intervention strategies on protein
expression
What Is Metabolomics?
“...the complete set of metabolites/low-molecularweight intermediates, which are context
dependent, varying according to the physiology,
developmental or pathological state of the cell,
tissue, organ or organism…”
Key Variables:
Length and Timing of Exposure,
Effective Concentration
25
Metabolomics-based Approaches
Brit J Nutrition 92:
549-555, 2004
Metabolomic Analysis of the Biochemical
Effects of Dietary Isoflavones
Pre-Soy
Post-Soy
Solanky et al., Analytical Biochemistry 323: 197-204, 2003
Metabolomic Response Depends on the
Quantity of Dietary Components
Toxicity
Response
Typical Intakes??
Cell Cycle
Inhibition
Apoptosis
Immune
Enhancement
Antioxidant
Carcinogen
Metabolism
Nutritional
Supranutritional
Toxic
Exposure
26
Metabolomic Response Will
Depend on the Timing of Exposure
to Dietary
eta y Components
Co po e ts
Genistein & Mammary Cancer:
Timing is Everything
Exposure Period
Tumors/Rat
None
8.9
Prenatal
8.8
Adult
8.2
Prepubertal
4.3
Prepubertal + Adult
2.8
LaMartiniere et al JNutr 132: 552S, 2002
Components are “complex
mixtures” - act synergistically
27
Soy Phytochemicals and Green Tea Inhibit
Human Mammary Tumors in Mice
Zhou et al, Int. J. Cancer 108: 8-14, 2004
Polymeals May Offer Special Attributes
Dietary Component
% Reduction
 Wine (150 ml/day)
32%
 Fish (114 g 4x/week)
14%
 Dark Chocolate (100 g/day)
21%
 Fruits and Vegetables
21%
(400 g/day)
 Garlic (2.7 g/day)
25%
 Almonds (68 g/day)
12%
76% decreased risk of CVD
Franco et al. BMJ 329:1447-1450, 2004
Functional Foods: Must Consider
Quantity Consumed
Form Consumed
Duration of Exposure
Desired Effect
28
Summary: Phytochemicals and
Functional Foods
Foods consist of thousands of different chemicals
• Each has the potential of being beneficial, neutral, or harmful to
the body
y and harmful in others
• Some mayy be beneficial in some ways
• Some chemicals may exert different effects on different people
or when taken at differing doses or at different life stages
In most cases, the health benefits observed with
intakes of certain foods cannot be ascribed to
individual phytochemicals
Genetic polymorphisms may determine who would
benefit
“Omic” Knowledge and Enabling Technologies Coupled
with Greater Knowledge about the Environment and
Behaviors Will Impact our Phenotypes.
GENES
Information
PROTEINS
Structure/Activity
METABOLITES
Composition
ORGANISM
Phenotype
Genomics
Proteomics
Metabolomics
Bio/Physiol/Kinetic
Systems
Integration of Nutrition and Genomics
Clinical Data
Genes
Proteins
Metabolites
Clinical & Family History
Functional Imaging
Laboratory Tests
B
I
O
I
N
F
O
R
M
A
T
I
C
S
H
E
A
L
T
H
&
P
R
E
V
E
N
T
I
O
N
VLW Go
29
While Diet Linked: Much Confusion Exists
About What to Eat
Internet Resources
• UC Davis Nutrigenomics Distance Learning and Listserv
(http://nutrigenomics.ucdavis.edu/)
• IOM: Nutrigenomics and Beyond
(http://www.iom.edu/CMS/3788/31286/43170.aspx)
• National Human Genome Research Institute
(http://www.genome.gov/10000464)
• National Library of Medicine’s Guide to Understanding Genetic
Conditions (http://ghr.nlm.nih.gov/)
(http://ghr nlm nih gov/)
• NCI’s Understanding Cancer Series: Gene Testing
(http://www.cancer.gov/cancertopics/UnderstandingCancer/genete
sting)
• NCI Series, Public Health Genomics: Closing the Gap Between
Human Genome Discoveries and Population Health
(http://dceg.cancer.gov/news/meetings-eventsupcoming/genomicscourse)
• CDC Office of Public Health Genomics
(http://www.cdc.gov/genomics/training.htm)
30
“Although humans make sounds with their mouths
and occasionally look at each other, there is no solid
evidence that they actually communicate among
themselves”
31