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What is DNA?. What is DNA Day?. What is DNA Day?. April 1953 Drs. James Watson and Francis Crick determined the structure of DNA (double helix). What is DNA Day?. April 1953 Drs. James Watson and Francis Crick determined the structure of DNA (double helix). April 2003

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slide4

What is DNA Day?

April 1953

Drs. James Watson and Francis Crick determined the structure of DNA(double helix)

slide5

What is DNA Day?

April 1953

Drs. James Watson and Francis Crick determined the structure of DNA(double helix)

April 2003

Human Genome Project determined the entire DNA sequence of a human(3 billion letters)

slide7

What is Pharmacogenomics?

Pharma = drug or medicine

Genomics = the study of genes

R

X

slide8

What is Pharmacogenomics?

Pharma = drug or medicine

Genomics = the study of genes

Personalized medicine tailored to your genes

R

X

slide13

No Effect/Hurt

Helped

Tumoricide

slide14

No Effect/Hurt

Helped

Tumoricide

Why?

slide15

How do scientists make personalized medicine?

You

Your cells

Your DNA

Picture credit: adapted from Riken Research: http://www.rikenresearch.riken.jp/eng/frontline/5514

slide16

How do scientists make personalized medicine?

You

Your cells

It’s all about what makes YOUR genetic code UNIQUE

Your DNA

Picture credit: adapted from Riken Research: http://www.rikenresearch.riken.jp/eng/frontline/5514

genetic code dna
Genetic Code: DNA

DeoxyriboNucleic Acid (DNA) contains all the information necessary to make a complete organism

DNA is composed of a combination of 4 nucleotides

genetic code dna1
Genetic Code: DNA

DeoxyriboNucleic Acid (DNA) contains all the information necessary to make a complete organism

DNA is composed of a combination of 4 nucleotides

A

Adenine

genetic code dna2
Genetic Code: DNA

DeoxyriboNucleic Acid (DNA) contains all the information necessary to make a complete organism

DNA is composed of a combination of 4 nucleotides

A

T

Adenine

Thymine

genetic code dna3
Genetic Code: DNA

DeoxyriboNucleic Acid (DNA) contains all the information necessary to make a complete organism

DNA is composed of a combination of 4 nucleotides

A

C

T

Adenine

Thymine

Cytosine

genetic code dna4
Genetic Code: DNA

DeoxyriboNucleic Acid (DNA) contains all the information necessary to make a complete organism

DNA is composed of a combination of 4 nucleotides

A

G

Adenine

Thymine

Cytosine

Guanine

C

T

the central dogma dna rna protein
The Central Dogma: DNARNAProtein

DNA: A long double-stranded string of nucleotides that encode for many genes.

Gene

the central dogma dna rna protein1
The Central Dogma: DNARNAProtein

DNA: A long double-stranded string of nucleotides that encode for many genes.

Gene

RNA

RNA: A single-stranded copy of one gene.

the central dogma dna rna protein2
The Central Dogma: DNARNAProtein

DNA: A long double-stranded string of nucleotides that encode for many genes.

Gene

RNA: A single-stranded copy of one gene.

RNA

Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons.

the central dogma dna rna protein3
The Central Dogma: DNARNAProtein

DNA: A long double-stranded string of nucleotides that encode for many genes.

Gene

RNA: A single-stranded copy of one gene.

Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons.

Codon 1

the central dogma dna rna protein4
The Central Dogma: DNARNAProtein

DNA: A long double-stranded string of nucleotides that encode for many genes.

Gene

RNA: A single-stranded copy of one gene.

Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons.

Codon 1

Codon 2

the central dogma dna rna protein5
The Central Dogma: DNARNAProtein

DNA: A long double-stranded string of nucleotides that encode for many genes.

Gene

RNA: A single-stranded copy of one gene.

Amino acid 2

Amino acid 1

Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons.

Codon 1

Codon 2

the central dogma dna rna protein6
The Central Dogma: DNARNAProtein

DNA: A long double-stranded string of nucleotides that encode for many genes.

Gene

RNA: A single-stranded copy of one gene.

Amino acid 2

Amino acid 1

Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons.

Codon 1

Codon 2

Protein!

a small change in the gene sequence can result in a very different protein
A small change in the gene sequence can result in a very different protein

DNA:

ATG GTG CTG TCT CCT

a small change in the gene sequence can result in a very different protein1
A small change in the gene sequence can result in a very different protein

DNA:

ATG GTG CTG TCT CCT

Amino Acids/Protein:

Met

a small change in the gene sequence can result in a very different protein2
A small change in the gene sequence can result in a very different protein

DNA:

ATG GTG CTG TCT CCT

Amino Acids/Protein:

Met

Val

a small change in the gene sequence can result in a very different protein3
A small change in the gene sequence can result in a very different protein

DNA:

ATG GTG CTG TCT CCT

Amino Acids/Protein:

Met

Val

Leu

a small change in the gene sequence can result in a very different protein4
A small change in the gene sequence can result in a very different protein

DNA:

ATG GTG CTG TCT CCT

Amino Acids/Protein:

Met

Val

Leu

Ser

a small change in the gene sequence can result in a very different protein5
A small change in the gene sequence can result in a very different protein

DNA:

ATG GTG CTG TCT CCT

Amino Acids/Protein:

Met

Val

Leu

Ser

Pro

a small change in the gene sequence can result in a very different protein6
A small change in the gene sequence can result in a very different protein

DNA:

ATG GTG CTG TCT CCT

Amino Acids/Protein:

Met

Val

Leu

Ser

Pro

a small change in the gene sequence can result in a very different protein7
A small change in the gene sequence can result in a very different protein

DNA:

DNA:

ATG GTG CTG TCT CCT

ATG GTG CTG TCT ACT

Amino Acids/Protein:

Met

Val

Leu

Ser

Pro

a small change in the gene sequence can result in a very different protein8
A small change in the gene sequence can result in a very different protein

DNA:

DNA:

ATG GTG CTG TCT CCT

ATG GTG CTG TCT ACT

Amino Acids/Protein:

Amino Acids/Protein:

Met

Met

Val

Val

Leu

Leu

Ser

Ser

Thr

Pro

a small change in the gene sequence can result in a very different protein9
A small change in the gene sequence can result in a very different protein

DNA:

DNA:

ATG GTG CTG TCT CCT

ATG GTG CTG TCT ACT

Amino Acids/Protein:

Amino Acids/Protein:

Met

Val

Leu

Ser

Thr

Met

Val

Leu

Ser

Pro

Words:

Tom and Sam are bad

a small change in the gene sequence can result in a very different protein10
A small change in the gene sequence can result in a very different protein

DNA:

DNA:

ATG GTG CTG TCT CCT

ATG GTG CTG TCT ACT

Amino Acids/Protein:

Amino Acids/Protein:

Met

Val

Leu

Ser

Thr

Met

Val

Leu

Ser

Pro

Words:

Tom and Sam are bad

Words:

Tom and Sam are sad

a small change in the gene sequence can result in a very different protein11
A small change in the gene sequence can result in a very different protein

DNA:

DNA:

ATG GTG CTG TCT ACT

ATG GTG CTG TCT CCT

Amino Acids/Protein:

Amino Acids/Protein:

Met

Val

Leu

Ser

Thr

Met

Val

Leu

Ser

Pro

Words:

Tom and Sam are bad

Words:

Tom and Sam are sad

Changes in DNA are called variations or mutations

Variations in the DNA (genotype) can cause observable changes (phenotype) in individuals

slide41

Variationsin our DNA

make us

UNIQUE!

slide42

No Effect/Hurt

Helped

Tumoricide

Why does Tumoricide work on some patients but not on others?

what are the reasons a person would react differently to drugs
What are the reasons a person would react differently to drugs?
  • Having the receptor (protein) to recognize the drug
  • Other physiological traits that enable you to respond to a drug
  • How your body processes the drugs after receiving it
drugs and receptors1
Drugs and Receptors

Receptor

(Protein)

Cell

drugs and receptors2
Drugs and Receptors

Receptor

(Protein)

Cell

drugs and receptors3
Drugs and Receptors

Drug

(Ligand)

Receptor

(Protein)

Cell

drugs and receptors4
Drugs and Receptors

Drug

(Ligand)

Receptor

(Protein)

Cell

your dna and drugs
Your DNA and Drugs

Variation in genes can cause variation in receptors

Cell

your dna and drugs1
Your DNA and Drugs

Variation in genes can cause variation in receptors

Cell

your dna and drugs2
Your DNA and Drugs

Variation in genes can cause variation in receptors

Cell

Cell

Cell

your dna and drugs3
Your DNA and Drugs

Variation in genes can cause variation in receptors

Cell

Cell

Cell

Cell

Cell

your dna and drugs4
Your DNA and Drugs

Variation in genes can cause variation in receptors

Too Many

(hypersensitive)

Cell

Cell

Cell

Cell

Cell

your dna and drugs5
Your DNA and Drugs

Variation in genes can cause variation in receptors

Too Many

(hypersensitive)

Too Few

(hyposensitive)

Cell

Cell

Cell

Cell

Cell

your dna and drugs6
Your DNA and Drugs

Variation in genes can cause variation in receptors

Too Many

(hypersensitive)

Too Few

(hyposensitive)

Mutated

(insensitive)

Cell

Cell

Cell

Cell

Cell

where drugs fit in
Where Drugs “Fit” In

Lock = Receptor Key = Drug

let s do a class case study1
Let’s do a class case study!
  • Taste the PTC strip

(This won’t hurt you - not a toxic chemical)

What do you taste?

let s do a class case study2
Let’s do a class case study!
  • Taste the PTC strip

(This won’t hurt you - not a toxic chemical)

What do you taste?

Why does the strip taste bitter to some and have no taste for others?

What is your hypothesis?

slide60

Why can some people taste PTC and others can’t?

PTC

PTC-Receptor

Taste cell

“This tastes bitter!”

slide61

Why can some people taste PTC and others can’t?

Non-binding PTC-Receptor

PTC

PTC

PTC-Receptor

Taste cell

Taste cell

“This tastes bitter!”

“I don’t taste anything!”

where does tasting ptc come from
Where does tasting PTC come from?

You have two copies of every gene: one from Mom and one from Dad

where does tasting ptc come from1
Where does tasting PTC come from?

You have two copies of every gene: one from Mom and one from Dad

where does tasting ptc come from2
Where does tasting PTC come from?

You have two copies of every gene: one from Mom and one from Dad

where does tasting ptc come from3
Where does tasting PTC come from?

You have two copies of every gene: one from Mom and one from Dad

  • Your two genes are the genotype
where does tasting ptc come from4
Where does tasting PTC come from?

You have two copies of every gene: one from Mom and one from Dad

  • Your two genes are the genotype
  • A gene can be dominant or recessive
where does tasting ptc come from5
Where does tasting PTC come from?

You have two copies of every gene: one from Mom and one from Dad

  • Your two genes are the genotype
  • A gene can be dominant or recessive
  • The expressed trait is a phenotype
tasting ptc is dominant t over inability taste ptc which is recessive t4
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt

For individuals with these genotypes, what would their phenotypes be?

tasting ptc is dominant t over inability taste ptc which is recessive t5
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt

“This tastes REALLY bitter!”

SUPERTASTER

tasting ptc is dominant t over inability taste ptc which is recessive t6
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt

“This tastes REALLY bitter!”

“This tastes bitter!”

SUPERTASTER

TASTER

tasting ptc is dominant t over inability taste ptc which is recessive t7
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt

“This tastes REALLY bitter!”

“I dont taste anything!”

“This tastes bitter!”

SUPERTASTER

TASTER

NON-TASTER

drug receptor summary
Drug receptor summary

Ability to taste PTC has a very strong genetic component

PTC = chemical and Drugs = chemical

Differences in ability to taste PTC is similar to differences in reactions to drugs

PTC

slide77

No Effect/Hurt

Helped

Tumoricide

Why?

slide78

Two Types of Breast Cancer

Y

Y

Y

Her2-

Her2+

  • Tumoricide is a personalized medication
  • Tumoricide only works for Her2+ breast tumors
slide79

No Effect/Hurt

Helped

Her2+

Her2-

Tumoricide

slide80

Screening for Her2+ Cells

Her2-

Her2+

American Journal of Clinical Pathology. 2008;129(2):263-273

slide81

Screening for Her2+ Cells

Tumoricide

= ?

+

American Journal of Clinical Pathology. 2008;129(2):263-273

slide82

Screening for Her2+ Cells

Tumoricide

= ✓

+

American Journal of Clinical Pathology. 2008;129(2):263-273

slide83

Breast Cancer

  • 1990
  • Surgery
  • Radiation
  • Chemotherapy (drugs)
  • 2012
  • Surgery
  • Radiation
  • Chemotherapy
    • Specialized treatments (for certain types of breast cancer)

http://www.ucdmc.ucdavis.edu/welcome/features/20080709_cancer_sweeney/index.html

what are the reasons a person would react differently to drugs1
What are the reasons a person would react differently to drugs?
  • Having the receptor (protein) to recognize the drug
  • Other physiological traits that enable you to respond to a drug
  • How your body processes the drugs after receiving it
the presence of receptors influence how we react to drugs like tumoricide or chemicals like ptc
The presence of receptors influence how we react to drugs like Tumoricide or chemicals like PTC

Y

Y

Y

Her2-

Her2+

Tumoricide Does Not Work

Tumoricide Works!

the presence of receptors influence how we react to drugs like tumoricide or chemicals like ptc1
The presence of receptors influence how we react to drugs like Tumoricide or chemicals like PTC

TT

tt

Tt

“This tastes REALLY bitter!”

“I dont taste anything!”

“This tastes bitter!”

SUPERTASTER

TASTER

NON-TASTER

slide88

Where are the PTC receptors?

Yummy!

They are on your taste buds!

what are taste buds
What are taste buds?

Taste buds are found on papillae on your tongue

what are taste buds1
What are taste buds?

Taste buds are found on papillae on your tongue

Papillae

bumps on your tongue

what are taste buds2
What are taste buds?

Taste buds are found on papillae on your tongue

Papillae

bumps on your tongue

Taste buds cells are found on the papilla

what are taste buds3
What are taste buds?

Taste buds are found on papillae on your tongue

PTC receptors are found on the taste buds

Papillae

bumps on your tongue

Taste buds cells are found on the papilla

what are taste buds4
What are taste buds?

Taste buds are found on papillae on your tongue

PTC receptors are found on the taste buds

Papillae

Nerve Cell

Transmits signal to brain

bumps on your tongue

Taste buds cells are found on the papilla

what are taste buds5
What are taste buds?

Taste buds are found on papillae on your tongue

Brain

Wow! This tastes really bitter

PTC receptors are found on the taste buds

Papillae

Nerve Cell

Transmits signal to brain

bumps on your tongue

Taste buds cells are found on the papilla

slide95

Question:

Are there other traits that can allow a person to more strongly taste PTC?

Hypothesis:

if a person has more taste buds then he she may be able to taste the ptc more strongly

Question:

Are there other traits that can allow a person to more strongly taste PTC?

Hypothesis:

If a person has more taste buds, then he/she may be able to taste the PTC more strongly.

slide97

Let’s test our hypothesis and count our taste buds!

  • Lollipop time! Lick your lollipop such that the blue gets all over your tongue…especially the tip of your tongue.
  • Once your tongue is really blue, place one hole reinforcer on the tip of your tongue—so it looks like the picture on the bottom on this slide.
  • Have your partner count the bumps or papillae on your tongue…these will not stain blue.

* Remember that your taste buds are on your papillae.

Therefore the number of papillae correlates to the

amount of taste buds on your tongue. *

slide98

Counting the number of tongue papillae

5 papillae

20 papillae

35 papillae

slide99

Counting the number of tongue papillae

5 papillae

20 papillae

35 papillae

Come to the front of the class to report your PTC phenotype (taster, super-taster and non-taster) and the number of papillae on your tongue

slide100
Please PAUSE and take a moment to count your taste buds and report your results on the spreadsheet at the front of the classroom
slide101

Ideal graph representing the number of tongue papillae related to the phenotype of PTC taste

These results support our hypothesis that the super-taster has more papillae!

slide102

Ideal graph representing the number of tongue papillae related to the phenotype of PTC taste

The number of papillae in the non-taster is variable.

Why would the number of papillae be variable in a non-taster?

slide103
Please PAUSE and discuss why you think being a PTC non-taster does not correlate with number of taste buds.
what does it take to be a ptc taster
What does it take to be a PTC Taster?

Two traits are important for determining PTC taste sensitivity

1) PTC receptor genotype—Do you have the receptors that enable you to taste PTC

what does it take to be a ptc taster1
What does it take to be a PTC Taster?

Two traits are important for determining PTC taste sensitivity

1) PTC receptor genotype—Do you have the receptors that enable you to taste PTC

2) The density of papillae on your tongue correlates to the sensitivity of tasting PTC

super-taster

taster

what are the reasons a person would react differently to drugs2
What are the reasons a person would react differently to drugs?
  • Having the receptor (protein) to recognize the drug
  • Other physiological traits that enable you to respond to a drug
  • How your body processes the drugs after receiving it
slide107

A Drug’s Life

  • ADME
  • Absorption
  • Distribution
  • Metabolism
  • Excretion

http://publications.nigms.nih.gov/medbydesign/chapter1.html

slide108

Metabolic enzymes

Enzymes

Metabolites

Drug

Liver

DNA variations in special proteins in the liver called enzymes can influence a person’s ability to metabolize certain drugs

slide109

Adverse Drug Reactions (ADR)

  • Definition- unwanted, negative response to a prescribed drug at normal doses and during normal use
    • Examples?
slide110

Adverse Drug Reactions (ADR)

  • Definition- unwanted, negative response to a prescribed drug at normal doses and during normal use
    • Examples?
  • There are multiple causes for ADRs
    • environmental basis
    • genetic basis
slide111

Adverse Drug Reactions (ADR)

  • Definition- unwanted, negative response to a prescribed drug at normal doses and during normal use
    • Examples?
  • There are multiple causes for ADRs
    • environmental basis
    • genetic basis
  • Poor metabolizers can experience ADRs at normally therapeutic drug doses
slide112

B

A

C

Case study: Nortriptyline metabolism

  • Three women of the same height, weight, age, and racial background are depressed and go to the doctor.
  • The doctor prescribes an antidepressant, Nortriptyline, at a dose of 100 mg.
  • Person A has an adverse reaction
  • Person B nothing happens
  • Person C gets better…
slide113

B

A

C

Case study: Nortriptyline metabolism

  • Three women of the same height, weight, age, and racial background are depressed and go to the doctor.
  • The doctor prescribes an antidepressant, Nortriptyline, at a dose of 100 mg.
  • Person A has an adverse reaction
  • Person B nothing happens
  • Person C gets better…

Why?

slide114

B

A

C

ADME of Nortriptyline

100mg Nortriptyline

Adverse reaction

Nothing happens

Gets better

How much active drug in blood?

slide115

B

A

C

ADME of Nortriptyline

100mg Nortriptyline

Adverse reaction

Nothing happens

Gets better

95mg

5mg

50mg

slide116

A

DNA variation influence drug metabolism

Enzymes

Metabolites

Drug

Liver

Poor

Metabolizer

95mg

slide117

B

DNA variation influence drug metabolism

Enzymes

Metabolites

Drug

Liver

Ultrarapid

Metabolizer

5mg

slide118

C

DNA variation influence drug metabolism

Enzymes

Metabolites

Drug

Liver

Intermediate Metabolizer

50mg

slide119

B

A

C

2012 - What do doctors do?

Poor Metabolizer

Ultrarapid Metabolizer

Decrease Dose

Increase Dose

Or change drug

slide120

Today One-size-fits-all drugs

  • Current drug development system develops drugs for the average patient
  • No simple way to determine who will respond well and who will respond poorly
  • One size does NOT fit all!
  • What’s the solution?
slide121

Today One-size-fits-all drugs

  • Current drug development system develops drugs for the average patient
  • No simple way to determine who will respond well and who will respond poorly
  • One size does NOT fit all!
  • What’s the solution?

Pharmacogenomics (PGx)

Personalized Medicine

slide122

April, 2050

  • You wake up feeling terrible, and you know it\'s time to see a doctor. In the office, the physician looks you over, listens to your symptoms, and decides to prescribe you a drug.
  • But first, the doctor takes a look at your DNA.
  • TODAY vs. FUTURE
  • Today = Drugs are One-Size-Fits-All
  • Future = Drugs Specific for You!
  • More effective & minimizes side effects
slide123

Summary

Genetic variation leads to phenotypic differences and differences in how we all react to drugs.

slide124

Summary

Genetic variation leads to phenotypic differences and differences in how we all react to drugs.

Having the receptor (protein) to recognize the drug

PTC and HER2 receptors

slide125

Summary

Genetic variation leads to phenotypic differences and differences in how we all react to drugs.

Having the receptor (protein) to recognize the drug

PTC and HER2 receptors

2. Other physiological traits that enable you to respond to a drug

Number of taste buds on tongue

slide126

Summary

Genetic variation leads to phenotypic differences and differences in how we all react to drugs.

Having the receptor (protein) to recognize the drug

PTC and HER2 receptors

2. Other physiological traits that enable you to respond to a drug

Number of taste buds on tongue

3. How drugs are processed in the body

Enzymes in liver metabolize drugs

slide127

Pharamcogenomics

Using people’s genetic information for the right drug at the right dose at the right time!

R

X

slide128

About the Scientist:

  • What do I study?
  • Why do I love science?
  • Questions?
slide129

Register for the 2nd Annual DNA Day 5K!

Run to Support Science Outreach and Education in NC

9:00 AM | Saturday, May 17th 2014

Run Through UNC Chapel Hill’s Campus

ncdnaday.org/5K

slide130

Join us for the 2nd annual NC DNA Day Science Festival after the 5K to do more fun hands-on science experiments!

Raffles

More!

Activities

Games

Contests

Experiments

May 17, 2014

UNC Student Union Great Hall

10am-12pm

ncdnaday.org/festival

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