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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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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

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


What is Pharmacogenomics?

R

X


What is Pharmacogenomics?

Pharma = drug or medicine

Genomics = the study of genes

R

X


What is Pharmacogenomics?

Pharma = drug or medicine

Genomics = the study of genes

Personalized medicine tailored to your genes

R

X






No Effect/Hurt

Helped

Tumoricide


No Effect/Hurt

Helped

Tumoricide

Why?


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


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


Variations different protein in our DNA

make us

UNIQUE!


No Effect/Hurt different protein

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 receptors
Drugs and Receptors drugs?

Cell


Drugs and receptors1
Drugs and Receptors drugs?

Receptor

(Protein)

Cell


Drugs and receptors2
Drugs and Receptors drugs?

Receptor

(Protein)

Cell


Drugs and receptors3
Drugs and Receptors drugs?

Drug

(Ligand)

Receptor

(Protein)

Cell


Drugs and receptors4
Drugs and Receptors drugs?

Drug

(Ligand)

Receptor

(Protein)

Cell


Your dna and drugs
Your DNA and Drugs drugs?

Variation in genes can cause variation in receptors

Cell


Your dna and drugs1
Your DNA and Drugs drugs?

Variation in genes can cause variation in receptors

Cell


Your dna and drugs2
Your DNA and Drugs drugs?

Variation in genes can cause variation in receptors

Cell

Cell

Cell


Your dna and drugs3
Your DNA and Drugs drugs?

Variation in genes can cause variation in receptors

Cell

Cell

Cell

Cell

Cell


Your dna and drugs4
Your DNA and Drugs 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 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 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 drugs?“Fit” In

Lock = Receptor Key = Drug


Let s do a class case study
Let drugs?’s do a class case study!


Let s do a class case study1
Let drugs?’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 drugs?’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?


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

PTC

PTC-Receptor

Taste cell

“This tastes bitter!”


Why can some people taste PTC drugs?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? drugs?

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? drugs?

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? drugs?

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? drugs?

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? drugs?

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? drugs?

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 t
Tasting PTC is drugs?dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt


Tasting ptc is dominant t over inability taste ptc which is recessive t1
Tasting PTC is drugs?dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt


Tasting ptc is dominant t over inability taste ptc which is recessive t2
Tasting PTC is drugs?dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt


Tasting ptc is dominant t over inability taste ptc which is recessive t3
Tasting PTC is drugs?dominant (T) over inability taste PTC which is recessive (t)

TT

Tt

tt


Tasting ptc is dominant t over inability taste ptc which is recessive t4
Tasting PTC is drugs?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 drugs?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 drugs?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 drugs?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 drugs?

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


No Effect/Hurt drugs?

Helped

Tumoricide

Why?


Two Types of Breast Cancer drugs?

Y

Y

Y

Her2-

Her2+

  • Tumoricide is a personalized medication

  • Tumoricide only works for Her2+ breast tumors


No Effect/Hurt drugs?

Helped

Her2+

Her2-

Tumoricide


Screening for Her2+ Cells drugs?

Her2-

Her2+

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


Screening for Her2+ Cells drugs?

Tumoricide

= ?

+

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


Screening for Her2+ Cells drugs?

Tumoricide

= ✓

+

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


Breast Cancer drugs?

  • 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


Where are the PTC receptors? like Tumoricide or chemicals like PTC


Where are the PTC receptors? like Tumoricide or chemicals like PTC

Yummy!

They are on your taste buds!


What are taste buds
What are taste buds? like Tumoricide or chemicals like PTC

Taste buds are found on papillae on your tongue


What are taste buds1
What are taste buds? like Tumoricide or chemicals like PTC

Taste buds are found on papillae on your tongue

Papillae

bumps on your tongue


What are taste buds2
What are taste buds? like Tumoricide or chemicals like PTC

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? like Tumoricide or chemicals like PTC

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? like Tumoricide or chemicals like PTC

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? like Tumoricide or chemicals like PTC

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


Question like Tumoricide or chemicals like PTC :

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 like Tumoricide or chemicals like PTC :

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.


Let like Tumoricide or chemicals like PTC ’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. *


Counting the number of tongue papillae like Tumoricide or chemicals like PTC

5 papillae

20 papillae

35 papillae


Counting the number of tongue papillae like Tumoricide or chemicals like PTC

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


Please like Tumoricide or chemicals like PTC PAUSE and take a moment to count your taste buds and report your results on the spreadsheet at the front of the classroom


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!


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?


Please related to the phenotype of PTC tastePAUSE 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? related to the phenotype of PTC taste

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? related to the phenotype of PTC taste

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


A Drug drugs?’s Life

  • ADME

  • Absorption

  • Distribution

  • Metabolism

  • Excretion

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


Metabolic enzymes drugs?

Enzymes

Metabolites

Drug

Liver

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


Adverse Drug Reactions (ADR) drugs?

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

    • Examples?


Adverse Drug Reactions (ADR) drugs?

  • 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


Adverse Drug Reactions (ADR) drugs?

  • 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


B drugs?

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…


B drugs?

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?


B drugs?

A

C

ADME of Nortriptyline

100mg Nortriptyline

Adverse reaction

Nothing happens

Gets better

How much active drug in blood?


B drugs?

A

C

ADME of Nortriptyline

100mg Nortriptyline

Adverse reaction

Nothing happens

Gets better

95mg

5mg

50mg


A drugs?

DNA variation influence drug metabolism

Enzymes

Metabolites

Drug

Liver

Poor

Metabolizer

95mg


B drugs?

DNA variation influence drug metabolism

Enzymes

Metabolites

Drug

Liver

Ultrarapid

Metabolizer

5mg


C drugs?

DNA variation influence drug metabolism

Enzymes

Metabolites

Drug

Liver

Intermediate Metabolizer

50mg


B drugs?

A

C

2012 - What do doctors do?

Poor Metabolizer

Ultrarapid Metabolizer

Decrease Dose

Increase Dose

Or change drug


Today drugs?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?


Today drugs?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


April, 2050 drugs?

  • 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


Summary drugs?

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


Summary drugs?

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


Summary drugs?

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


Summary drugs?

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


Pharamcogenomics drugs?

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

R

X


About the Scientist: drugs?

  • What do I study?

  • Why do I love science?

  • Questions?


Register for the 2 drugs?nd 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


Join us for the drugs?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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