DNA Day - Pharmacogenetics1. Todays Plan! What is DNA? Genetic Wheel Activity What is Pharmacogenomics? Super taster activity! How do drugs work? Wrap

DNA Day - Pharmacogenetics 1

Today’s Plan!• What is DNA?• Genetic Wheel Activity• What is Pharmacogenomics?• Super taster activity!• How do drugs work?• Wrap up and future science careers

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On April 25, 1953

Drs. James Watson and Francis Crick determined the structure of DNA

In April 2003,

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

Genome: the complete set of hereditary factors

What is DNA Day?

Protein

RNA copy

Information is stored in DNA

Genes contain instructions to make proteins

Proteins do most of the

work in a cell and provide much of its structure.

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A change in gene result in a change in protein

SAM AND TOM ATE THE HAMChange:

SAM AND TOM ATE THE HIM

Thr Pro GluGlu Lys Leu

ACT|CCT|GAG|GAG|AAG|CTG

ACT|CCT|GAG|GAG|AAG|CGG

Thr Pro GluGlu Lys Met Result: Changed meaning or function

Change in DNA is called a mutation

Variations in the DNA of different individuals can cause phenotypic changes in individuals


Why do people look different?

• Genetic variation– Eye color - common genetic variation – Down’s syndrome (trisomy 21) - rare genetic variation

• Environment – Diet– Exercise

Mendelian traits

Phenotype: Cleft ChinGenotype: cc

Phenotype: non-cleft chinGenotype: CC or Cc

Example

Mendelian traits

Phenotype: Cleft ChinGenotype: cc

Example

C

c

C cMom

Dad

What are mom and dad’s phenotype if their genotype is Cc? Non cleft chin

CC

Cc

Cc

cc

Name the phenotypes of their potential children.

• Just by looking around the room, we can see many examples of genetic variation.

• Some genetic traits, such as skin color and eye color, are controlled by multiple genes

• Others are controlled by only one gene

• We are going to look at 7 traits that are each determined by one gene with two possible alleles.

Variations in the DNA of different individuals can cause visible changes

in individuals

Single-gene Traits

Laugh dimples• ll no dimples (homozygous

recessive)• L dimples (heterozygous or

homozygous dominant)Tongue roll• tt can’t roll tongue into “U”

shape (homozygous recessive)

• T can roll tongue into “U” shape (heterozygous or homozygous dominant )

Single-gene TraitsCrossing Thumbs• cc right thumb on top of

clasped hands (homozygous recessive)

• C left thumb on top of clasped hands (heterozygous or homozygous dominant )

Pinkies• pp pinkies are straight when

pressed side by side (homozygous recessive)

• P pinkies bend away from each other, toward the ring fingers, when pressed side by side (heterozygous or homozygous dominant)

Single-gene Traits

Ear lobes• ee attached ear lobe

(homozygous recessive)• E free ear lobe

(heterozygous or homozygous dominant)

Widow’s peak• ww no widow’s peak

(homozygous recessive)• W has a widow’s peak

(heterozygous or homozygous dominant)

Single-gene Traits

Bending thumbs (Hitch-hiker’s thumb)

• bb thumb bends at 90 degree angle (homozygous recessive)

• B thumb is straight (heterozygous or homozygous dominant)

99

79

99

Genetic Wheel Results

• There are 128 possible combinations from the 7 traits illustrated on the genetic wheel.

• Are you the same as anyone else?

• If this much genetic variation exists in traits that are visible, imagine how different we all are in ways that we can’t see!

DNA summary

• DNA RNA protein : changes in DNA can lead to changes in protein function and phenotype• Genetic differences are inherited phenotypes are inherited

Differences in genetics also affect an individual’s response to drugs


What is Pharmacogenomics?What is Pharmacogenomics?

Personalized medicine tailored to your genes

Pharma = drug or medicine Genomics = the study of genes


Different responses to drugs

• Benefits: pain relief, prevents heart attacks

• Side effects: GI bleeding, Reye’s syndrome

Aspirin

What are ways a person would react differently to drugs?

1. Whether you have the protein to recognize the drug

2. Number of the proteins that recognize the drug

3. How your body processes the drugs after receiving it


What proteins recognize a drug (chemical)?

Receptors.

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• Drugs bind drug receptors on cells to cause effects

- drug = key- receptor = lock

• Genetic variation can cause variation in drug receptors

Cell

Drug(eg. Aspirin)

Receptor(protein)


Therapeutic Therapeutic responseresponse: NOTHING!

Pharmacogenomics being used TODAY!

Breast CancerCell

Drug that fits in the receptor is like a key in a lock

Therapeutic response: Death of Cancer Cell

Her2 Receptor

This breast cancer cell is considered Her2+ and the receptor can fit drugs made for it!

This breast cancer cell is considered Her2- and there is no receptor for the drug!

Herceptin is a personalized medication

•Breast cancer tumors can be divided into 2 classes: Her2+ or Her2-• Herceptin only works for Her2+ breast tumors


Taste this PTC strip

• This won’t hurt you - not a toxic chemical• What did you taste?

• Why did the strip taste bitter to one person and have no taste for another?

Hypothesis?


PTC Punnett square• Ability to taste PTC (T) is dominant over inability to taste

PTC (t)• 70% of population can taste PTC (TT or Tt), 30% can’t (tt)• Mom’s genotype is Tt and Dad’s genotype is Tt. What

could their kids be?

T

t

T t

TT :-( Tt :-|

Tt :-| tt :-)

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

• A key must fit into the lock to open a door

• A drug must be able to bind the receptor to cause an effect

• One genetic variant of the PTC receptor (PTC-R) binds PTC well - PTC tastes bitter

• One genetic variant of PTC-R can’t bind PTC- no taste- key doesn’t fit lock!

Taste cell

“This tastes bitter!”

PTC

PTC-R

Taste cell

Y

“I don’t taste anything!”


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

Y

“This tastes bitter!”

TASTER

“This tastes REALLY bitter!!!!”

SUPERTASTER

Y

“I don’t taste anything!”

Taste cell

NON-TASTER

YTaste cell

Taste cell


Drug receptor summary

• Ability to taste PTC has a very strong genetic component• PTC = chemical • Drugs = chemical• Differences in ability to taste PTC is similar to differences

in reactions to drugs

Now let’s do an activity to test a hypothesis!!



2. Number of the proteins that recognize the drug (receptors)



• Does everyone have the same number of receptors??



Tongue Anatomy

How do you think the number of taste buds will vary with

tasting PTC?


Counting taste bud density

1. Swirl the blue water in your mouth and spit back into cup

2. Place paper-hole reinforcer on the tip of tongue

3. The blue dye will stain everywhere except for taste buds


Counting taste bud density

4. Use a flashlight and magnifying glass to count the number of taste bud inside the hole

Examples

5

20

35


Go to excel file


What does it take to be a PTC Taster?

• PTC tasting genotype = PTC receptors that can bind PTC• High density of taste buds

5

20

35


PTC activity summary

• People vary in PTC genotype, therefore people vary in their tasting of PTC

• More tastebuds = greater ability to taste PTC (drug)• Listen to NPR sound file

How do drugs work in your body?How do drugs work in your body?



2. Number of the proteins that recognize the drug



How does the body process drugs?

• Absorption

• Distribution

• Metabolism

• Excretion


Today: April, 2011

Three women of the same height, weight, and age are depressed and go to the doctor. The doctor prescribes an

antidepressant, Nortripyline, at a dose of 100 mg.

• Person A has an adverse reaction• Person B nothing happens• Person C gets better…


Adverse Drug Reactions (ADR)• Definition- unwanted, negative reaction to a prescribed

drug– Examples

• There are multiple causes for ADRs– Some ADRs have a genetic basis– Some ADRs may have an environmental basis

• Poor metabolizers can experience ADRs at normally therapeutic drug doses


Genetic differences = variable drug metabolism

• Person A has an adverse reaction• Person B nothing happens• Person C gets better…

A

Give 100 mg Nortriptyline to each

B C

Measure mg nortriptyline in blood after 8 h95 mg 5 mg 50 mg


2011 -What do we do?

• Person A has an adverse reaction - Change dose/drug• Person B nothing happens - Change dose/drug• Person C gets better…

A

Give 100 mg Nortriptyline to each

B C

Measure mg nortriptyline in blood after 8 h95 mg 5 mg 50 mg


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)


April, 2050You 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-AllFuture = Drugs Specific for You!

More effective & minimizes side effects


Take home messages

• Genetic variation leads to phenotypic differences and differences in how we all process drugs

• Drugs are processed in the body• Today’s medicines are one-size fits all• Soon, we can tailor drugs to be specific to a person’s

genetics

END OF PRESENTATION

FEEL FREE TO DISCUSS YOUR RESEARCH AND CAREERS

Herceptin uses the immune system to kill tumor cells.

Documents

DNA Day - Pharmacogenetics1. Todays Plan! What is DNA? Genetic Wheel Activity What is Pharmacogenomics? Super taster activity! How do drugs work? Wrap