Pharmacogenomics PGx Personalized Medicine

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Todays 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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What is DNA Day?
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
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Genes contain instructions to make proteins
Information is stored in DNA
RNA copy

• Proteins do most of the work in a cell and
  provide much of its structure.

Protein
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A change in gene result in a change in protein
Change in DNA is called a mutation
ACTCCTGAGGAGAAGCTG
SAM AND TOM ATE THE HAM

• Change
• SAM AND TOM ATE THE HIM

ACTCCTGAGGAGAAGCGG
Result Changed meaning or function
Variations in the DNA of different individuals
can cause phenotypic changes in individuals
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Why do people look different?

• Genetic variation
• Eye color - common genetic variation
• Downs syndrome (trisomy 21) - rare genetic
  variation
• Environment
• Diet
• Exercise

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Mendelian traits
Example
Phenotype non-cleft chin Genotype CC or Cc
Phenotype Cleft Chin Genotype cc
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Mendelian traits
Example
Phenotype Cleft Chin Genotype cc
Non cleft chin
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Variations in the DNA of different individuals
can cause visible changes in individuals

• 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.

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Single-gene Traits

• Laugh dimples
• ll no dimples (homozygous recessive)
• L dimples (heterozygous or homozygous dominant)

• Tongue roll
• tt cant roll tongue into U shape (homozygous
  recessive)
• T can roll tongue into U shape (heterozygous or
  homozygous dominant )

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Single-gene Traits

• Crossing 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)

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Single-gene Traits

• Ear lobes
• ee attached ear lobe (homozygous recessive)
• E free ear lobe (heterozygous or homozygous
  dominant)

• Widows peak
• ww no widows peak (homozygous recessive)
• W has a widows peak (heterozygous or homozygous
  dominant)

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Single-gene Traits

• Bending thumbs (Hitch-hikers thumb)
• bb thumb bends at 90 degree angle (homozygous
  recessive)
• B thumb is straight (heterozygous or homozygous
  dominant)

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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 cant see!

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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
individuals response to drugs
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What is Pharmacogenomics?
Pharma drug or medicine Genomics the study
of genes

• Personalized medicine
• tailored to your genes

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Different responses to drugs
Aspirin

• Benefits pain relief, prevents heart attacks
• Side effects GI bleeding, Reyes syndrome

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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

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What proteins recognize a drug (chemical)?

• Receptors.

• Drugs bind drug receptors on cells to cause
  effects
• - drug key
• - receptor lock
• Genetic variation can cause variation in drug
  receptors

Receptor (protein)
Cell
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Pharmacogenomics being used TODAY!
Drug that fits in the receptor is like a key in a
lock
Breast CancerCell
This breast cancer cell is considered Her2- and
there is no receptor for the drug!
Therapeutic response NOTHING!
Therapeutic response Death of Cancer Cell
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Herceptin is a personalized medication

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

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Taste this PTC strip

• This wont 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?

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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
  cant (tt)
• Moms genotype is Tt and Dads genotype is Tt.
  What could their kids be?

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Why can some people taste PTC and others cant?
PTC

• 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 cant bind PTC- no
  taste- key doesnt fit lock!

PTC-R
Taste cell
This tastes bitter!
Y
Taste cell
I dont taste anything!
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Why can some people taste PTC and others cant?
Y
Y
Y
This tastes bitter!
This tastes REALLY bitter!!!!
I dont taste anything!
NON-TASTER
TASTER
SUPERTASTER
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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 lets do an activity to test a hypothesis!!
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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
   (receptors)
3. How your body processes the drugs after receiving
   it

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• Does everyone have the same number of receptors??

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Tongue Anatomy
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• How do you think the number of taste buds will
  vary with tasting PTC?

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• Counting taste bud density
• Swirl the blue water in your mouth and spit back
  into cup
• Place paper-hole reinforcer on the tip of tongue
• The blue dye will stain everywhere except for
  taste buds

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

Examples
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20
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Go to excel file
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What does it take to be a PTC Taster?

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

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20
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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?
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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

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How does the body process drugs?

• Absorption
• Distribution
• Metabolism
• Excretion

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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

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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

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Genetic differences variable drug metabolism
Give 100 mg Nortriptyline to each
A
B
C

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

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2011 -What do we do?
Give 100 mg Nortriptyline to each
A
B
C

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

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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!
• Whats the solution?

Pharmacogenomics (PGx)
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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

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Take home messages

• Genetic variation leads to phenotypic differences
  and differences in how we all process drugs
• Drugs are processed in the body
• Todays medicines are one-size fits all
• Soon, we can tailor drugs to be specific to a
  persons genetics

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END OF PRESENTATION FEEL FREE TO DISCUSS YOUR
RESEARCH AND CAREERS
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Herceptin uses the immune system to kill tumor
cells.