Transcript Pharmacogenomics PGx Personalized Medicine

DNA Day - Pharmacogenetics
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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
What is DNA Day?
On April 25, 1953
In April 2003,
Drs. James Watson and
Francis Crick determined
the structure of DNA
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
Protein
Proteins do most of the
work in a cell and provide
much of its structure.
A change in gene result in a change
in protein
Change in DNA is called a mutation
ACT|CCT|GAG|GAG|AAG|CTG
Thr Pro Glu Glu
Lys
Leu
ACT|CCT|GAG|GAG|AAG|CGG
Thr Pro Glu Glu
Lys Met
SAM AND TOM ATE THE HAM
Change:
SAM AND TOM ATE THE HIM
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
– Down’s syndrome (trisomy 21) - rare genetic variation
• Environment
– Diet
– Exercise
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Mendelian traits
Example
Phenotype: Cleft Chin
Genotype: cc
Phenotype: non-cleft chin
Genotype: CC or Cc
Mendelian traits
Example
Mom
C
c
C
CC
Cc
c
Cc
cc
Dad
Phenotype: Cleft Chin
Genotype: cc
What are mom and dad’s phenotype if their
genotype is Cc?
Non cleft chin
Name the phenotypes of their potential
children.
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.
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 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)
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
99
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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 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?
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,
Reye’s 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.
Drug
(eg. Aspirin)
• Drugs bind drug receptors on
cells to cause effects
- drug = key
Receptor
- receptor = lock
(protein)
Cell
• Genetic variation can cause
variation in drug receptors
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Pharmacogenomics being used
TODAY!
Drug that fits in the
receptor is like a key
in a lock
This breast cancer
cell is considered
Her2+ and the
receptor can fit
drugs made for it!
Her2
Receptor
Breast
CancerCell
This breast cancer
cell is considered
Her2- and there is no
receptor for the
drug!
Therapeutic
response:
Therapeutic response:
NOTHING!
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
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?
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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% can’t (tt)
• Mom’s genotype is Tt and Dad’s genotype is Tt. What
could their kids be?
T
t
T
TT :-(
Tt :-|
t
Tt :-|
tt :-)
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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!
PTC
PTC-R
Taste
cell
“This tastes bitter!”
Y
Taste
cell
“I don’t taste anything!”
Why can some people taste PTC and
others can’t?
YY
Taste
cell
Y
Taste
cell
Taste
cell
“I don’t taste anything!”
“This tastes bitter!”
NON-TASTER
TASTER
“This tastes REALLY
bitter!!!!”
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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 let’s 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?
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
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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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35
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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
5
35
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
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
95 mg
5 mg
50 mg
Measure mg nortriptyline in blood after 8 h
• 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
95 mg
5 mg
50 mg
Measure mg nortriptyline in blood after 8 h
• 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!
• What’s 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
• Today’s medicines are one-size fits all
• Soon, we can tailor drugs to be specific to a person’s
genetics
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END OF PRESENTATION
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RESEARCH AND CAREERS
Herceptin uses the immune system to
kill tumor cells.