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DNA Day - Pharmacogenetics

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1 DNA Day - Pharmacogenetics

2 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

3 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 SLIDE 1: What is DNA Day? DNA Day is April 25th because: Watson and Crick determined structure of DNA on April 25, 1953 Human Genome Project completed in April, 2003 3

4 Information is stored in DNA
Genes contain instructions to make proteins Information is stored in DNA RNA copy Gene = segment of DNA that tells the cell how to make a certain protein. Proteins work together to form the functional machinery that makes up a cell. The central dogma of molecular biology was established by Francis Crick in 1958. The Central Dogma states that DNA provides the instructions for making RNA, and RNA then provides the instructions for making protein. The overall concept of protein synthesis is basic, but the details of this process are quite complex and we wont go into those today. Basically DNA information is copied into messenger RNA (mRNA) by the process known as transcription and proteins are synthesized using the information in the mRNA as a template in a process known as translation. Can anyone tell me one of the differences between DNA and RNA? Bases: Thymine (DNA) and Uracil (RNA) Here are all the ways they differ: ・They differ in composition: 1.The sugar in RNA is ribose, not the deoxyribose in DNA. 2.The base uracil is in RNA instead of thymine. ・They also differ in size and structure: 1.RNA molecules are smaller (shorter) than DNA molecules, 2.RNA is single-stranded, not double-stranded like DNA. ・Another difference between RNA and DNA is in function. DNA has only one function-STORING GENETIC INFORMATION in its sequence of nucleotide bases. But there are three main kinds of ribonucleic acid, each of which has a specific job to do. 1.Ribosomal RNAs-exist outside the nucleus in the cytoplasm of a cell in structures called ribosomes. Ribosomes are small, granular structures where protein synthesis takes place. Each ribosome is a complex consisting of about 60% ribosomal RNA (rRNA) and 40% protein. 2.Messenger RNAs-are the nucleic acids that "record" information from DNA in the cell nucleus and carry it to the ribosomes and are known as messenger RNAs (mRNA). 3.Transfer RNAs-The function of transfer RNAs (tRNA) is to deliver amino acids one by one to protein chains growing at ribosomes. Proteins do most of the work in a cell and provide much of its structure. Protein

5 A change in gene result in a change in protein
Change in DNA is called a mutation ACT|CCT|GAG|GAG|AAG|CTG SAM AND TOM ATE THE HAM Thr Pro Glu Lys Leu Change: SAM AND TOM ATE THE HIM ACT|CCT|GAG|GAG|AAG|CGG SLIDE 11: How does an Altered Gene Result in an Altered Protein? Each 3-letter codon is translated into an amino acid. Example: SAM AND TOM ATE THE HAM – if we change A to I, does not make sense. If we change one letter in DNA, can change one letter in amino acid, and protein may not work properly Changes in DNA are called mutations. There are many types of mutations. Result: Changed meaning or function Thr Pro Glu Lys Met Variations in the DNA of different individuals can cause phenotypic changes in individuals 5 5

6 Why do people look different?
Genetic variation Eye color - common genetic variation Down’s syndrome (trisomy 21) - rare genetic variation Environment Diet Exercise If more advanced class: give more examples of ways we look different that is caused by genetic variation or ask them to list a few. Emphasize that a person’s environment also plays a role in how we are different. Start transitioning to not only how we look different but how we are different in other ways: diseases, reactions to drugs, etc. DNA Day - Pharmacogenetics

7 Mendelian traits Example Phenotype: Cleft Chin
***OPTIONAL FOR VOLUNTEERS WITH LESS TIME**** A Mendelian trait is one that is controlled by a single gene and shows a simple Mendelian inheritance pattern (ask them to remember Mendel’s pea experiments). In such cases, a mutation in a single gene can cause a disease that is inherited according to Mendel's laws. Examples include sickle-cell anemia, Tay-Sachs disease, cystic fibrosis and xeroderma pigmentosa. A disease controlled by a single gene contrasts with a multi-factorial disease, like arthritis, which is affected by several genes (and the environment) as well those diseases are inherited in a non-Mendelian fashion. An example of a visible mendelian trait is chin shape. The man with a cleft chin has a genotype of cc (one genotype from each parent). The man with a non-cleft chin has the genotype CC or Cc. C is dominant over c. And we do not know what his real genotype is unless we were to genotype his DNA at the gene for cleft-chin. Phenotype: Cleft Chin Genotype: cc Phenotype: non-cleft chin Genotype: CC or Cc

8 Mendelian traits Example C c Mom Dad CC Cc cc Phenotype: Cleft Chin
What are mom and dad’s phenotype if their genotype is Cc? CC Cc cc Name the phenotypes of their potential children. ***OPTIONAL FOR VOLUNTEERS WITH LESS TIME**** Here is an example of a Punnett square and will allow the students to understand the concept of genotype and phenotype. Phenotype: Cleft Chin Genotype: cc Non cleft chin

9 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.

10 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 )

11 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)

12 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)

13 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)


15 99 Genetic wheel with one person’s information

16 99 Genetic wheel with two people’s information filled in 79

17 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! I think it would be neat to go through the numbers, and ask the students to raise their hands if they have a result between numbers 1 and 10; 11 and 20; etc. If more than one student raises their hand for a set of numbers, investigate further and see if they have the same numbers. Everything has a genotype, and knowledge about genetic traits allows us to create a new phenotype. See next slide for examples.

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

19 What is Pharmacogenomics?
Pharma = drug or medicine Genomics = the study of genes Personalized medicine tailored to your genes Pharmacogenomics principle: assessing an individual patient's probability of benefit and/or adverse (bad) events from a specific medication Also, to identify patients at risk for toxicity or increase response to therapy for optimal medication and/or dose selection ***Great Resource: DNA Day - Pharmacogenetics

20 Different responses to drugs
Aspirin Benefits: pain relief, prevents heart attacks Side effects: GI bleeding, Reye’s syndrome Many while many drugs have benefits for most of the people that take them, some people who take certain drugs have side effects. For example, most people take aspirin and are fine, BUT sometimes severe side effects can occur. Side effects are Gastrointestinal bleeding or Reye’s syndrome. ***If asked, this is what Reye’s syndrome is: The precise mechanism by which Reye's syndrome occurs remains unknown. This serious illness is referred to as a syndrome because the clinical features that physicians use to diagnose it are quite broad. However, the major form of Reye’s syndrome reported in the United States is characteristically preceded by a viral-like flu illness or chickenpox. Many studies have demonstrated a strong association between aspirin taken for these viral illnesses and the development of Reye’s syndrome. Some studies indicate that a significant percentage of cases, particularly in very young children, are later re-categorized as other disorders or conditions -- as high as 25% in the UK and 50% in Australia. These re-categorized disorders, unlike the characteristic Reye’s syndrome, are not strongly linked to exposure to aspirin.At least five epidemiologic studies published in US medical journals,[2] including one study that was supported by funds from the aspirin industry,[3] have confirmed an association between the development of Reye's syndrome and the use of aspirin (a salicylate compound) for treating the symptoms of influenza-like illnesses or chicken pox.[2] The Centers for Disease Control and Prevention (CDC), the U.S. Surgeon General, the American Academy of Pediatrics (AAP) and the Food and Drug Administration (FDA) recommend that aspirin and combination products containing aspirin not be given to children under 19 years of age during episodes of fever-causing illnesses. Investigators at CDC have also cautioned against the use of medicines, including some anti-nausea medications, that contain salicylic acid or salicylate. Hence, in the US, it is advised that the opinion of a doctor or pharmacist be obtained before anyone under 19 years of age is given any medication containing aspirin (aka on some medicine labels as acetylsalicylate, salicylate, acetylsalicylic acid, or salicylic acid). DNA Day - Pharmacogenetics

21 What are ways a person would react differently to drugs?
Whether you have the protein to recognize the drug Number of the proteins that recognize the drug How your body processes the drugs after receiving it DNA Day - Pharmacogenetics

22 What proteins recognize a drug (chemical)?
Receptors. Drug (eg. Aspirin) Drugs bind drug receptors on cells to cause effects - drug = key - receptor = lock Genetic variation can cause variation in drug receptors Receptor (protein) Cell

23 Pharmacogenomics being used TODAY!
Drug that fits in the receptor is like a key in a lock Her2 Receptor This breast cancer cell is considered Her2+ and the receptor can fit drugs made for it! Breast CancerCell This breast cancer cell is considered Her2- and there is no receptor for the drug! Therapeutic response: Death of Cancer Cell Therapeutic response: NOTHING! DNA Day - Pharmacogenetics

24 Herceptin is a personalized medication
So if you know the type of tumor then you can prescribe the right drug. Herceptin will not work for Her2- classes of breast cancer. Breast cancer tumors can be divided into 2 classes: Her2+ or Her2- Herceptin only works for Her2+ breast tumors

25 DNA Day - Pharmacogenetics
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? Pass out the baggies for each pair of students. Tell them to remove the white strips and to put them on the tip of their tongue. Ask them if they tasted anything. Ask them why they think one person tasted bitter and one tasted nothing. Ask them to hypothesize why they think this is. DNA Day - Pharmacogenetics

26 DNA Day - Pharmacogenetics
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 Do a count of how many people in the classroom can and cannot taste the PTC TT :-( Tt :-| tt :-) DNA Day - Pharmacogenetics

27 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-R Taste cell “This tastes bitter!” Y Remember, 2 copies of PTC receptor- one from Mom, one from Dad Taste cell “I don’t taste anything!”

28 Why can some people taste PTC and others can’t?
Taste cell Taste cell Taste cell Remember, 2 copies of PTC receptor- one from Mom, one from Dad Ask them if they can give the genotype for each taste cell (which represents a person). Non-taster tt Taster Tt Supertaster TT “I don’t taste anything!” “This tastes bitter!” “This tastes REALLY bitter!!!!” NON-TASTER TASTER SUPERTASTER DNA Day - Pharmacogenetics

29 Now let’s do an activity to test a hypothesis!!
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!! DNA Day - Pharmacogenetics

30 What are ways a person would react differently to drugs?
Whether you have the protein to recognize the drug Number of the proteins that recognize the drug (receptors) How your body processes the drugs after receiving it DNA Day - Pharmacogenetics

31 DNA Day - Pharmacogenetics
Does everyone have the same number of receptors?? DNA Day - Pharmacogenetics

32 DNA Day - Pharmacogenetics
Tongue Anatomy Let’s look at the tongue’s anatomy The receptors and cells for mammalian taste Jayaram Chandrashekar, Mark A. Hoon, Nicholas J. P. Ryba & Charles S. ZukerNature 444, (16 November 2006) Taste buds are composed of TRCs (depending on the species), distributed across different papillae. Circumvallate papillae are found at the very back of the tongue and contains thousands (human) of taste buds. Foliate papillae are present at the posterior lateral edge of the tongue and contain a dozen to hundreds of taste buds. Fungiform papillae contain one or a few taste buds and are found in the anterior two-thirds of the tongue. TRCs project microvillae to the apical surface of the taste bud, where they form the 'taste pore'; this is the site of interaction with tastants. b, Recent molecular and functional data have revealed that, contrary to popular belief, there is no tongue 'map': responsiveness to the five basic modalities ム bitter, sour, sweet, salty and umami is present in all areas of the tongue DNA Day - Pharmacogenetics

33 How do you think the number of taste buds will vary with tasting PTC?
In addition to the genes that the students inherit, (** Don’t forget about the genes!**) Ask them whether they think tasting PTC will correlate with MORE or FEWER fungiform papillae

34 DNA Day - Pharmacogenetics
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 DNA Day - Pharmacogenetics

35 Counting taste bud density
4. Use a flashlight and magnifying glass to count the number of taste bud inside the hole Examples 5 35 20 DNA Day - Pharmacogenetics

36 DNA Day - Pharmacogenetics
Go to excel file Enter the number of fungiform papillae that each student counts under taster, supertaster and non-taster. The bar graph should correspond to more fungiform papillae for the tasters DNA Day - Pharmacogenetics

37 What does it take to be a PTC Taster?
PTC tasting genotype = PTC receptors that can bind PTC High density of taste buds Tell them it takes TWO things Genotype and high density fungiform papillae! 5 35 20 DNA Day - Pharmacogenetics

38 DNA Day - Pharmacogenetics
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 Click on the speaker to hear the sound file. If the teacher has speakers, this would be helpful. If you have speakers you can bring with you this would be helpful. If the link does not work we will provide you with the MP3. How do drugs work in your body? DNA Day - Pharmacogenetics

39 What are ways a person would react differently to drugs?
Whether you have the protein to recognize the drug Number of the proteins that recognize the drug How your body processes the drugs after receiving it DNA Day - Pharmacogenetics

40 How does the body process drugs?
Absorption Distribution Metabolism Excretion Drugs are taken into the body in many different ways. Inhaled like an asthma medicine, taken in pill or liquid form through the mouth, or intravenously like through an IV bag. Drugs are absorbed into the body, they are distributed throughout the body, then metabolized and broken down, then excreted. ** You can mention that many genes are responsible for the breakdown of most drugs. Examples for a more advanced class: Cytochrome P450 enzymes (aka CYPs): Detoxify substances and activate non-toxic substances into toxic substances There are also genes that transport the drugs into the cells, pump them around the body (from stomach to blood stream), involved in excretion.

41 DNA Day - Pharmacogenetics
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… DNA Day - Pharmacogenetics

42 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 Can you name examples of ADRs? Death Life-Threatening▪Hospitalization Nausea Rashes In 1994 ADRs accounted for 2.2 million serious cases and 1000,000 deaths = leading causes of hospitalization in US Environmental basis: diet, other drugs, pollution, concurrent other disease, Age, physical activity DNA Day - Pharmacogenetics

43 Genetic differences = variable drug metabolism
Give 100 mg Nortriptyline to each A B C Measure mg nortriptyline in blood after 8 h 95 mg 5 mg 50 mg Person A has an adverse reaction Person B nothing happens Person C gets better… DNA Day - Pharmacogenetics

44 DNA Day - Pharmacogenetics
2011 -What do we do? Give 100 mg Nortriptyline to each A B C Measure mg nortriptyline in blood after 8 h 95 mg 5 mg 50 mg Person A has an adverse reaction - Change dose/drug Person B nothing happens - Change dose/drug Person C gets better… Person A did not metabolize the drug quick enough and there is still a lot left in their blood causing side effects Person B metabolized the drug too quickly and it is excreted out of her system before it has a chance to work Person C metabolized the drug at a moderate rate which did not cause side effects but did leave enough drug in her blood stream to be effective. It is also drug specific so one person may metabolize one drug quicker than another. Also they may have a faulty receptor caused by a genetic variation that will cause them to not be able to receive any benefit to the drug. Like the PTC receptors! There are also environmental aspects. There is data that states that Grapefruit juice inhibits the breakdown of atorvastatin (a Statin) in the gut causing severe side effects DNA Day - Pharmacogenetics

45 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? Implications - Drug dosing needs to be personalized Pharmacogenomics (PGx) DNA Day - Pharmacogenetics

46 Future = Drugs Specific for You!
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 Pharmacogenomics offers a very appealing alternative. Imagine a day when you go into your doctor's office and, after a simple and rapid test of your DNA, your doctor changes her/his mind about a drug considered for you because your genetic test indicates that you could suffer a severe negative reaction to the medication. However, upon further examination of your test results, your doctor finds that you would benefit greatly from a new drug on the market, and that there would be little likelihood that you would react negatively to it. Researchers predict that the medicines of the future may not only look and work differently than those you take today, but tomorrow's medicines will be tailored to your genes. Knowing your unique genetic make-up could help your doctor prescribe the right medicine in the right amount, to boost its effectiveness and minimize possible side effects. DNA Day - Pharmacogenetics

47 DNA Day - Pharmacogenetics
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 DNA Day - Pharmacogenetics


49 Herceptin uses the immune system to kill tumor cells.
****Optional for a more advanced class or for people with more time****

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