today’s plan!

DNA Day - Pharmacogenetics*

DNA Day - Pharmacogenetics

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

*On April 25, 1953Drs. 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?

ProteinRNA copyInformation is stored in DNAGenes contain instructions to make proteins 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 SAM AND TOM ATE THE HAMChange:SAM AND TOM ATE THE HIM ACT|CCT|GAG|GAG|AAG|CTGACT|CCT|GAG|GAG|AAG|CGGResult: Changed meaning or function

Change in DNA is called a mutationVariations in the DNA of different individuals can cause phenotypic changes in individuals

DNA Day - Pharmacogenetics*Why do people look different?Genetic variationEye color - common genetic variation Downs syndrome (trisomy 21) - rare genetic variation

Environment DietExercise


Mendelian traitsPhenotype: Cleft ChinGenotype: ccPhenotype: non-cleft chinGenotype: CC or CcExample

Mendelian traitsPhenotype: Cleft ChinGenotype: ccExampleNon cleft chin

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 genesOthers 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 TraitsLaugh dimplesll no dimples (homozygous recessive)L dimples (heterozygous or homozygous dominant)

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

Single-gene TraitsCrossing Thumbscc right thumb on top of clasped hands (homozygous recessive)C left thumb on top of clasped hands (heterozygous or homozygous dominant )

Pinkiespp 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 TraitsEar lobesee attached ear lobe (homozygous recessive)E free ear lobe (heterozygous or homozygous dominant)

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

Single-gene TraitsBending thumbs (Hitch-hikers thumb)

bb thumb bends at 90 degree angle (homozygous recessive)

B thumb is straight (heterozygous or homozygous dominant)

Genetic Wheel ResultsThere 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!

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

DNA Day - Pharmacogenetics*What is Pharmacogenomics?Personalized medicine tailored to your genesPharma = drug or medicine Genomics = the study of genes


DNA Day - Pharmacogenetics*Different responses to drugsBenefits: pain relief, prevents heart attacks

Side effects: GI bleeding, Reyes syndromeAspirin


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 drugHow your body processes the drugs after receiving itDNA Day - Pharmacogenetics*


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

Cell Receptor(protein)

DNA Day - Pharmacogenetics*Therapeutic response: NOTHING!Pharmacogenomics being used TODAY!Breast CancerCell Drug that fits in the receptor is like a key in a lockTherapeutic response: Death of Cancer CellThis breast cancer cell is considered Her2- and there is no receptor for the drug!


Herceptin is a personalized medicationBreast cancer tumors can be divided into 2 classes: Her2+ or Her2- Herceptin only works for Her2+ breast tumors

DNA Day - Pharmacogenetics*Taste this PTC stripThis wont hurt you - not a toxic chemicalWhat did you taste?

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

Hypothesis?


DNA Day - Pharmacogenetics*PTC Punnett squareAbility 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?


Why can some people taste PTC and others cant? 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!Taste cellThis tastes bitter!PTCPTC-RTaste cellYI dont taste anything!

DNA Day - Pharmacogenetics*Why can some people taste PTC and others cant?YThis tastes bitter!TASTERThis tastes REALLY bitter!!!!SUPERTASTERYI dont taste anything!NON-TASTERY


DNA Day - Pharmacogenetics*Drug receptor summaryAbility to taste PTC has a very strong genetic componentPTC = chemical Drugs = chemicalDifferences in ability to taste PTC is similar to differences in reactions to drugs

Now lets do an activity to test a hypothesis!!


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 itDNA Day - Pharmacogenetics*


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


DNA Day - Pharmacogenetics*Tongue Anatomy


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

DNA Day - Pharmacogenetics*Counting taste bud density

Swirl the blue water in your mouth and spit back into cupPlace paper-hole reinforcer on the tip of tongueThe blue dye will stain everywhere except for taste buds


DNA Day - Pharmacogenetics*Counting taste bud density

4. Use a flashlight and magnifying glass to count the number of taste bud inside the holeExamples52035


DNA Day - Pharmacogenetics*Go to excel file


DNA Day - Pharmacogenetics*What does it take to be a PTC Taster?PTC tasting genotype = PTC receptors that can bind PTCHigh density of taste buds52035


DNA Day - Pharmacogenetics*PTC activity summaryPeople vary in PTC genotype, therefore people vary in their tasting of PTCMore tastebuds = greater ability to taste PTC (drug)Listen to NPR sound fileHow do drugs work in your body?


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 drugHow your body processes the drugs after receiving itDNA Day - Pharmacogenetics*


How does the body process drugs? Absorption Distribution Metabolism Excretion

DNA Day - Pharmacogenetics*Today: April, 2011Three 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 reactionPerson B nothing happensPerson C gets better


DNA Day - Pharmacogenetics*Adverse Drug Reactions (ADR)Definition- unwanted, negative reaction to a prescribed drugExamplesThere are multiple causes for ADRsSome ADRs have a genetic basisSome ADRs may have an environmental basisPoor metabolizers can experience ADRs at normally therapeutic drug doses


DNA Day - Pharmacogenetics*Genetic differences = variable drug metabolism

Person A has an adverse reactionPerson B nothing happensPerson C gets better

AGive 100 mg Nortriptyline to eachBC


DNA Day - Pharmacogenetics*2011 -What do we do?

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

AGive 100 mg Nortriptyline to eachBC


DNA Day - Pharmacogenetics*Today One-size-fits-all drugsCurrent drug development system develops drugs for the average patientNo simple way to determine who will respond well and who will respond poorlyOne size does NOT fit all!Whats the solution?

Pharmacogenomics (PGx)


DNA Day - Pharmacogenetics*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


DNA Day - Pharmacogenetics*Take home messagesGenetic variation leads to phenotypic differences and differences in how we all process drugsDrugs are processed in the bodyTodays medicines are one-size fits allSoon, we can tailor drugs to be specific to a persons genetics


END OF PRESENTATION

FEEL FREE TO DISCUSS YOUR RESEARCH AND CAREERS

Herceptin uses the immune system to kill tumor cells.

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

**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 properlyChanges in DNA are called mutations. There are many types of mutations.

*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 persons 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. ****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 Mendels 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. ****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.Genetic wheel with one persons information*Genetic wheel with two peoples information filled in *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.***

Pharmacogenomics principle: assessing an individual patient's probability of benefit and/or adverse (bad) events from a specific medicationAlso, to identify patients at risk for toxicity or increase response to therapy for optimal medication and/or dose selection

***Great Resource:http://biol.lf1.cuni.cz/ucebnice/en/pharmacogenetics.htm*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 Reyes syndrome.***If asked, this is what Reyes 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 Reyes 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 Reyes 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 Reyes 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). **www.herceptin.com

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. *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. *Do a count of how many people in the classroom can and cannot taste the PTC*Remember, 2 copies of PTC receptor- one from Mom, one from Dad*Remember, 2 copies of PTC receptor- one from Mom, one from DadAsk them if they can give the genotype for each taste cell (which represents a person). Non-taster ttTaster TtSupertaster TT**Lets look at the tongues anatomyThe receptors and cells for mammalian tasteJayaram Chandrashekar, Mark A. Hoon, Nicholas J. P. Ryba & Charles S. ZukerNature 444, 288-294(16 November 2006) Taste buds are composed of 50-150 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 bitter, sour, sweet, salty and umami is present in all areas of the tongue*In addition to the genes that the students inherit, (** Dont forget about the genes!**)Ask them whether they think tasting PTC will correlate with MORE or FEWER fungiform papillae*http://pinotblogger.com/wp-content/supertaster-howto.jpg*http://pinotblogger.com/wp-content/supertaster-howto.jpg*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*Tell them it takes TWO things Genotype and high density fungiform papillae!*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.*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 substancesThere are also genes that transport the drugs into the cells, pump them around the body (from stomach to blood stream), involved in excretion. *

*Can you name examples of ADRs?DeathLife-ThreateningHospitalization NauseaRashesIn 1994 ADRs accounted for 2.2 million serious cases and 1000,000 deaths = leading causes of hospitalization in USEnvironmental basis: diet, other drugs, pollution, concurrent other disease, Age, physical activity

**Person A did not metabolize the drug quick enough and there is still a lot left in their blood causing side effectsPerson B metabolized the drug too quickly and it is excreted out of her system before it has a chance to workPerson 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 *Implications - Drug dosing needs to be personalized *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.http://publications.nigms.nih.gov/medbydesign/foreword.html******Optional for a more advanced class or for people with more time****

www.herceptin.com

today’s plan!

Documents

homozygous recessivew

structure of dna

genetic traits

dna of different individuals

dna summary dna rna

homozygous recessivep

u shape homozygous recessivet

entire dna sequence