What is DNA What is DNA Day What
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What is DNA?
What is DNA Day?
What is DNA Day? April 1953 Drs. James Watson and Francis Crick determined the structure of DNA (double helix)
What is DNA Day? April 1953 April 2003 Drs. James Watson and Francis Crick determined the structure of DNA (double helix) Human Genome Project determined the entire DNA sequence of a human (3 billion letters)
What is Pharmacogenomics? R X
What is Pharmacogenomics? Pharma = drug or medicine Genomics = the study of genes R X
What is Pharmacogenomics? Pharma = drug or medicine Genomics = the study of genes Personalized medicine tailored to your genes R X
Case Study – Breast Cancer Patients
Case Study – Breast Cancer Patients Tumoricide
Case Study – Breast Cancer Patients
Case Study – Breast Cancer Patients 30%
No Effect/Hurt Helped Tumoricide
No Effect/Hurt Helped Tumoricide Why?
How do scientists make personalized medicine? Your cells Your DNA Picture credit: adapted from Riken Research: http: //www. rikenresearch. riken. jp/eng/frontline/5514
How do scientists make personalized medicine? Your cells It’s all about what makes Your DNA YOUR genetic code UNIQUE Picture credit: adapted from Riken Research: http: //www. rikenresearch. riken. jp/eng/frontline/5514
Genetic Code: DNA Deoxyribo. Nucleic Acid (DNA) contains all the information necessary to make a complete organism DNA is composed of a combination of 4 nucleotides
Genetic Code: DNA Deoxyribo. Nucleic Acid (DNA) contains all the information necessary to make a complete organism DNA is composed of a combination of 4 nucleotides A Adenine
Genetic Code: DNA Deoxyribo. Nucleic Acid (DNA) contains all the information necessary to make a complete organism DNA is composed of a combination of 4 nucleotides A T Adenine Thymine
Genetic Code: DNA Deoxyribo. Nucleic Acid (DNA) contains all the information necessary to make a complete organism DNA is composed of a combination of 4 nucleotides A T C Adenine Thymine Cytosine
Genetic Code: DNA Deoxyribo. Nucleic Acid (DNA) contains all the information necessary to make a complete organism DNA is composed of a combination of 4 nucleotides A T C G Adenine Thymine Cytosine Guanine
The Central Dogma: DNA RNA Protein DNA: A long double-stranded string of nucleotides that encode for many genes. Gene
The Central Dogma: DNA RNA Protein DNA: A long double-stranded string of nucleotides that encode for many genes. Gene RNA: A single-stranded copy of one gene. RNA
The Central Dogma: DNA RNA Protein DNA: A long double-stranded string of nucleotides that encode for many genes. Gene RNA: A single-stranded copy of one gene. RNA Protein: Proteins are composed of amino acids. Amino acids are made from triplets of nucleotides called codons.
The Central Dogma: DNA RNA Protein DNA: A long double-stranded string of nucleotides that encode for many genes. Gene RNA: A single-stranded copy of one gene. Codon 1 Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons.
The Central Dogma: DNA RNA Protein DNA: A long double-stranded string of nucleotides that encode for many genes. Gene RNA: A single-stranded copy of one gene. Codon 1 Codon 2 Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons.
The Central Dogma: DNA RNA Protein DNA: A long double-stranded string of nucleotides that encode for many genes. Gene RNA: A single-stranded copy of one gene. Codon 1 Codon 2 Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons. Amino acid 1 Amino acid 2
The Central Dogma: DNA RNA Protein DNA: A long double-stranded string of nucleotides that encode for many genes. Gene RNA: A single-stranded copy of one gene. Codon 1 Codon 2 Protein: Proteins are composed amino acids. Amino acids are made from triplets of nucleotides called codons. Amino acid 1 Amino acid 2 Protein!
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT
A small change in the gene sequence can result in a very different protein DNA: ATG Amino Acids/Protein: Met GTG CTG TCT CCT
A small change in the gene sequence can result in a very different protein DNA: ATG GTG Amino Acids/Protein: Met Val CTG TCT CCT
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG Amino Acids/Protein: Met Val Leu TCT CCT
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT Amino Acids/Protein: Met Val Leu Ser CCT
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT Amino Acids/Protein: Met Val Leu Ser Pro
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT Amino Acids/Protein: Met Val Leu Ser Pro
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT Amino Acids/Protein: Met Val Leu Ser Pro DNA: ATG GTG CTG TCT ACT
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT Amino Acids/Protein: Met Val Leu Ser Pro DNA: ATG GTG CTG TCT Amino Acids/Protein: Met Val Leu Ser Thr
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT Amino Acids/Protein: Met Val Leu Ser Pro Words: Tom and Sam are bad DNA: ATG GTG CTG TCT Amino Acids/Protein: Met Val Leu Ser Thr
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT Amino Acids/Protein: Met Val Leu Ser Pro Words: Tom and Sam are bad DNA: ATG GTG CTG TCT Amino Acids/Protein: Met Val Leu Ser Thr Words: Tom and Sam are sad
A small change in the gene sequence can result in a very different protein DNA: ATG GTG CTG TCT CCT Amino Acids/Protein: Met Val Leu Ser Pro Words: Tom and Sam are bad DNA: ATG GTG CTG TCT Amino Acids/Protein: Met Val Leu Ser Thr Words: Tom and Sam are sad Changes in DNA are called variations or mutations Variations in the DNA (genotype) can cause observable changes (phenotype) in individuals
Variations in our DNA make us UNIQUE!
No Effect/Hurt Helped Tumoricide Why does Tumoricide work on some patients but not on others?
What are the reasons a person would react differently to drugs? 1. Having the receptor (protein) to recognize the drug 2. Other physiological traits that enable you to respond to a drug 3. How your body processes the drugs after receiving it
Drugs and Receptors Cell
Drugs and Receptors Receptor (Protein) Cell
Drugs and Receptors Receptor (Protein) Cell
Drugs and Receptors Drug (Ligand) Receptor (Protein) Cell
Drugs and Receptors Drug (Ligand) Receptor (Protein) Cell
Your DNA and Drugs Variation in genes can cause variation in receptors Cell
Your DNA and Drugs Variation in genes can cause variation in receptors Cell
Your DNA and Drugs Variation in genes can cause variation in receptors Cell
Your DNA and Drugs Variation in genes can cause variation in receptors Cell Cell
Your DNA and Drugs Variation in genes can cause variation in receptors Too Many (hypersensitive) Cell Cell
Your DNA and Drugs Variation in genes can cause variation in receptors Too Many (hypersensitive) Too Few (hyposensitive) Cell Cell
Your DNA and Drugs Variation in genes can cause variation in receptors Too Many (hypersensitive) Too Few (hyposensitive) Cell Mutated (insensitive) Cell
Where Drugs “Fit” In Lock = Receptor Key = Drug
Let’s do a class case study!
Let’s do a class case study! • Taste the PTC strip (This won’t hurt you - not a toxic chemical) What do you taste?
Let’s do a class case study! • Taste the PTC strip (This won’t hurt you - not a toxic chemical) What do you taste? Why does the strip taste bitter to some and have no taste for others? What is your hypothesis?
Why can some people taste PTC and others can’t? PTCReceptor PTC Taste cell “This tastes bitter!”
Why can some people taste PTC and others can’t? PTCReceptor PTC Taste cell “This tastes bitter!” PTC Non-binding PTCReceptor Taste cell “I don’t taste anything!”
Where does tasting PTC come from? You have two copies of every gene: one from Mom and one from Dad
Where does tasting PTC come from? You have two copies of every gene: one from Mom and one from Dad
Where does tasting PTC come from? You have two copies of every gene: one from Mom and one from Dad
Where does tasting PTC come from? You have two copies of every gene: one from Mom and one from Dad • Your two genes are the genotype
Where does tasting PTC come from? You have two copies of every gene: one from Mom and one from Dad • Your two genes are the genotype • A gene can be dominant or recessive
Where does tasting PTC come from? You have two copies of every gene: one from Mom and one from Dad • Your two genes are the genotype • A gene can be dominant or recessive • The expressed trait is a phenotype
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) TT Tt tt
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) TT Tt tt
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) TT Tt tt
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) TT Tt tt
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) TT Tt For individuals with these genotypes, what would their phenotypes be? tt
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) Tt “This tastes REALLY bitter!” SUPERTASTER tt
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) Tt “This tastes REALLY bitter!” “This tastes bitter!” SUPERTASTER tt
Tasting PTC is dominant (T) over inability taste PTC which is recessive (t) Tt “This tastes REALLY bitter!” “This tastes bitter!” SUPERTASTER tt “I don’t taste anything!” NON-TASTER
Drug receptor summary PTC Ability to taste PTC has a very strong genetic component PTC = chemical and Drugs = chemical Differences in ability to taste PTC is similar to differences in reactions to drugs
No Effect/Hurt Helped Tumoricide Why?
Two Types of Breast Cancer Y Y Y Her 2 - Her 2+ • Tumoricide is a personalized medication • Tumoricide only works for Her 2+ breast tumors
No Effect/Hurt Helped Tumoricide Her 2 - Her 2+
Screening for Her 2+ Cells Her 2 - American Journal of Clinical Pathology. 2008; 129(2): 263 -273 Her 2+
Screening for Her 2+ Cells + American Journal of Clinical Pathology. 2008; 129(2): 263 -273 Tumoricide =?
Screening for Her 2+ Cells + American Journal of Clinical Pathology. 2008; 129(2): 263 -273 Tumoricide =✓
Breast Cancer 1990 • Surgery • Radiation • Chemotherapy (drugs) 2012 • Surgery • Radiation • Chemotherapy • Specialized treatments (for certain types of breast cancer) http: //www. ucdmc. ucdavis. edu/welcome/features/20080709_cancer_sweeney/index. html
What are the reasons a person would react differently to drugs? 1. Having the receptor (protein) to recognize the drug 2. Other physiological traits that enable you to respond to a drug 3. How your body processes the drugs after receiving it
The presence of receptors influence how we react to drugs like Tumoricide or chemicals like PTC Y Y Y Her 2 - Her 2+ Tumoricide Does Not Work Tumoricide Works!
The presence of receptors influence how we react to drugs like Tumoricide or chemicals like PTC TT Tt “This tastes REALLY bitter!” “This tastes bitter!” SUPERTASTER tt “I don’t taste anything!” NON-TASTER
Where are the PTC receptors?
Where are the PTC receptors? Yummy! They are on your taste buds!
What are taste buds? Taste buds are found on papillae on your tongue
What are taste buds? Taste buds are found on papillae on your tongue Papillae bumps on your tongue
What are taste buds? Taste buds are found on papillae on your tongue Papillae bumps on your tongue Taste buds cells are found on the papilla
What are taste buds? Taste buds are found on papillae on your tongue PTC receptors are found on the taste buds Papillae bumps on your tongue Taste buds cells are found on the papilla
What are taste buds? Taste buds are found on papillae on your tongue PTC receptors are found on the taste buds Papillae bumps on your tongue Nerve Cell Transmits signal to brain Taste buds cells are found on the papilla
What are taste buds? Taste buds are found on papillae on your tongue PTC receptors are found on the taste buds Brain Wow! This tastes really bitter Papillae bumps on your tongue Nerve Cell Transmits signal to brain Taste buds cells are found on the papilla
Question: Are there other traits that can allow a person to more strongly taste PTC? Hypothesis:
Question: Are there other traits that can allow a person to more strongly taste PTC? Hypothesis: If a person has more taste buds, then he/she may be able to taste the PTC more strongly.
Let’s test our hypothesis and count our taste buds! 1) Lollipop time! Lick your lollipop such that the blue gets all over your tongue…especially the tip of your tongue. 2) Once your tongue is really blue, place one hole reinforcer on the tip of your tongue—so it looks like the picture on the bottom on this slide. 3) Have your partner count the bumps or papillae on your tongue…these will not stain blue. * Remember that your taste buds are on your papillae. Therefore the number of papillae correlates to the amount of taste buds on your tongue. *
Counting the number of tongue papillae 5 papillae 20 papillae 35 papillae
Counting the number of tongue papillae 5 papillae 20 papillae 35 papillae Come to the front of the class to report your PTC phenotype (taster, super-taster and non-taster) and the number of papillae on your tongue
Please PAUSE and take a moment to count your taste buds and report your results on the spreadsheet at the front of the classroom
Ideal graph representing the number of tongue papillae related to the phenotype of PTC taste These results support our hypothesis that the super-taster has more papillae!
Ideal graph representing the number of tongue papillae related to the phenotype of PTC taste The number of papillae in the non-taster is variable. Why would the number of papillae be variable in a non-taster?
Please PAUSE and discuss why you think being a PTC non-taster does not correlate with number of taste buds.
What does it take to be a PTC Taster? Two traits are important for determining PTC taste sensitivity 1) PTC receptor genotype—Do you have the receptors that enable you to taste PTC
What does it take to be a PTC Taster? Two traits are important for determining PTC taste sensitivity 1) PTC receptor genotype—Do you have the receptors that enable you to taste PTC 2) The density of papillae on your tongue correlates to the sensitivity of tasting PTC super-taster
What are the reasons a person would react differently to drugs? 1. Having the receptor (protein) to recognize the drug 2. Other physiological traits that enable you to respond to a drug 3. How your body processes the drugs after receiving it
A Drug’s Life ADME • Absorption • Distribution • Metabolism • Excretion http: //publications. nigms. nih. gov/medbydesign/chapter 1. html
Metabolic enzymes Enzymes Metabolites Drug Liver DNA variations in special proteins in the liver called enzymes can influence a person’s ability to metabolize certain drugs
Adverse Drug Reactions (ADR) • Definition- unwanted, negative response to a prescribed drug at normal doses and during normal use – Examples?
Adverse Drug Reactions (ADR) • Definition- unwanted, negative response to a prescribed drug at normal doses and during normal use – Examples? • There are multiple causes for ADRs – environmental basis – genetic basis
Adverse Drug Reactions (ADR) • Definition- unwanted, negative response to a prescribed drug at normal doses and during normal use – Examples? • There are multiple causes for ADRs – environmental basis – genetic basis • Poor metabolizers can experience ADRs at normally therapeutic drug doses
Case study: Nortriptyline metabolism Three women of the same height, weight, age, and racial background are depressed and go to the doctor. The doctor prescribes an antidepressant, Nortriptyline, at a dose of 100 mg. • Person A has an adverse reaction • Person B nothing happens • Person C gets better… B A C
Case study: Nortriptyline metabolism Three women of the same height, weight, age, and racial background are depressed and go to the doctor. The doctor prescribes an antidepressant, Nortriptyline, at a dose of 100 mg. • Person A has an adverse reaction • Person B nothing happens • Person C gets better… Why? B A C
ADME of Nortriptyline 100 mg Nortriptyline A Adverse reaction B Nothing happens How much active drug in blood? C Gets better
ADME of Nortriptyline 100 mg Nortriptyline A Adverse reaction 95 mg B Nothing happens 5 mg C Gets better 50 mg
DNA variation influence drug metabolism Enzymes A Metabolites Drug Liver Poor Metabolizer 95 mg
DNA variation influence drug metabolism Enzymes B Metabolites Drug Liver Ultrarapid Metabolizer 5 mg
DNA variation influence drug metabolism Enzymes C Metabolites Drug Liver Intermediate Metabolizer 50 mg
2012 - What do doctors do? A B Poor Metabolizer Ultrarapid Metabolizer Decrease Dose Increase Dose Or change drug C
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?
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) Personalized Medicine
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
Summary Genetic variation leads to phenotypic differences and differences in how we all react to drugs.
Summary Genetic variation leads to phenotypic differences and differences in how we all react to drugs. 1. Having the receptor (protein) to recognize the drug PTC and HER 2 receptors
Summary Genetic variation leads to phenotypic differences and differences in how we all react to drugs. 1. Having the receptor (protein) to recognize the drug PTC and HER 2 receptors 2. Other physiological traits that enable you to respond to a drug Number of taste buds on tongue
Summary Genetic variation leads to phenotypic differences and differences in how we all react to drugs. 1. Having the receptor (protein) to recognize the drug PTC and HER 2 receptors 2. Other physiological traits that enable you to respond to a drug Number of taste buds on tongue 3. How drugs are processed in the body Enzymes in liver metabolize drugs
Pharamcogenomics Using people’s genetic information for the right drug at the right dose at the right time! R X
About the Scientist: • What do I study? • Why do I love science? • Questions?
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