Obvious that genetics plays a role in physical characteristics. What of behavioral? Just as height is product of genes and nutrition, it is likely that behavioral, emotional and cognitive differences are also predicated on this interplay.
The Age of Personalized Medicine - Daniel A. Notterman, M.A., M.D.
The Age of Personalized MedicineDaniel A. Notterman, MA, MDProfessor of Pediatrics, Biochemistry and Molecular BiologyVice-Dean for Research and Graduate Studies, College of MedicineAssociate Vice-President for Health Science Research, Penn StateUniversity
DNA: Wonder Molecule• The 3 billion base pairs in each cell fit into a space just 6 microns across (head of a pin = 2000 microns across).• If you stretched the DNA in one cell all the way out, it would be about 2 meters (6 feet) long.• All the DNA in all your cells put together would be about twice the diameter of the Solar System.
Human Diversity Factoids Any two humans are more than 99 percent the same at the DNA level. This still implies more than 50 millions chances for us to differ. These differences explain gtctagagcc accgtccagg gagcaggtag ctgctgggct ccggggacac tttgcgttcg 61 ggctgggagc gtgctttcca cgacggtgac acgcttccct ggattggcag ccagactgcc individual susceptibility to 121 ttccgggtca ctgccatgga ggagccgcag tcagatccta gcgtcgagcc ccctctgagt disease, response to drugs or 181 caggaaacat tttcagacct atggaaacta cttcctgaaa acaacgttct gtcccccttg 241 ccgtcccaag caatggatga tttgatgctg tccccggacg atattgaaca atggttcact reaction to the environment. 301 gaagacccag gtccagatga agctcccaga atgccagagg ctgctccccc cgtggcccct We can now determine the 361 gcaccagcag ctcctacacc ggcggcccct gcaccagccc cctcctggcc cctgtcatct most important 2-4 million 421 tctgtccctt cccagaaaac ctaccagggc agctacggtt tccgtctggg cttcttgcat 481 tctgggacag ccaagtctgt gacttgcacg tactcccctg ccctcaacaa gatgttttgc differences in a day, for $500. 541 caactggcca agacctgccc tgtgcagctg tgggttgatt ccacaccccc gcccggcacc In a couple of years we’ll be 601 cgcgtccgcg ccatggccat ctacaagcag tcacagcaca tgacggaggt tgtgaggcgc able to measure all—for 661 tgcccccacc atgagcgctg ctcagatagc gatggtctgg cccctcctca gcatcttatc 721 cgagtggaag gaaatttgcg tgtggagtat ttggatgaca gaaacacttt tcgacatag under $1,000. 781 gtggtggtgc cctatgagcc gcctgaggtt ggctctgact gtaccaccat ccactacaa 841 tacatgtgta acagttcctg catgggcggc atgaaccgga ggcccatcct caccatcatc 901 acactggaag actccagtgg taatctactg ggacggaaca gctttgaggt gcgtgtttg 961 gcctgtcctg ggagagaccg gcgcacagag gaagagaatc tccgcaagaa aggggagcct 1021 caccacgagc tgcccccagg gagcactaag cgagcactgc ccaacaacac cagctcctct 1081 ccccagccaa agaagaaacc actggatgga gaatatttca cccttcagat ccgtgggcgt 1141 gagcgcttcg agatgttccg agagctgaat gaggccttgg aactcaagga tgcccaggct 1201 gggaaggagc caggggggag cagggctcac tccagccacc tgaagtccaa aaagggtcag 1261 tctacctccc gccataaaaa actcatgttc aagacagaag ggcctgactc agactga
Biology 102INTRODUCTION TOPERSONALIZED MEDICINE
The Human Genome Project A revolution in genetics Conception Competition Completion The Human Genome Project Started in 1990 and completed in 2003 The goal was to define and annotate about 25,000 genes The estimated cost was of $ 2.3B The project led the way to a new horizon in genetic testing
What Is Personalized Medicine?The systematic use of biologic and environmental information about anIndividual patient to: 1. define disease risk 2. select or optimize treatment and lifestyleSince every person is genetically unique, ultimately each patient will receive aunique prescription—based on the intersection of their biologic andenvironmental profile.
Genetics is not everything! Same Genome: Different Environment
What Is Needed To ApplyPersonalized Medicine? Biological Data Genomics (all of our DNA information) Metabolomics (all of our chemical information) Environment External, social, cultural, b ehavioral Phenotype Normal physiology and systems biology (how the body works) Disease and health characteristics Automated personal phenotype unit (human black box)
Personalized Medicine: Why Now?Large biologic data sets (GENOTYPE)Large Clinical Data Sets (PHENOTYPE) Computer performance
Personalized Medicine Why does it matter ? In treating all people with a certain lung cancer without having a genetic test, 10% of people might respond.In treating people who have a genetic test and are found to have a tumor mutation, 85% of people treated for that mutation might respond. The best drug for a specific disease in a particular person.
… And Results In Better And Less Expensive Care. Risk of hospitalization among patients who underwent VKORC1 and CYP2C9 genotyping, as compared with a historical control group, 6 months after the initiation of warfarin therapy.NEJM, 3/24/2011
A Personalized Approach ToLeukemia In Children Pui C and Evans W. N Engl J Med 1998;339:605-615
Personalized Care: Breast CancerThe Problem:On clinical grounds alone, it may not be known whether aspecific woman should have chemotherapy in addition totamoxifen.A Case:A 42 year-old woman is found to have a 1.5 cm mass in herright breast. Excisional biopsy establishes that it is malignant.A single lymph node in the axilla is positive for a “micrometastasis.” The cancer is ER+. To make a better predictionof the risk of recurrence, she receives an OncotypeDx BreastCancer Assay Assay®
OncotypeDx• Recommended since 2007 for evaluation of woman with node-negative ER + breast cancer.• About a third of the patients have received a change in treatment recommendation based on this test.
Personalized Approach To Cancer:Malignant Melanoma A 26 year-old graduate student went to a dermatologist because of a mole on the nape of his neck. His girlfriend had noticed a recent change in color.
Malignant MelanomaAn excisional biopsy was performed. Unfortunately, the lesion was deep. He was offered and received standard chemotherapy. 5 mm
Malignant Melanoma 2007 The patient did well for 6 months. At that time he developed a cough. A chest X ray was positive and a PET/CT revealed widespread metastasis. He died within 3 months.
Melanoma 2013:Targeting Treatment To A Specific Variant In The Melanoma Gene • Zelboraf® is an inhibitor of a cancer driver called B-Raf, which is frequently implicated in malignant melanoma. • It works only in the 60% of patients whose melanomas have a specific B-Raf It is essential to personalize therapy by mutation. In these patients, tumour determining the genetic composition of an regression is observed in a significant proportion. In patients without this individual’s cancer. mutation, Zelboraf® can stimulate cancer growth.
Risk To Brain Health: ApoE• ApoE is known to be an important risk for Alzheimer’s Disease.• From 10 to 50% of people have 1 high risk allele (form of the gene) called ApoE4• Recent studies also implicate this allele (ApoE4) in the outcome of traumatic brain injury (TBI)—head trauma. ApoE Risk Genotype • ApoE4 increases the risk of Dementia 2,2 Hyperlipidemia Pugilistica (chronic TBI). Does this apply to (Type II) other forms of athletics where concussion 2,3 Risk of AD occurs? 3,3 Normal • Should athletes be screened for ApoE4? 3,4 Risk of AD • ApoE4 is also associated with a worse outcome 4,4 Risk of AD following acute TBI—as in an auto accident. (20X by 75)
Age-related macular degeneration • Most common cause of irreversible vision loss in Western world for people over 60 (1 in 2000) • Genetics: 45% to 70% • Environment: 30% to 55% • Smoking, diet poor in antioxidants or zinc, high fat, possible sunlight exposure
Making The Diagnosis: Sequencing in a Child with Intractable IBD• 5 year old child with extensive history of GI issues – presumed to be Crohn’s disease (IBD).• Over 100 operations in 3 years in addition to immunosuppression.• DNA samples were collected and prepared for sequencing.• Identified a point mutation in XIAP which causes immunodeficiency and colitis.• Bone marrow transplant: CURED!• Demonstration of the clinical utility of sequencing and its implications for disease gene discovery and clinical diagnosis. Worthey E, et al. (2011) Genet Med Mar;13(3):255-62.
Whole Genome Sequencing in the NICU • Newborns with genetic diseases are often desperately ill. • Standard genetic diagnosis can take days to weeks, so the infant may have died before diagnosis is known. • Many times, the physicians don’t think of the correct genetic test to order. • 3700 genetic disease genes remain to be identified.
2 Day Whole GenomeAnalysis for SickNewborns • To check capabilities, 2 babies were retrospectively diagnosed. • Then Illumina 2500 was used to diagnose 3 babies and a whole family. • 50 hours. • $7666, potentially a cost saving. • Correct diagnosis was made in each case. Science Tran Medicine, 2012.
Prenatal Testing for Trisomy and other Genetic Disorders Male fetus’s Y Chromosome in mother’s blood
Where are we headed with Personalized Medicine?• Monogenetic treatment stratification—now• Genome on an iPhone for medical care—now to 2 years• Rapid diagnosis of ~10,000 genetic disorders—now• Comprehensive treatment and risk stratification—10 years• Automated precise prescription dispenser based on genotype and phenotype—20 to 30 years