Presentation on theme: "Personalized Medicine - Genomics"— Presentation transcript:
1 Personalized Medicine - Genomics Maria Judit Molnar2014
2 The Personal Genome Project is a long term, large cohort study Aims to sequence and publicize the complete genomes and medical records of 100,000 volunteers, in order to enable research into personal genomics and personalized medicine.It was initiated by Harvard University in 2005.
3 Personal Genome Project The individuals agree to make their genome and their health records public.„volunteers… willing to share their genome sequence and many types of personal information with the research community and the general public,Aim: to understand genetic and environmental contributions to human traits.”
4 The project publish the genotype (the full DNA sequence),phenotype: medical records, various measurements, MRI images, etc.all data are within the public domainmade available over the Internet so that researchers can test various hypotheses about the relationships among genotype, environment and phenotype.
7 RisksCuriosity may be just suspicion co-opted by endorphins. I had no idea what I was blundering into. But I figured I could start learning now about privacy and public good, research and entrepreneurship, risk and susceptibility – all the dangers of knowing the full story – or I could bump up against them later, along with the rest of unwitting humanity.Richard Powers
8 Dealing with bad newsWe know what happens to people who do get the worst news. They don’t sink into despair or throw themselves off bridges; they handle it perfectly well. Most of us cope using some combination of denial resignation and religion.Steven Pinker
9 Genotype and phenotype When the connection between the ACTN3 gene and muscle type was discovered, parents and coaches started swabbing the cheeks of children so they could steer the ones with the fast-twitch variant into sprinting and football.Steven Pinker
15 The roots„ It’s far more important to know what person the disease has than what disease the person has.”Hippocrates (BC. 400)Asdd date
16 The paradigm of the classic treatments Trial and errorSymptomDiagnosisTreatment DosageNon specific Non selectiv UniformizedPhenotypeDoes not evaluate the different therapeutic response - the blockbuster concept
17 The medicine in the XX. century „One fits to all”The target is the diseaseEvidence based medicinestatistical approach using the rule of large numbers, resulting in statistically meaningful conclusions
18 “The dose makes the poison.” But differently for genetically different individualsThe revolution of the molecular biology:Right DiseaseRight PatientRight DrugRight TimeParacelsus( )
20 The results in 2013The most drugs are not or partially effective in the 60% of the treated patientsSide effects are responsible for100,000 death2 million hospitalisations100 billion USD cost for healthcare in USA50%- of the cases is related genetics
21 Personalized Medicine: The Answer? DefinitionThe use of information and data from a patient’s genotype andphenotype (level of gene expression and/or clinicalinformation) to:stratify diseaseselect a medicationprovide a therapyinitiate a preventative measure that is particularly suited to that patient at the time of administration
22 Personalized Medicine is an emerging practice of medicine that uses an individual's genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of diseaseFocus on the clinical needs!“Bench to Bedside” “Bedside to Bench to Bedside”However genomic determinate the potential biological and physiological reactions of the individual, we can not miss the analysis of the environmental effects.The bigest weakness of the clinic nowadays is the lack of the exact diagnosis and the inapropriate determination of the stadium of the disease.
23 The classical therapy: UniformisationObservationTreatmentUncertainrespondIndependently from the heterogeneity of the population try to get in large cohorts positiv results/risk ratio with the treatment (clinical utility)Targeted therapy:Differenciate, diagnostics and drug co-developmentObservationTesting (Biomarker)TreatmentPredictedrespondTargeted therapies help by identificatioon of the patients with the best respond and less side effectsBiomarkers are such diagnostic tools, wich may predict the therapeutic respond to a certain drug
24 The key drivers of the paradigm change in the healthcareHealthcare pressure:Risk / benefit ratioEconomical pressure:Cost / benefit ratioNew Technologies:Expanding possibilitiesIn summary, when we look at the three drivers of change in healthcare today, the most obvious answer is to invest in Personalised Healthcare.At Roche, we are addressing the need for highly differentiated medicines through systematic implementation of PHC approaches.PHC approaches help us to focus on the true value of our clinically differentiated medicines so that patients benefit from enhanced efficacy and greater safety. This kind of innovation that targets a medicine to specific patients will be recognized and rewarded by the healthcare community.Needs of highly differentiated healthcare, which effects the health of the person and societyOnly the really innovative medicine is justifiedInnovative ~ Personalized, Differentiated
25 The Power of Information - Moore’s law Computer processing power is doubling every 18 monthsAmount of data is doubling every 18 monthsPower of technology
26 Technological improvement Genomic revolution of the end of the 20.th centuryCompleting the Human Genom Project (2000)„Only” 25 thousand genes – vs 100 thousandComputed genotyping, DNA microarray„$1000 Genom”„Nobody expected”:25thousand genes – 9 million SNPThe function of 30% of the genes is unclearedThe role of deletions, duplications, CNVsMicrosatellite polymorphismsEpigeneticForrás: Jose de Leon, Pharm Res 59 (2009) alapján
28 A new era in genomics medicine? Human genome projectDirect-to-consumer genomicsIntellectual property disputesCatalonaMyriad GeneticsHenrietta LacksPersonal Genome Project
29 Drug discovery paradigm shift: a problem or an opportunity? Ever increasing demand for safer medicineStark realization that drug discovery is expensive and slowshrinking budgets, consolidation, outsourcingCurrent drug inventory is large, diverse and possibly has a lot more to offer than was initially thoughtIncreasing availability of genomic data and tools to use/understand it
33 Complex disorders: limited success rate Age related macula degeneration
34 Apolipoprotein E Genotype and Alzheimer Disease Metaanalysis of 40 study5.930 patient and control
35 Thorlakur Jonsson et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline and Alzheimer DiseaseThorlakur Jonsson et al.Nature 2012; 488, 96–99 (02 August 2012) doi: /nature11283A coding mutation (A673T) in the APP gene protects against Alzheimer’s diseaseThis substitution results in an approximately 40% reductionin the formation of amyloidogenic peptides in vitro.
36 The change of disease concept Environmental factors Traditional: reductionist, one single factorCausal factorDiseaseNew conception: multifactorialBasicriskPreclinicalprogressionDisease onsetDiseaseprogressionIrreversiblechangesEnvironmental factors
37 intermediate phenotype New Disease ConceptMonogenic diseaseOther SNPsEnvironmentMutationEgészségregyakorolthatásEffect on thehealthintermediate phenotypeIntermedierphenotypeComplex, polygenic, multifactorial diseaseOther SNPsEnvironmentEffect on thehealthEgészségregyakorolthatásIntermedierphenotypeKöztes fenotípusSNP combinations
38 The old paradigm: Treatment of the disease Switch drug againSwitch drugSelect drugDiagnosisDisease severityTimeReactive medical care
39 To effective health management Right DrugMonitoringDiagnosis/PrognosisDisease severityPredispositionScreeningTimeEfficient medical care
40 Social expectations Cheaper, more effective drug development Forrás: Business Insights: Expanding Applications of Personalized Medicine, 2009
44 Scruples Healthpolitical questions Regulatory issues Financing aspects Insurance consequenceUSA: Genetic Information Nondiscrimination Act (2008)Ethical questionsHow to sell the test laymens?The Act prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future. The legislation also bars employers from using individuals' genetic information when making hiring, firing, job placement, or promotion decisions44
46 What will likely happen?? Personalized medicine will involve pharmacogenomic treatment approaches that transcend the „one-size-fits-all” approachPersonalized medicine will focus on keeping people well and treating disease at its earliest stages!Laboratory medicine will lead the way!„Disease signatures” comprised of hundreds or thousands of data point will be the biomarkers of the futureDrug companies will develope their markets around interventional treatments for „disease signatures”!!
47 The POTENTIAL for Personalized Medicine A „Wellness” Vision A new comprehensive and integrated approach to wellness – prevention of chronic disease, early detection of disease risk and individualized treatment plansPredictive toxicology for new drug candidates – ability to predict which individuals will benefit and those who might be most at risk for experiencing serious side-effectsHealthyPre-diseaseDiseasedRecoveringEarlier disease detectionNew interventional therapiesNew diagnostics Disease prediction Preventative therapiesPersonalized treatmentInformed treatment decisionsRoutine ComprehensiveHealth Status MonitoringNew diagnosticsAccurate disease diagnosisReal-time Disease Reoccurrence MonitoringImproved economics of disease screeningReduced occupational exposuresMore timely therapyReduced unnecessary referralsMore efficient treatment plansImproved outcomesTimely medical interventionsReduced hospitalizationsPeople adopting healthier lifestylesTimely testing of environmental exposures
48 The POTENTIAL for Personalized Medicine Increased Healthcare Quality and Reduced Costs (?) Predict and prevent chronic diseasesKeep people out of the hospitalEliminate adverse drug eventsImprove drug developmentCreate new markets
49 The POTENTIAL for Personalized Medicine Transform Healthcare Markets TodayHC markets on numbers of sick people might be treated with a new drugMetricMorbidity and mortality ratesOutcomePeople suffer and die from chronic and preventable diseases with multiple hospitalizationsTomorrowHC markets based on numbers of people with preventable diseasesMetricNumber of people positive for valid predictive biomarkersOutcomeNew era of interventional therapeuticsPeople will live healthier, pain-free lives and die of old age or trauma with minimal hospitalizationsMultiplex biomarkers to predict and guide treatment of early chronic Dz
51 Current Personalized Medicine Approaches Limited To: PharmacogenomicsElectronic Health RecordsGreat Start –But does not yet address the all technologies required for prediction and prevention
52 State of the Art in HC Measurement Technologies Despite Major Progress over the Last 25 Years, Healthcare Measurement Technological Capabilities is Limited to:Digitalizing medical recordsMeasuring a few serum biomarkersIdentifying simple genetic defects/differencesImaging gross anatomical features and detect major changesImaging some disease-associated molecular mechanismComparing mRNA expression patterns between healthy and diseased cellsStatistical analysis of research for evidence-based medicine
53 The Personalized Medicine Gap The lack of adequate measurement technology limits the vision for personalized medicineWe simply do not have the tools to measure the biochemical details of the human body with the resolution needed to fully-realize the amazing potential of personalized medicine
54 Need to Know the Root Cause of Chronic Disease But… Human Cells are Extremly Complex
55 Diseases are the result of perturbations in complex biomolecular networks
56 PM in the clinical practice PreventionBRCA1/2 - Breast and ovarian tu. prophyilactic tamoxifen and surgeryEffectivityOncologyHerceptin – breast cancerCetuximab – colon tumorRare disease: cystic fibrosisIvacaftor G551D mutation in CFTR geneSafetyVKOR/CYP2C9 – warfarin dosing
58 Multiplex Tests are Already Starting to Have an Impact OncoType DXAnalyzes by qPCR, mRNA expression of a panel of 21 genes within a tumor todetermine a Recurrence ScoreMammaPrintMicroarray-based prognostic breast cancer mRNA expression profiling test of 70 genesAlloMapqPCR-based expression profile of 11 genes to assist physicians in managing heart transplant patients for potential organ rejectionTissue of OriginMicroarray technology considers 15 common malignant tumor types, including bladder, breast,and colorectal tumors based on mRNA expression on 1,550 genes
61 New Technologies for Determination of „Disease Signatures” Changes in biomolecular networks indicative of the onset or progression of diseaseNormal Human System100 trillion cells billion basepairs30,000 genes million different proteins ,000’s of molecular events organs and organ systemsABNORMALITIESMultiplex MeasurementsComputer IntegrationDiscovery DecisionsIncreased Drug PipelineImproved DiagnosticsNew Predictive BiomarkersDecrease Adverse EventsDisease SignaturesCell- or Tissue-specific Disease Probablity ScoreImprove Clinical OutcomeFewer Errors & MisdiagnosesPredict Disease OnsetPrevent DiseaseReduce Health Care CostsClinical Decisions
62 Changes due to P4 Medicine More innovative, patient-centered, proactive medicine that will be predictive, preventive, personalized and participatory rather than reactiveThe role of physician is changingPatients increasingly need „coaches” to help them dealing with complexity of „data clouds”, monitor their health and wellnessBroadening the definition of patient (not only limited to thick persons)Social media and e-health will influence the healthcare
63 ? Fears from the P4 Payer: increasing expenses? Physician: decreasing margin?Patient: certain drugs are inaccessible?Authorities: how to deal the complex situation?Diagnostic lab: more test with bed financing?Industry:Narrowing market?New financing strategy??
64 Ethics Too soon for conclusions New ideas about self, privacy, medicine, and freedom
65 ConclusionWe tend to overestimate the effect of technology in the short run and underestimate the effect in the long runAmara’s LawFiguring out how to use that information to improve your medical care is personalized medicine's next great challenge