Molecular Medicine: a possible future? The Future of DNA Venice September

Transcription

1 Molecular Medicine: a possible future? The Future of Science - Fifth World Conference The Future of DNA Venice September

2 From Hesy-Ra to Banting and Best

3 Linus Pauling and Molecular Diseases

4 The predicament of Modern Medicine Beetween a rock and a hard place

5 Getting out of the predicament Diagnosis Stratification Prevention Risk assessment Molecular Imaging Targeted therapy Therapy Chemo- prevention

6 Diagnosis: Molecular classification Leukemia and Lymphoma Disease of the blood 2 types: leukemia & lymphoma 3 types of leukemia (acute, chronic, preleukemia) and 2 types of lymphoma (indolent, aggressive) 38 types of leukemia; 51 types of lymphoma

7 Diagnosis: Molecular classification Leukemia 90 and Lymphoma Disease of the blood 2 types: leukemia & lymphoma types of leukemia (acute, chronic, preleukemia) and 2 types of lymphoma (indolent, aggressive) 38 types of leukemia; 51 types of lymphoma

8 Risk assessment: hereditary cancers

9 Molecular Imaging g PET Neurochemical Classification: Alzheimer Disesease (AD)/ Dementia with Lewy Bodies (DLB)/ Frontotemporal Dementia (FTD) [ 11 C]PiB [ 11 C]DTBZ AD DLB FTD

10 Targeted therapy: molecular radiotherapy Anti-CD20 radio-immunotherapy in NHL FDG-PET Before Rx After Rx

11 Targeted therapy: molecular drugs Gleevec in CML

12 Stratification: mechanism-based m therapy Anti-ErbBs molecular drugs Source: Citri & Yarden, NRMCB 2006

13 A few problems in Molecular Medicine Speed of translation into benefits for the patient Identification of disease genes Reverse-engineering engineering of the cellular masterplan Trial and error approach in patients management Focus on the disease and not on the patient Impact of the environment on genes

14 Speed of translation CML from genetics to therapy Nowell and Hungerford identify the Philadelphia chromosome Gleevec enters clinical practice

15 Identification of disease genes

16 Accelleration of discovery

17 Accelleration of discovery

18 Whole Genome Association Studies

19 Whole Genome Association Studies

20 Whole Genome Association Studies

21 The first HapMap p success story

22 and the others

23 and the others

24 and the others

25 and the others

26 and the others

27 and the others

28 and the others

29 and the others

30 and the others

31 and the others

32 Not just WGA

33 Not just WGA

34 Not just WGA Network biology and HUBS

35 Not just WGA Network biology and HUBS Source: Brodsky & Medzhitov, NCB 2009

36 Beyond WGA

37 Beyond WGA

38 From diseases to patients

39 Ever feel like you get every side effect in the book? Increasing Fatality Risk (annual) 1 in in in in in in 10 2 Lightning Plane Crash Murder Car Crash Pharmacogenomics Source: Consumer Reports, 9/99 Lethal adverse drug reaction

40 Pharmacogenomics m 101

41 Pharmacogenomics m 102 A range of drug metabolism phenotypes is observed for individuals based upon the particular cytochrome P-450 genes they ypossess Source: Caraco, NEJM 2004

42 Projected benefits for the patient Diagnose more precisely Provide more effective treatment. Select specific treatment that best fits disease Predict risk before symptoms occur Manage disease more effectively Target the medication to the disorder. Avoid adverse drug reactions. Avoid delay from false starts. Provide earlier treatment. Take preventive action. Eliminate unnecessary treatment. Provide better timing. Adjust treatment as disease changes.

43 Projected benefits for society Overutilization Utilization only by those who can benefit. Inappropriate care More tailored care that precisely fits the disease. High costs Less spent on unnecessary care. Patient safety Precise treatments reduce sideeffects

44 A 5-year plan I take no responsibility for this (I got this from a Francis Collins slide) Identification of most of the heritable risks for common diseases Complete genome sequencing for $1000 or less Interoperable electronic medical records Increased emphasis on individualized prevention Detailed molecular analysis of all tumors Growing list of targeted therapeutics with extensive public- private partnership Reimbursement decisions based on evidence and comparative effectiveness

45 with all this talk about benefits Gleevec as 1 st line therapy for CML 6 years increased survival over interferon- ron alpha therapy $43,100/per life-year saved Source: Reed et al., Cancer 2004

46 with all this talk about benefits Let s not forget the greatest benefit of all

47 David Hilbert s epitaph p Wir mussen wissen Wir werden wissen

48 David Hilbert s epitaph p

49 David Hilbert s epitaph p

50 Prevalence estimates of diabetes in 2025

51 Trial and error approach Observe Diagnose Treat Monitor response Adjust

52 Genes and Environment Genetics Behavior Environment Muscle distrophy Parkinson s Obesity Artherosclerosis Alzheimer Familial Breast Cancer Sporadic Breast Cancer Lung Cancer Drug Abuse

53 A few problems in Molecular Medicine Speed of translation into benefits for the patient Identification of disease genes Reverse-engineering engineering of the cellular masterplan Trial and error approach in patients management Focus on the disease and not on the patient Impact of the environment on genes

54 Not just WGA Network biology and HUBS

55 Risk and chemoprevention Tamoxifen (and alikes) and breast cancer Source: Jordan, NRC 2007

56 Prevention: PKU If one were to construct a fantasy about a human genetic disease for which all is known and a cure available, phenylketonuria is likely to come to mind. In what other genetic disorder have the following been accomplished: characterization and mapping of the relevant gene; identification of the mutations; determination of enzyme structure and functional sites; identification of the clinical and biochemical characteristics; correlations of genotype with phenotype; prenatal diagnosis; recognition of the teratogenic risks in the maternal condition; development of treatment that prevents mental retardation; production of an animal model that mimics the biochemical phenotype and expresses much of the clinical phenotype; and, as if these were not enough, establishment shment of newborn screening ng for the disease so that virtually all affected individuals in the developed world receive preventive treatment?

57 Prevention: PKU If one were to construct a fantasy about a human genetic disease for which all is known and a cure available, phenylketonuria is likely to come to mind. In what other genetic disorder have the following been accomplished: characterization and mapping of the relevant gene; identification of the mutations; determination of enzyme structure and functional sites; identification of the clinical and biochemical characteristics; correlations of genotype with phenotype; prenatal diagnosis; recognition of the teratogenic risks in the maternal condition; development of treatment that prevents mental retardation; production of an animal model that mimics the biochemical phenotype and expresses much of the clinical phenotype; and, as if these were not enough, establishment shment of newborn screening ng for the disease so that virtually all affected individuals in the developed world receive preventive treatment?