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Genomic medicine and Personalized Medicine

Genomic medicine and Personalized Medicine. Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute PAEA Annual Meeting October 27, 2007. 完全健康. 绝对死亡. 健康 , 亚临床 , 疾病与损伤 , 濒死. 出现临床症状（疾病）. 卫生资源. 严重 疾病. 1%. 70%. 高危险状态（早期病理改变）. 19%. 慢性病. 中危险状态. 80%. 30%. 相对健康 / 一般小病.

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Genomic medicine and Personalized Medicine

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  1. Genomic medicine and Personalized Medicine Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute PAEA Annual Meeting October 27, 2007

  2. 完全健康 绝对死亡 健康,亚临床,疾病与损伤,濒死 出现临床症状（疾病） 卫生资源 严重 疾病 1% 70% 高危险状态（早期病理改变） 19% 慢性病 中危险状态 80% 30% 相对健康/一般小病 低危险状态

  3. 医疗卫生事业发展面临的问题 • 诊断治疗系统耗费了大量卫生费用，而效益低下 • 诊断治疗没有个性化，导致过度治疗，事倍功半

  4. 我国十一五科学发展规划有关人口与健康部分的指导方针我国十一五科学发展规划有关人口与健康部分的指导方针 • 重点前移 • 将医学研究的重点从“诊断治疗”前移到“预测预防” • 重心下移 • 政府重点投入社区医疗、基层医疗

  5. 面对目前医疗卫生改革的难题除了政策层面的体制改革，在技术层面我们能够做什么？面对目前医疗卫生改革的难题除了政策层面的体制改革，在技术层面我们能够做什么？ • 基因组医学能给我们带来什么？ • 根据易感基因，预测疾病发生的概率，做到个性化预防 • 根据同一种疾病对对同一种药物的不同反应进行基因分型，做到个性化治疗 • 以导致疾病的相关基因作为靶点，开发新的治疗药物。

  6. Collins et al., Nature 4/24/03

  7. Collins et al., Nature 4/24/03

  8. A SMALL SAMPLING OF COOL THINGS ABOUT THE GENOME • Humans have fewer protein-coding genes than expected – only about 20,000 • Only about 1.5% of the human genome is involved in coding for protein, but there are numerous complex critical functions encoded in the rest of the DNA instruction book • We are all 99.9% the same at the DNA level

  9. Cystic fibrosis Adult onset diabetes AIDS

  10. SNP A SNP B

  11. Searching for genetic causes of disease in the pre-genome era

  12. “Genome Wide Association” Approach to Common Disease:The View from 2002 • Identify all 10 million common SNPs • Collect 1000 cases and 1000 controls • Genotype all DNAs for all SNPs • That adds up to 20 billion genotypes • At 50 cents a genotype, that’s $10 billion for each disease – completely out of the question

  13. Genome Wide Association Approach to Common Disease:The View from 2007 • Identify an optimum set of 300,000 tag SNPs • Collect 1000 cases and 1000 controls • Genotype all DNAs for all SNPs • That adds up to 600 million genotypes • Genotyping just dropped to $0.0012, so that’s $800,000 for each disease

  14. Searching for genetic causes of disease in the genome era

  15. CF3 GCKR FTO CDKN2A 8q24 #2 8q24 #3 8q24 #4 8q24 #5 8q24 #6 ATG16L1 IRGM 5p13 3p21 10q21 NKX2 PTPN2 IL12B CDKN2A IGF2BP2 CDKAL1 HHEX SLC30A8 Cholesterol Obesity Coronary Dz Prostate cancer Age Related Macular Degeneration Crohn’s Disease Type 2 Diabetes CFB/C2 LOC387715 8q24 IL23R TCF7L2 IBD5 NOD2 CFH PPAR Confirmed genetic contributors to common human diseases(April 2007) KCNJ11 2000 2001 2002 2003 2004 2005 2006 2007

  16. IBD5 NOD2 PPAR CTLA4 KCNJ11 PTPN22 2000 2001 2002 2003 2004 MEIS1 LBXCOR1 BTBD9 C3 8q24 ORMDL3 4q25 TCF2 GCKR FTO C12orf30 ERBB3 KIAA0350 CD226 16p13 PTPN2 SH2B3 FGFR2 TNRC9 MAP3K1 LSP1 8q24 Confirmed genetic contributors to common human diseases (August 2007) CDKN2A 8q24 #2 8q24 #3 8q24 #4 8q24 #5 8q24 #6 ATG16L1 5p13 10q21 IRGMNKX2-3 IL12B 3p21 1q24 PTPN2 TCF2 CDKN2A IGF2BP2 CDKAL1 HHEX SLC30A8 Age Related Macular Degeneration Crohn’s Disease Type 1 Diabetes Systemic Lupus Erythematosus Asthma Restless leg syndrome Gallstone disease Cholesterol Obesity Coronary Disease QT interval Atrial Fibrillation Type 2 Diabetes Prostate cancer Breast cancer Colon cancer NOS1AP IFIH1 PCSK9 CFB/C2 LOC387715 8q24 IL23R TCF7L2 CD25 IRF5 PCSK9 CFH 2005 2006 2007

  17. IBD5 NOD2 PPAR CTLA4 KCNJ11 PTPN22 2000 2001 2002 2003 2004 MEIS1 LBXCOR1 BTBD9 C3 8q24 ORMDL3 4q25 TCF2 GCKR FTO C12orf0 ERBB3 KIAA030 CD226 16p13 PTPN2 SH2B3 FGFR2 TNRC9 MAP3K1 LSP1 8q24 CDKN2A 8q24 #2 8q24 #3 8q24 #4 8q24 #5 8q24 #6 ATG16L1 5p13 10q21 IRGMNKX2-3 IL12B 3p21 1q24 PTPN2 TCF2 CDKN2B/A IGF2BP2 CDKAL1 HHEX SLC30A8 Confirmed genetic contributors to common human diseases (Sept 2007) Age Related Macular Degeneration Crohn’s Disease Type 1 Diabetes Systemic Lupus Erythematosus Asthma Restless leg syndrome Gallstone disease Multiple sclerosis Rheumatoid arthritis Glaucoma Cholesterol Obesity Coronary Disease QT interval Atrial Fibrillation Type 2 Diabetes Prostate cancer Breast cancer Colon cancer LOXL1 IL7R TRAF1 STAT4 ABCG8 GALNT2 PSRC1 NCAN TBL2 TRIB1 KCTD10 ANGLPT3 GRIN3A NOS1AP IFIH1 PCSK9 CFB/C2 LOC387715 8q24 IL23R TCF7L2 CD25 IRF5 PCSK9 CFH 2005 2006 2007

  18. http://cancergenome.nih.gov

  19. We wouldn’t think of buying shoes in a single size So why should we be satisfied with one-size-fits-all medicine?

  20. Accelerated by Human Genome Project and HapMap Identify Genetic Defect(s) Diagnostics Preventive Medicine Time Disease with Genetic Component

  21. Taking a good family history will be supplemented, not supplanted, by genetic testing

  22. ---- 95% confidence interval curves Recurrence score for individual patients Genomics Is Not Just About Heredity: Using Gene Expression To Predict Cancer Recurrence Multigene assay predicts recurrence of tamoxifen-treated, node-negative breast cancer Gene expression analysis was combined with an algorithm for calculating risk for distant recurrence Source: Paik, et al., N Engl J Med, December 2004

  23. Accelerated by Human Genome Project and HapMap Identify Genetic Defect(s) Pharmacogenomics Diagnostics Preventive Medicine Time Disease with Genetic Component

  24. 药物的反应与副作用 M. Wortman Technology Review, Feb. 2001

  25. Analysis of VKORC1 and CYP2C9 reveal variable warfarin dose response • Variants at these two genes account for ~60% of variability in therapeutic dose • Prospective trials now underway • FDA has added information about genetics to label Needs low-dose Needs high-dose Slow P450 metabolizers Rieder, M. et al. NEJM 352: 2285-2293, 2005

  26. Accelerated by Human Genome Project and HapMap Identify Genetic Defect(s) Pharmacogenomics Diagnostics • Therapeutic • Developments • Gene Therapy • Drug Therapy Preventive Medicine Time Disease with Genetic Component

  27. Imatinib (Gleevec™) – Specifically Targets • An Abnormal Protein, Blocking • Its Ability To Cause Chronic Myeloid Leukemia Chromosome 9;22 translocation Bcr-Ablfusion protein Bcr-Ablfusion protein Gleevec™ Normal CML

  28. Prediction: Physician Assistants Will Play a Lead Role in the Personalized Medicine Revolution And lots of resources are being developed to assist you…

  29. “81% of programs expressed the need to enhance the quality and extent of genetic and molecular medicine in their curricula…”

  30. www.surgeongeneral.gov/familyhistory

  31. www.nchpeg.org

  32. http://pa.nchpeg.org

  33. “Genetics 101” – basic concepts in genetic and genomic science The family history Preconception and prenatal genetics Newborn screening and pediatric genetics Adult genetics 6. Cancer genetics 7. The genetics of common disease 8. Pharmacogenetics 9. Ethical, legal, and social aspects of genetics 10. Genetic counseling and genetic referrals Top 10 Topics For PA Education In Genetics/Genomics

  34. Personalized Medicine:A future dream

  35. Betty’s story in 2015 • Betty completes the Surgeon General’s family history tool at age 25, learns of uncles with early heart disease. • She consults her PA, who works in a practice that has made an effort to stay informed about genomic medicine. She suggests complete genome sequencing for $1000. • Betty inquires about the risk of genetic discrimination, but effective legislation has outlawed this. • She is found to have three gene variants that have been shown conclusively in well validated studies to increase her risk of early heart attack 4-fold. • She and her PA design a program of prevention based on diet, exercise, and medication precisely targeted to her genetic situation.

  36. Betty’s story continues • Betty does well until age 75. • She develops left arm pain that she assumes is due to gardening, but her care providers know her higher risk and diagnose an acute MI. • Referring to her genome sequence, the PA and MD choose the drugs that will work best to treat her. • She survives and is alive and well in the 22nd century.

  37. Personalized Medicine:Could the dream become a nightmare?

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