pharmacogenomics and bioinformatics

生物資訊與生技服務業之前瞻剖析,陳廣典, Ph.D.生命科學系長庚大學醫學院,生物資訊學,Why Bioinformatics? Genomic Data Explosion,Revised Feb 16, 2005,分子生物學的基本原則 DNA - RNA - 蛋白質 - 表型(Phenotype) 分子特質序列，結構，機能分子作用程序機制，專一性，調控,生物資訊的典型範例:基因體序列資訊 - mRNA (level) - 蛋白質序列 - 蛋白質結構 - 蛋白質功能 - 表型關聯性鉅量的資訊產生標準化統計量,Genetic material,Information transfer (mRNA)Protein synthesis (tRNA/mRNA)Some catalytic activity,Most cellular functions are performed or facilitated by proteins. Primary biocatalystCofactor transport/storageMechanical motion/supportImmune protectionControl of growth/differentiation,分子生物學進入資訊科學的時代,Genetics: single-gene levelWhat does this gene do?When is it expressed?What does it interact with?Etc.,Genomics: genetics on a genome levelWhat is the structure of the genome?What are all the genes in this organism?When are they expressed?What do they do and how do they interact to produce a cell?How are the genes in one organism similar to other organisms?Etc.,Genomics and the human genome,The Human Genome Project,The genome sequence is complete!approximately 3.2 billion base pairs.,1986The U.S. Department of Energy (DOE) hosts a meeting to discuss plans to sequence the human genome.1990US Congress endorses $3 billion for NIH to accomplish the human genome project. 1993 NIH and DOE publish a revised plan to complete the human genome by 2005.1998Craig Venter announces a new company, Celera, and declares to sequence the human genome within 3 years for $300 million. 2000Celera sequences the 180-Mb genome of the Drosophila and validates Venters whole-genome shotgun method. 2001 The HGP consortium and Celera publish their working draft.2003The completion of sequencing of the human genome.,The Human Genome ProjectHistory and Background,48 pages,62 pages,2/16, 2001,2/15, 2001,HGP Data Reported by Celera and Public Consortium,Bold Words from Francis Collins:,“The history of biology was forever altered a decade ago by the bold decision to launch a research program that would characterize in ultimate detail the complete set of genetic instructions of the human being.”,Francis S. Collins Director of the National Human Genome Research InstituteN Engl J Med 1999 882:42-65,Systems Biology providing the global perspective,Bioinformatics is keyIntegrating sciences to promote understanding,Growth in Selected Configurations - 2001,Sangers Supercomputer Facility,The Hottest Job in US Job Market,BioinformaticianThe fusion of biology and computer science is the hottest of the hot in science right now, and its going to heat up even more. Bioinformaticians, also known as computational bi- ologists, use computer modeling to predict which drugs will work on which illnesses, shaving the time and cost of getting new products to market. No wonder drug makers are salivating over these professionals, especially in the wake of human-genome mapping. Chris Smith, who works as a bioinformatician at the San Diego Supercomputer Center, predicts that there will be a 100 percent increase per year in the field for the next five years at least. Even now a bioinformatician with three to five years of experience can command $120,000. How to become one: Youll need graduate training in a biological science such as chemistry, biochemistry or molecular biology, and familiarity with computer technologies. Even better: a bioinformatics degree from one of the dozen universities now offering it.,Chris Taylor in SmartM, 2002,(天下雜誌 268期 2003),全球經濟產業面臨之問題,梭羅(Lester Thurow)科技進步產能過剩通貨緊縮全世界的潛在生產總量，要比全世界的預期消費總量至少多出三分之一造成：工業生產和勞動力的低度利用率延緩消費因應之道：抱住現金 降低債務問題：沒有投資就無法刺激成長,醫藥產業理由:科技與知識並沒有造成醫藥業的產能過剩，反而使得藥物的上市審核更加嚴謹醫藥的消費並不會因為壓抑購買慾而降低人口的老化(aging population)造成醫療支出的攀升,有何產業可對抗通貨緊縮？,疾病研究藥物研發,藥物基因體學,解決生技醫療產業面臨之關鍵問題,Definitions of Pharmacogenomics,Colin Dykes, CSO of VariagenicsPharmacogenomics is the use of any information that is derived from the genome, whether it is genetic and inheritance is involved or whether it is just purely the study of genomics, to define markers for drug response.,Definitions of Pharmacogenomics,Gualberto Ruao, CEO of GenaissancePharmacogenomics is personalized medicine. The personalization of treatment could be in terms of dosage, the actual medication, or in the context of the indication you were after, but by the end of the day it boils down to using the DNA of each person to guide therapy and develop personalized therapeutic products.,Definitions of Pharmacogenomics,Trevor Nicholls, CEO of OxagenPharmacogenomics is the understanding of the genetic profile of individual patients to enable them to receive the most effective and safe treatment for the particular condition they are suffering from.,藥物基因體學,A personalized approach to medicine,and to know all this prior to the patient taking the medicine,What is Personalised Medicine?,Personalised Medicine is about enabling clinicians to prescribe the:Right DrugAt the Right DoseFor the Right Disease To the Right Patient,Blockbuster vs. Personalized,Advantages of Pharmacogenomic Approaches,Increase Drug EfficacyIncrease Drug Safety,M. Wortman Technology Review, Feb. 2001,藥物的反應與副作用,Example 1:sedative and analgesic narcotic: codeine5-10 % of Caucasians show little or no analgesic effect,Increase Drug Efficacy,Example 2:Mab against HER2-driven metastatic breast cancer : Herceptin25-30% breast cancer patients show HER2 overexpression, can respond to Herceptin treatment.,Increase Drug Efficacy,Example 1:oral anticoagulant: warfarin0.2-1% of population show a high risk of over-anticoagulation and bleeding.,Increase Drug Safety,Example 2:antidepressant: Paxil5-10 % of Caucasians show defect in CYP2D6 and attenuate Paxil degradation.,Increase Drug Safety,Example 2.1:antidepressant: Paxil,Increase Drug Safety,Adverse Drug Reaction (ADR),For hospitalized patients (FDA CDER, 2004)Misuse of pharmaceuticals (3 million yearly)100,000 DEATH yearly4th leading cause of death US$136 billion yearly,Cyclooxygenase-2Reduce inflammation & musculoskeletal painNSAID (non-steroidal anti-inflammatory drugs)Rheumatology medication (Arthritis)Celecoxib (Celebrex), Pfizer 1999, Rank 22/200Rofecoxib (Vioxx), Merck, Rank 175/200Valdecoxib (Bextra), Pfizer 2.5-fold increased risk of major fatal and non-fatal cardiovascular events. (Aug. 2004),Cox-2 Inhibitors,Molecular Biomarker Discovery,The role of molecular biomarkers in disease management. Areas where molecular biomarkers will benefit personalized medicine include disease predisposition, screening and prognosis, as well as drug response and drug monitoring. The nature of the markers (DNA, mRNA or protein) will vary with the disease and the stage of their application. Rx indicates treatment.,The path to personalized medicineJ. M. Meyer & G. S. GinsburgCurrent Opinion in Chemical Biology, Vol. 6, p434438 (2002),A Booming Market for Biomarkers,Biomarkers can reduce the costs of drug development by replacing complex measurements with a biochemical test.- a 28.5% compound annual growth rate.,Year,Revenues ($ billion),Data Courtesy of Frost & Sullivan, 2004,Estimated Bioinformatics Market Revenue,Year,Revenues ($ billion),Frost & Sullivan (New York, NY, USA, 2000),Year,Revenues ($ billion),Measurement of Investment Effectiveness,Bottleneck,藥物研發的投資與時程,Drug makers turn to be bioinformatics companies,Pfizers (NYSE:PFE)Johnson & Johnsons (NYSE:JNJ)GlaxoSmithKline (NYSE:GSK)Improve drug making process by improving their ability to find the right targets for drugsthe drugs to affect those targetsThe right patient populations for testing that will lead to FDA approval,Bioinformatics Takeover Candidates,Frost report breaks down into 4 parts:Sequencing instrumentation: Applied Biosystems (NYSE: ABI), Amersham Pharmacia BiotechStandalone analysis software packages: Accelrys (merger of several companies), a unit of Pharmacopeia (Nasdaq: PCOP), Cognia, Large-Scale Biology (Nasdaq: LSBC), Paracel (owned by Celera), SAS InstituteDatabase content service provider: Compugen (Nasdaq: CGEN), Incyte Genomics (Nasdaq: INCY), Structural Bioinformatics, DoubleTwist, Celera Genomics, and Gene Logic (Nasdaq: GLGC)Laboratory information management systems: Applied Biosystems, Business Objects SA, Silicon Graphics (NYSE: SGI), SPSS (Nasdaq: SPSS), ThermoLab Systems,藥物基因體學加速了藥物的開發與篩選流程,基因體時代前後之藥物開發比較,生物資訊,臨床醫療,藥物研發,個體化醫療,基礎生物研究,醫療診斷,Compound Progressed into Phase I Clinical Development (GSK 2000),Genome-based Target Identification & Drug Development (20002003),Glaxo SmithKline R&D Annual Review, 2002,Genome-based Drug Discovery,個體化醫療,Drug Discovery: Tailored Medicine No Longer Science FictionThe great promise of pharmacogenomics, to create custom drugs based on an individuals genetic makeup, is slowly becoming reality as companies begin to identify specific biomarkers associated with various genes and diseases. Although many in the industry estimate that it will be another five years or so before personalized medicine becomes widely available, most seem enthusiastic about current research and findings. In addition, the FDA is encouraging companies to submit more pharmacogenomics data, and is expected to issue guidelines for its submission later this year.,Genetic Engineering News09/01/2004,Challenges of Biomarker Market,However, biomarker tests usua