The New Biology From Science in the Modern World to the Genetics

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,The New Biology: From Science in the Modern World to the Genetics of Diabetes,Gilbert S. Omenn, M.D., Ph.D.,University of Michigan, Ann Arbor, MI, USA,SuperCourse of Science Conference,6 January 2009,Bibliotheca Alexandrina, Egypt,1,A Call for Renewal of Science in Muslim Countries,Our Muslim forefathers first held up the torch of rationality, tolerance, and advancement of knowledge throughout the Dark Ages of medieval Europe. astronomy, math, chemistry,Ibn Al-Haytham (10,th,C) laid down rules for the scientific method of observation, experiment, and search for truth. Ibn Al-Nafis (13,th,C) emphasized respect for contrarian views to be tested with evidence. Then came Taqlid.,Science requires freedom to enquire, challenge, think, and envision the unimagined.,-Ismail Serageldin, SCIENCE 8-08-08,2,Education is the most powerful weapon which you can use to change the world.,Nelson Mandela,3,The Bibliotheca Alexandrina,A beacon and compass for science, education, and peace in the Muslim world and the broader developing world,An institution with a stunning legacy, magnificent architecture, a splendid leader, fully digitalized resources, and remarkable, diverse initiatives, includingamong many others-the SuperCourse of Science.,A leading force for cooperation and collaboration among equals between North and South.,4,Europe: Investing in Intelligence,“Research and innovation are the main keys to Europes development. They are also the most efficient way to respond to the challenges set by Asias large emerging economies and to lay the foundation for sustainable development for the entire planet.”,-Nicolas Sarkozy,14 May, 2008,5,FRONTIER SCIENCE AND GRAND CHALLENGES: INVESTING IN HIGH-POTENTIAL INDIVIDUALS AND HIGH-PAYOFF SCIENTIFIC FIELDS,Gilbert S. Omenn,University of Michigan,French Presidency of the EU,Symposium Celebrating Frontier Science,Paris, 7 October, 2008,6,Kudos to the EU on the Launch of the Frontiers of Science Program,Investments in young scientists and their individual investigator-initiated projects,Sufficient funding to make a difference,High standards,The “Ideas Program”, complementary to the 7,th,Framework cooperative networks,Congratulations to those honored today,The rest of the world has noticed!,7,Grand Challenges for S&T and Society,Pursue the unknowns in each scientific discipline from math to biology to education.,Mobilize multidisciplinary research and development for food security, energy, health, green chemistry.,Combine S&T with political will and social purpose to overcome poverty and hunger, scarcity of water, and climate change, for sustainable economic development.,-G.S. Omenn, SCIENCE 15 Dec 2006,8,Obama Statement on Science,Saturday December 13 announcement of Presidential Science and Technology Adviser John Holdren, Co-Chairs of Presidents Committee of Advisers on Science and Technology (PCAST) genetics pioneers Harold Varmus and Eric Lander, and ecologist Jane Lubchenco,Affirmation of the importance of science,Commitment to integrity of review of scientific issuesexpect support for stem cell research, teaching of evolution, and control of greenhouse gases/climate change.,9,U.N. MILLENIUM DEVELOPMENT GOALS,These goals for peace, security, development, human rights and fundamental freedoms (1990 to 2015) are people-centered, time-bound, and measurable.,Eradicate extreme poverty (10 million validated SNPs.,Haplotype structures can be obtained via genome-wide LD, haplotype blocks (1 KB to 1 MB), and haplotype-tagging SNPs, respecting recombination hotspots and variable LD.,19,ESTIMATED COSTS OF GENOTYPING,When Human Genome sequence published in 2001, along with 10M common SNPs identified, proposed case/control studies of 1000 + 1000 participants with 20B genotypes $0.50 had cost estimate of $10B.,HapMap brought cost of 300,000 tagging SNPs $0.003 to $2M per common disease (5000x decrease in 4 years).,Now we have even more powerful analyses with “next-generation sequencing of the genome”,Computational muscle: “Skate where the puck is gonna be” (Gretzky) in planning big studies,20,A Golden Age for the Public Health Sciences,Sequencing and analyzing the human genome is generating genetic information that must be linked with information about:,Nutrition and metabolism,Lifestyle behaviors,Diseases and medications,Microbial, chemical, physical exposures,Every discipline of public health sciences needed,.,21,NIH National Centers for Biomedical Computing,Informatics for IntegratingBiology and the Bedside (i2b2),Isaac Kohane, PI,Center for Computational Biology,(CCB),Arthur Toga, PI,Multiscale Analysis of Genomic,and Cellular Networks (MAGNet),Andrea Califano, PI,National Alliance for Medical,Imaging Computing (NA-MIC),Ron Kikinis, PI,The National Center For,Biomedical Ontology (NCBO),Mark Musen, PI,Physics-Based Simulation of,Biological Structures (SIMBIOS),Russ Altman, PI,National Center for Integrative Biomedical Informatics (NCIBI),Brian D. Athey, PI,22,Multi- and Interdisciplinary Research will be Required to Solve the “Puzzle” of Complex Diseases and Conditionssuch as Diabetes,Genes,Behavior,Diet/Nutrition,Infectious agents,Environment,Society,?,23,Global Health Network,44,000 Faculty,3500 Universities,174 Countries,24,Supercourse Mirror Sites,42,Mirrored Sites,MOH Egypt, Sudan, China, Mongolia, Russia,25,East-West Collaboration,26,A.Husseini (Birzeit University, West Bank): “Diabetes in the Arab World”, from the SuperCourse,27,Prevalence Estimates of Diabetes in selected Arab Countries 20 Years old in the Year 2025,Dev Countries/World/Tunisia/Oman/Saudi Arabia/,Egypt,Prevalence Estimates of Diabetes in selected Arab Countries 20 Years in the year 2025,Developing cournties,World,Tunisia,Oman,Saudi Arabia,Egypt,28,29,Genetics of Diabetes and Its Complications: Layers of Complexity,Craig L. Hanis, Ph.D., University of Texas at Houston; delivered at Univ Pittsburgh,23 October, 2001,#1 ranked “Genetics and Diabetes” lecture at pitt.edu/super1/,30,Rising Interest in the Genetics of Diabetes and Its Complications,31,A Brief History of the Genetics of Diabetes,Nightmare,Headache,Heterogeneity,Complexity,Interactions,Linkage,Disequilibrium,32,Complex Inheritance,Model Free Linkage Approaches,Affected Pairs,Concordant Sib Pairs,Discordant Sib Pairs,Association Based Mapping,Transmission Disequilibrium Testing,Parent - Offspring Trios (pairs),Traditional Associations,SNP-based mapping,33,Fine Mapping,Ultimately a search for association of disease with single-nucleotide polymorphisms (SNP),Criteria for selecting samples,Affected/Unaffected,Segregating/Non-segregating,Haplotype Determination,enhanced by pedigrees?,34,Type 2 Diabetes in 3 Ethnic Groups,35,Genome-Wide Association (GWA) Studies,GWA studies represent a systematic search with nucleic acid probes (chips) for variants in the genome statistically associated with particular diseases or traits.,“Next-generation sequencing” is replacing chip arrays.,Only 2% of the DNA codes for protein products, so few of these variants actually occur in such coding genes, but they may still influence regulation of gene function.,Tremendous investment and output past several years,has transformed the genetic side of molecular epidemiology, but neglected non-genetic variables,Variants give clues to unsuspected genes and pathways potentially involved in diseases like diabetes mellitus.,I focus rest of the lecture on genomics and diabetes, as a bridge to the WHO course starting today on Epidemiology of Diabetes.,36,First GWA Studies for T2DM,In 2007, five GWA studies were reported:,They replicated earlier evidence for three genome variants: TCF7L2, PPARG, and KCNJ11.,They identified at least six additional variants in or near these loci: SLC30A8, IGF2BP2, FTO, HHEX-IDE, CDKAL1, CDKN2A-CDKN2B.,Only one (SLC30A8) is a likely functional variant at the protein level.,Variants in FTO are associated also with body mass index.,37,Interpretation of GWA Studies of Type 2 Diabetes,These studies are unbiased by previous hypotheses of predisposing genes,The results are limited by modest effects and need for stringent statistical thresholds and very large sample sizes.,The largest allelic OR for any established variant is = 1.35 for TCF7L2; at least nine others (now about 20) have OR 1.1-1.2.,The aggregate attributable risk is 10 percent.,38,Meta-Analysis of GWA Data for Susceptibility Loci for Type 2 Diabetes,Zeggini et al, Nature Genetics 2008,Common variants at multiple loci have modest but reproducible association with risk of T2DM.,Three studies combined (DGI, FUSION, WTCCC): 10,128 individuals of European descent; 2.2 million SNPs genotyped/extended with imputed SNPs from haplotype variation,Used both Affy 500K and Illumina 317K chips,Tried to replicate findings analysis for 11 variants with p200,000 SNPs that reported at least one SNP exceeding statistical significance threshold of p0.8,Sanna et al and Lettre et al, Nature Genetics 2008,Body mass index comprises height and weight measures.,Several rare mutations are definitely associated with height in Mendelian syndromes,Common variants in transcription factor HMGA2 are associated with height in the general population.,GWA studies from Finland and Sardinia reveal an association of osteoarthritis-associated locus GDF5-UQCC-perhaps through bone growth Sanna et al,With six populations, 10 additional loci have now been associated Lettre et al, and the two above confirmed; however, together they (and others) account for just 2 percent of population variation in height. They do expand our ideas of biological regulation of height.,47,Classic Approach of Detecting Large-Effect Rare Mutations,Three of the T2DM-associated variant loci were actually discovered through analysis of the heterogeneity of the disorder,Rare Mendelian mutants of KCNJ11, WFS1, and HNF1B can cause diabetes, including Maturity-Onset Diabetes of the Young. These variants have been confirmed repeatedly by GWA.,Their potential pathways relevant to diabetes biology are shown in next slide.,Rare or small-effect loci may still be clues to underlying pathophysiology and targets to treat.,Copy-number variants are also missed in GWA studies.,48,Processes involved in genetic predisposition to type 2 diabetes, based on the best candidates within each signal and human physiological studies. Most genes implicated in diabetes susceptibility act through effects on beta-cell function or mass. McCarthy and Hattersly, 2008,49,Resources to Keep up with Field,U.S. NIH (NCI-NHGRI) maintain an ongoing catalog of published genome-wide association studies,There are many databases of gene sequences and variants, and protein variants to assist in annotation of the potential biological roles of variants in or near mapped genes.,Statistical compendia for tests and adjustments for bias due to selection, misclassification, and population stratification are established; see McCarthy et al, Nature Reviews/Genetics 2008.,GWAS Graphical User Interface: graphical browser Chen et al, Bioinformatics 2008,50,Special Challenges & Opportunities in Muslim Countries,Nearly all GWA studies have been performed on Causasians of European origins.,It is very likely that different variants will be important in African and Asian populations, so population-based studies of the kind recently initiated here for cardiomyopathy would be expected to yield interesting and useful findings.,51,General Challenges and Opportunities for Diabetes Epidemiologists,This explosion of new findings about potential genetic predispositions to Type 2 Diabetes, and analogous findings for T1 Diabetes, explains only a modest aggregate proportion of risk explained by the genetic variants (10%).,More and larger GWA and re-sequencing studies will find more variants, probably of smaller and smaller effect.,The big effects are almost surely to be found among non-genetic variables (environmental, behavioral, dietary), as in our early diagram-and in gene-environment interactions.,52,53,KEY COMPONENTS OF THE VISION,An avalanche of genomic information: validated SNPs, haplotype blocks, candidate genes/alleles, proteins, & metabolites-associated with disease risk,Powerful computational methods,Effective linkages with better environmental and behavioral datasets for eco-genetic analyses,Credible privacy and confidentiality protections,Breakthrough tests, vaccines, drugs, behaviors, and regulatory actions to reduce health risks and cost-effectively treat patients in the US and globally.,54,Getting Ahead of the Science: Personalized Genomics,23andme is a company in California, offering:,Disease Risks: prematuregenome variants associated with various diseases, but very little of the attributable risk known,Ancestry testing: GoodHaplotypes tied to population origins (Africa, Europe, Asia),Geneology/family roots: Good, using Y chromosome and mitochondrial DNA,55,Synthetic Biology, an Emerging Field,Interdisciplinary science and engineering to design and build novel biological functions and systems to:,Gain insights into what makes life tick, constructing genetic circuits to achieve what nature evolved over eons,Develop powerful biotechnologies by integrating biological components, circuits and replicating organisms,Applications:,Engineered microorganisms that produce drugs,Biosensors for detecting abnormalities and diseases,Microorganisms that convert renewable resources into energy carriers,Microorganisms to remediate hazardous material contaminated sites”environmental biotechnology”,Safety regimens will be critical.,56,Engineering Life: Building a FAB for Biology,The BIO FAB Group: David Baker, George Church, Jim Collins, Drew Endy, Joseph Jacobson, Jay Keasling, Paul Modrich, Christina Smolke and Ron Weiss (Scientific American 2006),BIOLOGICAL COMPONENTS are the basis of an approach to biotechnology modeled on electronics engineering.,Principles and practices learned from engineering succes