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The New Biology: From Science in the Modern World to the Genetics of Diabetes

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Common variants at multiple loci have modest but reproducible association with risk of T2DM. ... Rare or small-effect loci may still be clues to underlying ... – PowerPoint PPT presentation

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Title: The New Biology: From Science in the Modern World to the Genetics of Diabetes


1
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

2
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 (10th C) laid down rules for the
    scientific method of observation, experiment, and
    search for truth. Ibn Al-Nafis (13th 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

3
Education is the most powerful weapon which you
can use to change the world.
Nelson Mandela
4
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.

5
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

6
  • 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

7
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 7th
    Framework cooperative networks
  • Congratulations to those honored today
  • The rest of the world has noticed!

8
Grand Challenges for ST 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 ST 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

9
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.

10
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 (lt1/day 1 billion
    people)
  • and hunger--by 50
  • Achieve universal primary education for boys and
    girls
  • Promote gender equality and empower women
  • Reduce child mortality rate before age 5 by 67
  • Improve maternal health--reduce mortality ratio
    by 75
  • Combat HIV/AIDS, malaria and other
    diseases---begin to
  • reverse incidence and spread
  • Ensure environmental sustainabiity--50 reduction
    in
  • those without safe drinking water
  • 8. Develop a global partnership for development

11
GRAND CHALLENGES IN GLOBAL INFECTIOUS DISEASES (7
Goals, 14 Challenges)Gates Foundation
  • Improve childhood vaccines (3)
  • Create new vaccines (3)
  • Control insects that transmit agents of disease
    (2)
  • Improve nutrition to promote health (1)
  • Improve drug treatment of infectious diseases (1)
  • Cure latent and chronic infection (2)
  • Measure health status accurately and economically
    (2)

12
Its a New World in Life Sciences
  • New Biology---New Technology
  • Genome Expression Microarrays
  • Comparative Genomics, Epigenetics,
  • miRNA Gene Regulation
  • Proteomics, incl alternative splice isoforms
  • Bioinformatics
  • Systems Biology

Path to predictive, personalized,
preventive (P3) healthcare
13
Biology as an Information Science Historical
Milestones
  • The molecule of inheritance is DNA, not protein
    1944
  • The Watson-Crick double-helix model of DNA
    permits transcription and replication and
    mutations 1953
  • 46, not 48, human chromosomes 1956
  • The triplet code for proteins demonstrated 1960
  • The principle of unity in diversity applies to
    all living things---at all levels from molecules
    to cells to organ functions to ecosystems
  • Systems biology combines the digital code of
    genetics with environmental and behavioral inputs
    and perturbations (Leroy Hood)
  • Latest Synthetic Biology (George Church)

14
The DNA Pioneers
15
The Historic Weekend of Feb 15-16, 2001
16
U.S. Leaders of the Human Genome Project
Eric Lander
J. Craig Venter and Francis Collins
Ari Patrinos
17
Protein
DNA
18
(No Transcript)
19
Avalanche of Genomic Information
  • The International HapMap Consortium aims to
    genotype 1 million SNPs from 270 individuals.
  • Direct associations of individual SNP alleles
    with disease phenotypes (including linkage
    disequilibrium, LD) are more powerful than
    linkage-based indirect association analyses.
  • dbSNP has gt10 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.

20
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 _at_ 0.50 had cost estimate of
    10B.
  • HapMap brought cost of 300,000 tagging SNPs _at_
    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

21
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.

22
NIH National Centers for Biomedical Computing
Informatics for Integrating Biology and the
Bedside (i2b2) Isaac Kohane, PI
Physics-Based Simulation of Biological Structures
(SIMBIOS) Russ Altman, PI
National Center for Integrative Biomedical
Informatics (NCIBI) Brian D. Athey, PI
National Alliance for Medical Imaging Computing
(NA-MIC) Ron Kikinis, PI
The National Center For Biomedical Ontology
(NCBO) Mark Musen, PI
Multiscale Analysis of Genomic and Cellular
Networks (MAGNet) Andrea Califano, PI
Center for Computational Biology (CCB) Arthur
Toga, PI
23
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 ???
24
Global Health Network
44,000 Faculty 3500 Universities 174
Countries
25
Supercourse Mirror Sites
42 Mirrored Sites, MOH Egypt, Sudan, China,
Mongolia, Russia
26
East-West Collaboration
27
A.Husseini (Birzeit University, West Bank)
Diabetes in the Arab World, from the SuperCourse
28
Prevalence Estimates of Diabetes in selected
Arab Countries gt 20 Years old in the Year 2025
Dev Countries/World/Tunisia/Oman/Saudi
Arabia/Egypt
29
(No Transcript)
30
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
www.pitt.edu/super1/
31
Rising Interest in the Genetics of Diabetes and
Its Complications
32
A Brief History of the Genetics of Diabetes
Nightmare
Disequilibrium
Headache
Linkage
Interactions
Heterogeneity
Complexity
33
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

34
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?

35
Type 2 Diabetes in 3 Ethnic Groups
36
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.

37
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.

38
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 lt 1.35 for TCF7L2 at least nine
    others (now about 20) have OR 1.1-1.2.
  • The aggregate attributable risk is lt10 percent.

39
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 plt10-5 with 53,975 samples
  • Found at least six more previously unknown loci
    JAZF1, CDC123-CAMK1D, TSPAN8-LGR5, THADA,
    ADAMTS9, NOTCH2. The first three are probably
    associated with insulin release.

40
Complementary Strategy GWA Studies of Risk
Factors for T2 Diabetes Mohlke et al, Hum Mol
Genetics 2008
  • Classic genetic epidemiology studies estimate
    genetic effects explain 25 of variance for 20
    measures of cardiovascular function, 51 for five
    anthropologic measures, and 40s for 38 blood
    tests, including cholesterol and metabolism.
  • They reviewed GWA studies of gt200,000 SNPs that
    reported at least one SNP exceeding statistical
    significance threshold of plt5x10-8 for
    cholesterol and lipid levels, obesity, myocardial
    infarction, or coronary heart disease.

41
Cholesterol, Lipoproteins, Lipids and CRP Mohlke
et al, Hum Mol Genetics 2008
  • Glucokinase regulator (GCKR) initially associated
    with triglycerides
  • Then with HDL-C, LDL-C, TG and 11 additional
    previously reported SNP variants and 7 new loci
  • SNPs near SORT1-PSRC1-CELSR2 loci were associated
    with LDL-C a SNP explained 58-86 of the
    inter-individual variability in transcript levels
    for these three neighboring genes.
  • 7 variants are associated with C-reactive protein
    levels, including CRP itself, APOE, leptin
    receptor, and HNF1 homeobox A (HNF1A).

42
Fat Mass and Obesity Genes
  • A 2005 review cited 127 gene candidates and 253
    quantitative trait loci reported from linkage
    studies of obesity. Hardly any were confirmed.
  • In 2007 two independent GWA studies identified
    obesity-associated variants in the first intron
    of the FTO gene now replicated many times. FTO
    encodes a 2-oxoglutarate-dependent nucleic acid
    demethylase whose relation to obesity or BMI is
    not yet understood.

43
Informative Heterogeneity
  • The initial association of FTO with diabetes was
    not replicated in several well-powered GWA
    studies.
  • Whether or not FTO turns up in T2DM GWA studies
    depends entirely on the inclusion criteria for
    casesif obese individuals are excluded, as in
    the GWA studies above, FTO is not associated if
    they are included, FTO is associated (indirectly)
    with T2DM.

44
Obesity and MC4R (chromosome 18q21)
  • Two recent large GWA studies for obesity-related
    traits identified associated SNPs near the
    melanocortin-4 receptor (MC4R) gene. This
    receptor is a major target in drug development
    for obesity. Mutations in MC4R can produce a rare
    extreme form of childhood obesity.
  • BMI, insulin resistance, and waist circum-ference
    were associated with these variants 188 kb
    downstream of MC4R. What is actually happening
    with these allelic substitutions is unknown, but
    under investigation.
  • Together FTO and MC4R account for only 1.2 kg/m2
    variation in BMI in adults.

45
Other Quantitative Metabolic Variables
  • For fasting glucose level, there are common
    sequence variants in glucokinase (GCK) promoter
    and in islet-specific glucose-6-phosphatase,
    catalytic 2 (G6PC2).
  • Uric acid levels are associated with variants at
    solute carrier/glucose transporter SLC2A9.
  • Surprisingly, none for high blood pressure or
    systolic or diastolic blood pressures.

46
Evidence for Association of T2DM with Several
Traits on Chromosome 9p21 SNPs in 10,128 GWA
samples. Arrows locations of SNPs. Black bars
recombination hotspots. Genes and transcripts at
the bottom.
47
Stature/HeightHeritability gt0.8 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.

48
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.

49
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
50
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

51
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.

52
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 (lt10).
  • 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.

53
(No Transcript)
54
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.

55
Getting Ahead of the Science Personalized
Genomics
  • 23andme.com 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

56
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 sitesenvironmental biotechnology
  • Safety regimens will be critical.

57
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
    successes, especially standardization of parts
    and automation of processes can help transform
    biotechnology and genetic engineering from a
    specialized craft into a mature industry.

58
  • Pierre Teilhard de Chardin
  • 1881-1955
  • The future belongs to those who give the
  • next generation hope.

59
  • There are those who look at things the way
    they are, and ask, why?...
  • I dream of things that never were, and ask,
    why not?
  • --Robert F.
  • Kennedy (1968)
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