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 IntegratingBiology 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 DiabetesZeggini 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 DiabetesMohlke 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, Lipidsand 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 gt0.8Sanna 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)