Darwinian Medicine Basic theory with Practical Uses for Public Health 150 Years after The Origin EvolutionEvolution justjust nownow beingbeing appliedapplied inin manymany areasareas ofof medicinemedicine AA historicalhistorical transitiontransition inin howhow wewe understandunderstand diseasedisease AA RecentRecent FloweringFlowering On the Aims and Methods of Ethology Niko Tinbergen, 1983 Recent and Upcoming Meetings Humboldt University, Berlin York Hull Medical School University of Copenhagen NESCENT meeting at Duke American Institute for Biological Sciences American Physiological Society University of Arizona Wissenschaftskolleg zu Berlin American Clinical Epidemiology Society National Academy Sackler Symposium Origins of Darwinian Medicine "The purport of the following pages is an endeavor to reduce the facts belonging to animal life into classes, orders, genre and species; and by comparing them with each other to unravel the theory of diseases". Darwin,Darwin, 17941794 ErasmusErasmus DarwinDarwin OpeningOpening paragraphparagraph ofof ZoonomiaZoonomia,, E Conchis Omnia (Everything From Shells! ) Erasmus Darwin 1731-1802 Origins of evolution in medicine ErasmusErasmus DarwinDarwin——PhysicianPhysician RobertRobert DarwinDarwin——PhysicianPhysician CharlesCharles DarwinDarwin——MedicalMedical schoolschool dropoutdropout BecauseBecause hehe hatedhated geology!geology! What is Darwinian Medicine? Darwinian (Evolutionary) Medicine TheThe enterpriseenterprise ofof usingusing thethe basicbasic sciencescience ofof evolutionaryevolutionary biologybiology inin thethe servicesservices ofof medicinemedicine andand publicpublic healthhealth Darwinian Medicine—NOT! NotNot radicalradical inin anyany wayway NotNot aboutabout improvingimproving thethe speciesspecies NotNot opposedopposed toto ordinaryordinary medicinemedicine NotNot aa methodmethod ofof practicepractice NotNot aa sourcesource ofof quickquick curescures NotNot justjust aboutabout modernmodern diseasesdiseases NotNot justjust aboutabout thethe valuevalue ofof defensesdefenses EvolutionEvolution isis aa basicbasic medicalmedical sciencescience withwith manymany untappeduntapped applicationsapplications Don’t Doctors Know Evolution? No,No, notnot eveneven thethe basicsbasics 30 20 10 Std. Dev = 1.76 Mean = 1 0 N = 33.00 0 1 2 3 4 5 6 7 8 9 Evolutionary Biology Faculty in Medical Schools Selection is everywhere Explanations based on history YourYour pennypenny jarjar WhatWhat grocersgrocers stockstock WhatWhat isis onon TVTV WhoWho becomesbecomes anan academicacademic WhoWho isis herehere today!today! Natural Selection When heritable variations in a trait influence reproductive success, the trait will inevitably change over the generations. Dogs from Wolves in a Blink Natural Selection When heritable variations in a trait influence reproductive success, the trait will inevitably change over the generations. Darwin: On the various contrivances by which British and foreign orchids are fertilised by insects. London, John Murray, 1862. Why would an orchid have A spur 30 cm. long? Xanthopan morganii praedicta Angraecum sesquipedale The Star Orchid of Madagascar Four lines of work 1. Infection and fast evolution Still being developed 2. Constructing phylogenies Established, new applications 3. Evolutionary genetics Some old, much that is new 4. Why selection left our bodies vulnerable New questions just being asked 1. Studies of Fast Evolution PathogenPathogen evolutionevolution ImmuneImmune systemsystem CancerCancer clonesclones Last Week’s JAMA—Fatal Threats MRSAMRSA (Klevans, et al., JAMA) 9%9% resistantresistant 10%10% mortalitymortality raterate inin hospitalhospital 18,65018,650 deaths/yeardeaths/year vsvs AIDSAIDS 12,50012,500 Strep.Strep. PneumPneum.. UntreatableUntreatable (Pichichero, JAMA) Because of vaccine? Emergence of these non-PCV7 strains appears to have occurred as a consequence of replacement of PCV7 strains Avoiding the e-word Antonovics, PLOS Biology, 2007 2. Constructing Phylogenies LevelsLevels ofof selectionselection PleiotropyPleiotropy QuirksQuirks thatthat InteractInteract withwith environmentsenvironments VariationVariation Phylogenetic relationships of 21 pathogenic E Coli. Lacher, et al., in press PREDICTING the Evolution of INFLUENZA Bush, et al. 1999 Cancer Illustration from Merlo, 2006 3. Evolutionary Genetics LevelsLevels ofof selectionselection PleiotropyPleiotropy QuirksQuirks thatthat InteractInteract withwith environmentsenvironments VariationVariation Antagonistic Pleiotropy Blasco, 2005 Pleiotropy Telomere length Cawthon et al., Lancet, 2003 Crespi- Sig. Sel for Schiz genes ProcRoyalSoc 2007 Quirks NotNot diseasedisease genes,genes, justjust variationsvariations thatthat interactinteract withwith environmentsenvironments toto causecause diseasedisease MyopiaMyopia ApoApo EE 44 Genes for Type I Diabetes to protect against freezing in the ice-age ? As published in The New York Times! Myopia 4. Asking why the body isn’t better Gertrude Stein on Her Deathbed ““ TheThe answer,answer, thethe answer,answer, whatwhat isis thethe answer?answer? TheThe answer,answer, thethe answer,answer, whatwhat isis thethe answer?...answer?... No,No, nono thatthat’’ss notnot it.it. WhatWhat isis thethe question?question?”” Why has natural selection left the body so vulnerable? PartsParts ofof thethe bodybody OthersOthers areare botchedbotched areare exquisiteexquisite Why? The Old Answer: Natural selection is just too weak to make the body better. The New Answer ThereThere areare sixsix reasonsreasons whywhy naturalnatural selectionselection leavesleaves thethe bodybody vulnerablevulnerable toto diseasedisease Six Reasons Why Diseases Exist Selection is slow 1. Mismatch: body in a novel environment 2. Competition with fast evolving organisms Selection is constrained 3. Every trait is a trade-off 4. Constraints on natural selection We misunderstand 5. Organisms shaped for R/S, not health 6. Defenses and suffering 1. Mismatch BreastBreast CancerCancer MUCHMUCH moremore commoncommon nownow HormoneHormone exposureexposure 400+400+ cyclescycles now,now, aboutabout 110110 thenthen NightNight lightlight exposureexposure Atheroma Cholesterol levels ModernModern AmericanAmerican 200200 2020 prepre--industrialindustrial 131131 55 hunterhunter--gatherergatherer 123123 RuralRural ChineseChinese 127127 •• Eaton,Eaton, etet al.al. Myopia Figure 1 (A) Percentage of patients achieving remission or response at week 12 or 24 after initiating ova therapy. (B) Mean change in Crohn's disease activity index (CDAI, mean (SD)) for respondents to ova therapy. CDAI <150 is remission. p<0.0001, week 12 or week 24 compared with baseline (time 0). Summers, R W et al. Gut 2005;54:87-90 Copyright ©2005 BMJ Publishing Group Ltd. 2. Competition with other organisms MostlyMostly coveredcovered alredyalredy——FastFast SelectionSelection Eco-Evo approach to pathogens Pallen, Nature 2007 3. Every trait is a trade-off Gout MostMost genesgenes areare tradetrade--offsoffs Uric Acid Concentration/SMR vs. MLSP 0.3 0.25 0.2 0.15 0.1 0.05 0 Uric Acid/SMRUric (mg/100ml)/(cal/g/day) 0 102030405060708090100 -0.05 Years Why does the body make bilirubin? Why Bilirubin? Sedlak and Snyder, Pediatrics, 2004 More Bili Æ Fewer Heart Attacks Bili and Antioxidant in Neonates Hammerman et al., 1998 Why is there Aging? SomeSome genesgenes thatthat causecause ageingageing havehave nono selectiveselective costcost inin thethe wildwild OthersOthers offeroffer advantagesadvantages earlyearly inin lifelife whenwhen selectionselection isis strongerstronger Implication:Implication: DisruptingDisrupting agingaging associatedassociated genesgenes isis likelylikely toto causecause problemsproblems If mortality stayed at early adulthood rates throughout life 4. Constraints PathPath dependencedependence BlindBlind spotspot DangerousDangerous childbirthchildbirth pathwaypathway MutationsMutations HuntingtonHuntington’’ss diseasedisease MuscularMuscular dystrophydystrophy Path Dependence 5. Health is not selection’s goal The vulnerable sex SexSex mortalitymortality ratioratio %% malesmales whowho diedie inin aa yearyear ----------------divideddivided byby-------------- %% femalesfemales whowho diedie inin aa yearyear M.R.M.R. >> 1.01.0 meansmeans thatthat proportionatelyproportionately moremore malesmales thanthan femalesfemales areare dyingdying 2000 U.S. Mortality from All Causes and the Male:Female Mortality Ratio (M:F MR) All causes 10000 3 1000 2.5 100 2 M:FMR 10 1.5 Mortality Rate 100,000) (per 1 1 <1 1 -4 5 -9 14 10 - 19 15 - 24 20 - 29 25 - 34 30 - 39 35 - 44 40 - 49 45 - 54 50 - 59 55 - 64 60 - 69 65 - 74 70 - 79 75 - Male Age Female M:FMR 6 Australia Belguim Canada 5 Colombia El Salvador Finland 4 France Greece 3 Ireland Italy Japan M:F Mortality Ratio 2 Norway Poland Singapore 1 Russia Spain Sweden 0 Switzerland 75+ Ukraine 0 to 4 0 to 9 5 to 10 to 14 10 to 19 15 to 24 20 to 29 25 to 34 30 to 39 35 to 44 40 to 49 45 to 54 50 to 59 55 to 64 60 to 69 65 to 74 70 to USA Age Group USA 20th Century 3.16602 3.1 3 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2 1.9 1.8 1.7 1.6 1.5 1.4 1.3 1.2 1.1 Composition of Excess Male Life Years Lost by Cause Hypertension 0% Other Cardiovascular 23% Dis e as e Diabetes Mellitus 26% 1% Pneum onia & Influenza 1% Cerebrovascular Dis e as e 1% Congenital Abnormalities Non-Auto Accidents 2% 10% Liver Disease & Cirrhosis 3% Suicide Malignant Hom icide 9% Ne oplas m s Auto Accidents 7% 8% 9% Kruger and Nesse, 2006 M:F MR East Germany/M:F