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

On the Aims and

Methods of Ethology Niko Tinbergen, 1983 A Recent Flowering A Recent Flowering 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 10 - 14 15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 45 - 49 50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 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 MR West Germany Before and After Unification

1.15

1.1

1.05

1

0.95

0.9

0.85 1980-1984 1985-1989 1990-1994 1995-1999 6. Defenses and suffering

„„ DefectsDefects „„ DefensesDefenses

‹SeizuresSeizures ‹FeverFever

‹CancerCancer ‹CoughCough

‹ParalysisParalysis ‹PainPain

‹JaundiceJaundice ‹FatigueFatigue

‹InjuryInjury ‹AnxietyAnxiety Defenses and Suffering

„ WhyWhy areare defensesdefenses aversive?aversive? „ WhyWhy soso muchmuch unnecessaryunnecessary painpain andand suffering?suffering? IfIf thethe immediateimmediate andand directdirect purposepurpose ofof ourour lifelife isis notnot suffering,suffering, thenthen ourour existenceexistence isis thethe mostmost illill--adaptedadapted toto itsits purposepurpose inin thethe world.world. Schopenhauer,Schopenhauer, 18511851 Smoke Detector Principle Nesse, 2005

„ ExpressExpress responseresponse wheneverwhenever ‹ CR

„ FalseFalse alarmsalarms areare NormalNormal „ ThisThis isis whywhy wewe cancan blockblock pain,pain, coughcough andand nauseanausea safelysafely (Except(Except forfor 11 timetime outout ofof 1000!)1000!) „ Implication:Implication: ItIt shouldshould bebe safesafe toto blockblock muchmuch suffering,suffering, butbut wewe mustmust THINKTHINK 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 What Evolution Offers Public Health

„ EstablishedEstablished methodsmethods „ NewNew researchresearch methodsmethods „ NewNew researchresearch questionsquestions „ AA feelingfeeling forfor thethe organismorganism

‹ ThereThere isis nono normalnormal genomegenome

‹ TheThe bodybody isis notnot aa machinemachine The Body is NOT a Machine

„ NoNo designdesign „ NoNo blueprintsblueprints „ NoNo normalnormal genomegenome „ SelectionSelection leftleft thethe bodybody fullfull ofof maladaptationsmaladaptations asas wellwell asas adaptationsadaptations

So Many Missing Studies

„ WiseWise toto blockblock symptomssymptoms ofof influenza?influenza? „ VaccineVaccine influencesinfluences onon virulencevirulence „ RhinorrheaRhinorrhea aa defense,defense, oror forfor virus?virus? „ WisdomWisdom teeth,teeth, why?why? „ FastFast spermsperm →→ shortshort life?life? „ LightsLights forfor babies?babies? „ RisksRisks ofof centralcentral heating?heating? Next Steps for Evolution and Public Health

„ FastFast growthgrowth butbut disperseddispersed communitycommunity „ AA textbooktextbook andand aa journaljournal „ AA webweb resourceresource „ TrainingTraining programsprograms „ ResearchResearch FundingFunding New Resources in New Media

JustJust completed!completed!

A complete course 3838 talks with slides Mount on a server

Leading authorities Up to the minute

INTERESTING! http://EvolutionAndMedicine.org

Public Health

„ AA practicalpractical field,field, andand aa goodgood thingthing tootoo „ HowHow cancan wewe improveimprove healthhealth now?now?

„ ButBut littlelittle evolutionaryevolutionary basicbasic sciencescience

Bimodality Bias

„ EvaluationsEvaluations areare usuallyusually bimodalbimodal „ WeWe judgejudge thing,thing, people,people, andand groupsgroups asas GOODGOOD oror BADBAD „ ForFor evolutionaryevolutionary reasonsreasons thatthat gogo backback toto bacteriabacteria goinggoing towardstowards oror awayaway „ FIGHTFIGHT BimodalityBimodality Bias!Bias! „ DonDon’’tt judgejudge wholewhole fieldsfields „ AssessAssess oneone hypothesishypothesis atat aa timetime Signals of Recent Selection

„ PrevalentPrevalent mutationsmutations withwith highhigh linkagelinkage disequilibriumdisequilibrium

‹ ADHADH——KenKen KiddKidd

‹ LactaseLactase——inin herdersherders

‹ DRD4DRD4--7Rpt7Rpt----MoyzisMoyzis

‹ G6PD/G6PD/ CD4OLCD4OL——LanderLander--MalariaMalaria

‹ ApoApo E?E? ——SapolskySapolsky andand FinchFinch

‹ BDNF??BDNF??——Sen/NesseSen/Nesse DepressionDepression A Biological View of the Body

„ MedicineMedicine isis stillstill fleeingfleeing vitalismvitalism „ TheThe metaphormetaphor ofof bodybody asas machinemachine roserose withwith DescartesDescartes andand peakedpeaked withwith SchrSchröödingerdinger’’ss ““WhatWhat IsIs Life?Life?”” „ ButBut itit isis seriouslyseriously misleadingmisleading ‹ NoNo blueprint,blueprint, justjust genesgenes withwith variationvariation ‹ NotNot optimal,optimal, notnot oneone aspectaspect ‹ NotNot forfor health,health, butbut reproductionreproduction Politics

„ RightRight——CreationistsCreationists whowho fearfear evolutionevolution willwill undermineundermine moralitymorality „ LeftLeft——vividvivid memoriesmemories ofof eugenicseugenics andand fearsfears thatthat explanationsexplanations forfor badbad behaviorbehavior willwill bebe usedused toto justifyjustify itit Dangers and Opportunities

„ MediaMedia „ PoliticsPolitics „ MedicineMedicine „ FundingFunding agenciesagencies „ BimodalityBimodality biasbias Media

„ ControversyControversy „ CuresCures „ BizarreBizarre ideasideas makemake goodgood memesmemes „ Fast,Fast, New,New, NewsNews Now!Now! Dangers and Opportunities

„ EvolutionaryEvolutionary biologistsbiologists deeplydeeply involvedinvolved

‹ AlthoughAlthough warywary ofof appliedapplied sciencescience „ MedicalMedical researchersresearchers

‹ WhoWho lovelove thethe powerpower ofof evolutionaryevolutionary theorytheory „ DoctorsDoctors andand NursesNurses

‹ WhoWho valuevalue ““aa feelingfeeling forfor thethe organismorganism”” „ CuriousCurious peoplepeople everywhereeverywhere whowho wantwant toto understandunderstand whywhy diseasesdiseases existexist Main Points

„ EvolutionaryEvolutionary MedicineMedicine isis notnot oneone thingthing

‹ ItIt isis aa basicbasic sciencescience forfor medicinemedicine

‹ SuggestsSuggests newnew studies,studies, notnot newnew curescures

‹ ManyMany applications,applications, notnot justjust oneone „ ExamplesExamples fromfrom fourfour mainmain areasareas „ ItIt killskills thethe falsefalse analogyanalogy ofof bodybody asas machinemachine „ WeWe cancan helphelp itit growgrow upup healthyhealthy Outline

„ OriginsOrigins andand currentcurrent floweringflowering „ FourFour mainmain lineslines ofof workwork „ KillerKiller thethe analogyanalogy ofof bodybody asas machinemachine „ OpportunitiesOpportunities andand dangersdangers „ WhatWhat wewe cancan dodo toto fosterfoster hybridhybrid vigorvigor

The Long Eclipse

„ InIn FlexnerFlexner’’ss timetime (1910)(1910) evolutionevolution waswas dismisseddismissed „ TheThe SynthesisSynthesis broughtbrought usus poppop geneticsgenetics „ PreviousPrevious applicationsapplications mostlymostly fastfast evolutionevolution andand physiology/anatomyphysiology/anatomy „ NewNew studiesstudies ofof adaptationadaptation finallyfinally broughtbrought moremore evolutionevolution toto medicine.medicine. Disease and evolution

„ DiseaseDisease isis notnot shapedshaped byby naturalnatural selectionselection „ ButBut vulnerabilityvulnerability toto diseasedisease hashas been.been. „ NaturalNatural selectionselection cancan helphelp explainexplain maladaptationmaladaptation asas wellwell asas adaptationadaptation Two Complementary Explanations

1.1. ProximateProximate explanationsexplanations areare aboutabout howhow aa traittrait worksworks.. 2.2. EvolutionaryEvolutionary explanationsexplanations areare aboutabout howhow aa traittrait increasesincreases fitnessfitness.. Phyloproteonomics Abu-Asab, 2006 Levels of selection

„ HaigHaig

‹ ParentParent OffspringOffspring ConflictConflict

‹ ComplicationsComplications ofof pregnancypregnancy Modern environments and disease

„ SeeSee MismatchMismatch sectionsection belowbelow…… Constructive Engagement

„ UnderstandingUnderstanding aa proposalproposal inin depthdepth „ InhibitingInhibiting globalglobal approvalapproval oror criticismcriticism „ SayingSaying whatwhat isis rightright andand whatwhat isis wrongwrong inin detail,detail, withwith suggestionssuggestions forfor datadata thatthat wouldwould settlesettle thethe questionquestion „ ThisThis goesgoes againstagainst humanhuman nature!nature!

Fig. 1. Possible cross-species transmission events giving rise to SIVcpz as a recombinant of different monkey-derived SIVs

J. L. Heeney et al., Science 313, 462 -466 (2006)

Published by AAAS

Mean Negative Affect Scores vs. BDNF Genotype (Sen, Nesse, Weder, Burmeister’s 2004)

95

85

75

Mean Neuroticism +/- 1 SEM Mean Neuroticism p=0.0057 Negative Affect Score Negative Affect

65 N = 20 161 255 Met/Met Val/Met Val/Val N=20 N=161 N=255 BDNF Genotype „ Table 2. Human genes identified that influence HIV infection and disease. Gene products Allele(s) Effect Barriers to retroviral infection TRIM5 SPRY species specific Infection resistance, capsid specific ABOBEC3G Polymorphisms Infection resistance, hypermutation Influence on HIV-1 infection Coreceptor/ligand CCR5 32 homozygous Infection CCL2, CCL-7, CCL11 Infection (MCP1, MCP3, eotaxin), H7 Cytokine IL-10 5'A dominant Infection Influence on development of AIDS Coreceptor/ligand CCR5 32 heterozygous Disease progression CCR2 164 dominant Disease progression CCL5 (RANTES) ln1.1c dominant Disease progression CCL3L1 (MIP1 ) Copy number Disease progression DC- SIGN Promoter variant Parenteral infection Cytokine IL-10 5'A dominant Disease progression IFN- 179T dominant Disease progression Innate KIR3DS1 (with HLA-Bw4) 3DS1 epistatic Disease progression Adaptive HLA-A, HLA-B, HLA-C Homozygous Disease progression HLA- B*5802, HLA-B*18 Codominant Disease progression HLA-B*35-Px Codominant Disease progression HLA-B*27 Codominant Disease progression HLA-B*57, HLA-B*5801 Codominant Disease progression ABOBEC3G Polymorphisms Infection resistance, hypermutation

Influence on HIV-1 infection

Coreceptor/ligand

CCR5 32 homozygous Infection

CCL2, CCL-7, CCL11 Infection

(MCP1, MCP3, eotaxin), H7

Cytokine

IL-10 5'A dominant Infection

Influence on development of AIDS

Coreceptor/ligand

CCR5 32 heterozygous Disease progression

CCR2 164 dominant Disease progression

CCL5 (RANTES) ln1.1c dominant Disease progression

CCL3L1 (MIP1 ) Copy number Disease progression

DC-SIGN Promoter variant Parenteral infection

Cytokine

IL-10 5'A dominant Disease progression

IFN- 179T dominant Disease progression

Innate

KIR3DS1 (with HLA-Bw4) 3DS1 epistatic Disease progression

Adaptive

The Knowledge Gap Illustrated (From the 2003 Bennett award paper) Rats exposed to a cat for 10 minutes “Our results show that a single 10-min exposure to a predator significantly enhanced plasma corticosterone and ACTH concentrations in maladapted, behaviorally “symptomatic” animals, but not in well-adapted or control rats”

Darwinian Medicine Future www.EvolutionAndMedicine.org OlinOlin Hall,Hall, CarletonCarleton College,College, 19671967 Sophomore invertebrate biology Why is there aging?

„ HighlyHighly heritableheritable „ BigBig differencesdifferences inin lifelife--spanspan inin closelyclosely relatedrelated speciesspecies „ So,So, whywhy isnisn’’tt lifelife longer?longer?

‹ MaybeMaybe toto ensureensure aa turnoverturnover ofof individualsindividuals soso thethe speciesspecies cancan evolve?evolve? Not a theory but a principle

„ IFIF individualsindividuals varyvary onon aa traittrait thatthat influencesinfluences thethe numbernumber ofof offspringoffspring „ AndAnd thatthat variationvariation isis passedpassed onon „ THENTHEN thethe groupgroup willwill changechange overover timetime

„ ADAPTATIONADAPTATION:: IndividualsIndividuals getget betterbetter „ SPECIESSPECIES:: NewNew speciesspecies splitsplit offoff fromfrom oldold Breeding Natural Selection

Honeycreepers Two Kinds of Explanation

““NoNo biologicalbiological problemproblem isis solvedsolved untiluntil bothboth thethe proximateproximate andand thethe evolutionaryevolutionary causationcausation hashas beenbeen elucidated.elucidated. Furthermore,Furthermore, thethe studystudy ofof evolutionaryevolutionary causescauses isis asas legitimatelegitimate aa partpart ofof biologybiology asas isis thethe studystudy ofof thethe usuallyusually physicophysico-- chemicalchemical proximateproximate causes.causes.”” E.E. Mayr,Mayr, 19821982 TheThe GrowthGrowth ofof BiologicalBiological ThoughtThought Two Complementary Explanations

1.1. ProximateProximate explanationsexplanations areare aboutabout howhow aa traittrait worksworks.. 2.2. EvolutionaryEvolutionary explanationsexplanations areare aboutabout howhow aa traittrait increasesincreases fitnessfitness.. Disease and evolution

„ DiseaseDisease isis notnot shapedshaped byby naturalnatural selectionselection „ ButBut vulnerabilityvulnerability toto diseasedisease hashas been.been. „ NaturalNatural selectionselection cancan helphelp explainexplain maladaptationmaladaptation asas wellwell asas adaptationadaptation Darwinian Medicine

„ NotNot radicalradical inin anyany wayway „ NotNot opposedopposed toto allopathicallopathic medicinemedicine „ NotNot aa methodmethod ofof practicepractice „ JustJust aa basicbasic medicalmedical sciencescience whosewhose powerpower isis justjust beingbeing recognizedrecognized

Medical school

„ WhyWhy isis therethere aging?aging?

‹ ThingsThings wearwear out,out, obviously!obviously!

‹ And,And, naturalnatural selectionselection isnisn’’tt thatthat greatgreat

‹ StopStop askingasking questionsquestions andand memorizememorize more!more! Hanging out with evolutionary biologists

„ WhyWhy dodo organismsorganisms dodo whatwhat theythey do?do? „ WhyWhy isis therethere sexsex atat all?all? „ WhyWhy areare somesome speciesspecies social?social? „ FINEFINE QUESTIONS!!QUESTIONS!! I ask a biologist: “Why is there aging?”

ColleagueColleague BobbiBobbi LowLow ““WHAT!!!WHAT!!! replies:replies: YouYou havehave nevernever readread WilliamsWilliams 1957?!!!1957?!!!”” What about my lovely model?

““DonDon’’tt youyou eveneven knowknow thethe problemproblem withwith groupgroup selection?selection?”” Some General Principles

„ ImperfectionsImperfections cannotcannot bebe eliminatedeliminated becausebecause naturalnatural selectionselection isis tootoo weakweak andand randomrandom „ SelectionSelection shapesshapes traitstraits toto benefitbenefit thethe speciesspecies „ PathogensPathogens evolveevolve toto coco--existexist withwith hostshosts „ NaturalNatural selectionselection shapesshapes healthhealth andand longevitylongevity „ GeneticGenetic diseasedisease resultsresults fromfrom mutationsmutations thatthat naturalnatural selectionselection cancan’’tt eliminateeliminate „ AgingAging resultsresults becausebecause bodybody partsparts wearwear outout „ NaturalNatural selectionselection cannotcannot influenceinfluence anythinganything afterafter reproductionreproduction endsends Current Views

„ ImperfectionsImperfections areare presentpresent forfor 66 reasonsreasons „ NaturalNatural selectionselection shapesshapes traitstraits forfor genesgenes „ PathogensPathogens evolveevolve toto maximizemaximize replicationreplication „ NaturalNatural selectionselection shapesshapes thethe bodybody toto maximizemaximize reproductivereproductive successsuccess „ Common genetic disease results mainly from quirks interacting with novel environments „ Aging results because of pleiotropy „ Natural selection continues after reproduction Pain

„ EXPERIENCEEXPERIENCE meansmeans somethingsomething isis wrongwrong „ CAPACITYCAPACITY isis usefuluseful „ CongenitalCongenital absenceabsence VERYVERY rarerare

‹ 3535 inin USAUSA „ Why?Why? LackLack ofof painpain causescauses earlyearly deathdeath Fixed defenses

„ SkinSkin „ InnateInnate immuneimmune responsesresponses „ StomachStomach acidacid „ EarEar waxwax „ CellsCells shedshed steadilysteadily Inducible Defenses (Tollrian, Harvell, Clark, Dill, Lima, Pulliam, et al.)

„ LatentLatent traitstraits expressedexpressed onlyonly inin responseresponse toto aa cuecue associatedassociated withwith aa dangerdanger

‹ DevelopmentalDevelopmental changeschanges——size,size, shapeshape

‹ SustainedSustained——tanning,tanning, calluscallus formationformation

‹ TemporaryTemporary——PhysiologicalPhysiological defensesdefenses

‹ EmotionsEmotions——AdjustAdjust bodybody toto situationssituations withwith adaptiveadaptive challengeschallenges Daphnia Different morphology induced by exposure to chemical cues from predator

The Ecology and Evolution of Inducible Defenses by Ralph Tollrian Stress

„ TooToo muchmuch cortisolcortisol isis badbad „ TooToo littlelittle isis fatalfatal

‹ AddisonAddison’’ss diseasedisease If stress is so useful, why not express it all the time?

„ Many of us DO! However… „ It consumes energy „ It decreases ability to do other things „ It damages tissues!

‹ Why? Because it is precisely those changes that damage tissues that must be packaged away in an emergency kit, to be opened only when the costs are worth it. Fever

„ AA DefenseDefense thatthat fightsfights infectioninfection „ EvidenceEvidence ‹ BlockingBlocking feverfever cancan slowslow recoveryrecovery ‹ DoesDoes increasingincreasing feverfever help?help? "La FiËvre" by Matthew J. Kluger, La Recherche 12: 688-696, 1981. Diarrhea

„ ClearsClears pathogenspathogens andand toxinstoxins „ BlockingBlocking diarrheadiarrhea causescauses complicationscomplications inin ShigellosisShigellosis infectioninfection ––DupontDupont HL,HL, HornickHornick RB:RB: AdverseAdverse effecteffect ofof LomotilLomotil therapytherapy inin shigellosis.shigellosis. JAMAJAMA 1973;1973; 226:226: 15251525--15281528 Anxiety

„ ReallyReally usefuluseful toto escapeescape andand avoidavoid danger!danger! „ PeoplePeople complaincomplain aboutabout tootoo muchmuch anxietyanxiety „ WhatWhat aboutabout hypophobics?hypophobics? Fear of Heights at 18 vs. Severe Falls in Childhood Poulan, et al., 1998

14.00% 12.00% Fear of 10.00%

8.00% Heights

6.00%

4.00%

% with Mild or% Sev. Ht. Fear at 18 2.00%

0.00% Fall with severe injury (hypophobia?) n=60 No fall with severe injury (fearful?) n=789 The Clinical Illusion (that Defenses are Defects)

„ CliniciansClinicians areare proneprone toto thinkthink thatthat defensesdefenses areare thethe problemproblem because:because:

‹ DefensesDefenses areare expressedexpressed whenwhen therethere isis aa problemproblem

‹ TheyThey areare painfulpainful

‹ BlockingBlocking themthem isis oftenoften safesafe

Love joins hate; aggression, fear; expansiveness, withdrawal, and so on; in blends designed not to promote the happiness of the individual, but to favor the maximum transmission of the controlling genes. E. O. Wilson, 1975 PainPain oror sufferingsuffering ofof anyany kind,kind, ifif longlong continued,continued, causescauses depressiondepression andand lessenslessens thethe powerpower ofof action;action; yetyet itit isis wellwell adaptedadapted toto makemake aa creaturecreature guardguard itselfitself againstagainst anyany greatgreat oror suddensudden evil.evil.

CharlesCharles Darwin,Darwin, 1887,1887, pp.pp. 5151--5252 The First Noble Truth

„„LifeLife IsIs SufferingSuffering

The Mystery about Defenses

„ Natural selection should shape near- optimal defense regulation mechanisms „ But we are plagued by excess anxiety, pain and sadness, & other defenses „ And we know, from general medicine, that they often can be blocked safely „ Why are defenses expressed excessively? How Should Defense Regulation Have Been Shaped by Natural Selection?

„ MonitorMonitor cuescues associatedassociated withwith dangerdanger „ IfIf thethe costcost ofof thethe defensedefense << harmharm reduction,reduction, expressexpress defense.defense. „ ExpressExpress allall--oror--nonenone defensedefense iff:iff:

C(D)C(D) << C(HC(HNoDNoD)) -- C(HC(HwDwD)) What if the Cue is Unreliable?

„ SignalSignal detectiondetection analysisanalysis needed:needed:

‹ CostCost ofof falsefalse alarmalarm

‹ CostCost ofof missedmissed alarmalarm

‹ CostCost ofof HarmHarm ifif DefenseDefense (correct(correct response)response)

‹ ProbabilityProbability thatthat HarmHarm isis presentpresent (S/N(S/N ratio)ratio)

„ ExpressExpress defensedefense wheneverwhenever

C(D)C(D) << pHpH ((((C(HC(HNoDNoD)) -- C(HC(HwDwD)))) At what p(Harm) is Defense Expression100% Worthwhile? 90%

80%

70%

60% 50% 2:12:1

40%

30% Worthwhile 5:15:1 20% 20:120:1 10% P Harm at which Defense Expression is Expression Defense at which Harm P 0% 1 5 9 131721252933 Ratio of Cost of Harm to Cost of Defense Should you flee from a noise?

„ IsIs itit aa monkey?monkey?…… oror aa tiger?!!tiger?!! „ CostCost ofof fleeing=fleeing= 200200 caloriescalories „ CostCost ofof notnot fleeingfleeing ifif aa tiger=tiger= 200,000200,000 caloriescalories „ RatioRatio isis 1000:11000:1 „ Optimum:Optimum: FleeFlee wheneverwhenever pp (tiger)(tiger) >> 1/10001/1000

999999 /1000/1000 panicpanic attacksattacks willwill bebe unnecessary,unnecessary, butbut perfectlyperfectly normalnormal

““FewFew failuresfailures areare asas unforgivingunforgiving asas failurefailure toto avoidavoid aa predator.predator. BeingBeing killedkilled greatlygreatly decreasesdecreases futurefuture fitnessfitness”” LimaLima andand Dill,Dill, 1989,1989, p.p. 619619 Signal Detection Theory Green and Swets, 1966

Signal: Signal: PresentPresent Absent

Decision: HitHit FalseFalse AlarmAlarm RespondRespond (Correct (False Positive, detection) Type I error) Decision: MissedMissed RespResp.. CorrectCorrect Do not Respond (False negative, RejectionRejection Type II error) Signal comes from real danger

Signal comes from noise

Signal Detection Theory: To get high detection you have to accept many false alarms

1.0 …… d′=2 …… d′=1 … d′=0 HitsHits … …… .0.5 …… …… …… … …… ….0 0------False Alarms-----→1.0 Optimal Response Threshold p(x|s) p(n) v(rej.) + v(f.a.) p(x|n) p(s) v(hit) + v(miss)

If the Defense is Graded?

„ OptimalOptimal DefenseDefense dependsdepends onon howhow HarmHarm declinesdeclines withwith increasingincreasing DefenseDefense „ FindFind pointpoint ofof minimalminimal costcost 5 At cost minimum C(D) = C(H) 4

3 C(H) C(D) 2 C(Tot)

1

0 12141 CD= LD0.05, CH= 1/(LD+0.1). 5

4

3 C(H) At optimum, C(D) C(D) 2 C(Tot) is greater than C(H) 1

0 12141 B) CD =1+LD0.05, CH=1/(LD+0.1 Regulation of Defenses: The Perils of Positive Feedback

„ When danger is likely, threshold should decrease, expressing the defense more readily „ Positive feedback system, prone to runaway escalation. Panic and Agoraphobia

„ Panic is a false alarm fight-flight response „ The experience of panic seems to down-regulate the panic threshold „ Any hint of danger releases a panic response „ When you have recently been the object of a predator attack, agoraphobia is useful indeed! Immune responses

„ OneOne exposureexposure inducesinduces anan responseresponse „ SecondSecond exposureexposure arousesarouses fasterfaster strongerstronger responseresponse „ PathologicalPathological extreme:extreme: AnaphylaxisAnaphylaxis Nausea and Vomiting

„ OneOne exposureexposure toto novelnovel taste/odortaste/odor andand toxintoxin conditionsconditions nauseanausea „ SDPSDP explainsexplains generalizationgeneralization toto relatedrelated odorsodors „ RepeatedRepeated exposureexposure increasesincreases sensitivitysensitivity „ Example:Example: ConditionedConditioned nauseanausea andand vomitingvomiting inin chemotherapychemotherapy Depression

„ FirstFirst episodeepisode 80%80% precipitatedprecipitated byby lifelife eventevent „ ByBy thethe fourthfourth episode,episode, precipitantsprecipitants areare nono moremore commoncommon inin depressivesdepressives thanthan controlscontrols „ KindlingKindling isis aa neurologicalneurological metaphormetaphor „ ButBut thisthis maymay representrepresent positivepositive feedback,feedback, withwith decreaseddecreased motivationmotivation arisingarising everever moremore quicklyquickly inin responseresponse toto unpropitiousunpropitious situationssituations Implications

„ AA theoreticaltheoretical foundationfoundation forfor generalgeneral medicinemedicine

‹ ButBut mostmost ofof thethe researchresearch hashas yetyet toto bebe donedone „ EssentialEssential foundationfoundation forfor pharmacologypharmacology

‹ PharmacologicalPharmacological utopiautopia possible?possible? Pharmacological Utopia?

„ Most Suffering is normal but unnecessary ‹ Many false alarms ‹ Repeated arousal changes threshold ‹ Modern environment relatively safe „ So we should be able to safely block most defenses and suffering „ Except for the one time in a hundred, when the defense will essential! Medicine uses some evolution

„ AntibioticAntibiotic resistanceresistance „ EvolutionaryEvolutionary geneticsgenetics „ HumanHuman phylogenyphylogeny But much is missing

„ CoCo--evolutionevolution andand armsarms racesraces „ SubtleSubtle evolutionaryevolutionary geneticsgenetics „ EvolutionEvolution andand behaviorbehavior „ EvolutionEvolution andand developmentdevelopment „ AskingAsking whywhy naturalnatural selectionselection hashas leftleft thethe bodybody soso vulnerablevulnerable Percent of schools that include topic in medical curriculum (n=55) Nesse & Schiffman, 2000

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

s ic . f s y c e s s r. omy ion nt tion -of i lu e ogen st o d di ev ra e body-envi ive anat at ic resistanc ation sel. bal an phyl isease tgenes at Kin selectionm ot d of ign t i h um ibi Mu par fense regulatLife history trait ult or Des e Path dependenceH nt irulence f e V Populationl. genet Levels of selection D at A Com Se Host-patho. arms race m Mismatc oxi Pr The Future “What actions would bring the full power of evolutionary biology to bear on human disease?

1. Include questions about evolution in medical licensing examinations

2. Ensure evolutionary expertise in agencies that fund biomedical research.

3. Incorporate evolution into every relevant high school, undergraduate, and graduate course.

Nesse, Omenn, Stearns, Science, 2006

..

You could design a better body in one afternoon!

„ EliminateEliminate thethe appendixappendix „ TakeTake outout thethe wisdomwisdom teethteeth „ TurnTurn thethe eyeeye insideinside outout „ MakeMake bonesbones strongerstronger „ ImproveImprove immuneimmune responsesresponses „ MakeMake bloodblood clotclot aa bitbit moremore slowlyslowly „ InstallInstall aa zipperzipper soso babiesbabies cancan exitexit moremore easily!easily! An Example—The Eye

→An organ of extreme perfection? →Or, a design so poor that no one would want credit? First half of medical school: An organ of perfection

1. Upper eyelid 2. Lower eyelid 3. Lateral angle 4. Medial angle 5. Lacrimal caruncle 6. Limbus 7. Iris 8. Pupil 9. Lacrimal papilla 10 Sclera In the Clinic: A botched design

••GlaucomaGlaucoma ••CataractsCataracts ••MyopiaMyopia ••PresbyopiaPresbyopia ••IritisIritis ••CornealCorneal cloudingclouding ••RetinalRetinal detachmentdetachment

1. Mismatch

„ OurOur bodiesbodies werewere nevernever designeddesigned toto copecope withwith thisthis novelnovel environmentenvironment „ SelectionSelection isis slowslow „ TheThe mismatchmismatch explainsexplains mostmost chronicchronic diseasedisease „ OurOur fulfilledfulfilled desiresdesires areare killingkilling usus 5. Health is not selection’s goal Selection maximizes reproductive success, NOT health, longevity, & happiness

„ AgeingAgeing „ TheThe feeblefeeble sexsex “The human mind treats a new idea the way the body treats a strange protein; it rejects it.” Peter Medawar

Origins of Control Theory

„ ErwinErwin ShrShröödingerdinger’’ss classicclassic ““WhatWhat isis Life?Life?”” howhow organismsorganisms avoidavoid entropyentropy byby usingusing energyenergy toto createcreate andand maintainmaintain orderorder 1944)1944) „ WeinerWeiner expandedexpanded thethe basicbasic principleprinciple ofof feedbackfeedback controlcontrol intointo cyberneticscybernetics (1948)(1948) „ ShannonShannon andand WeaverWeaver codifiedcodified informationinformation theorytheory (1949).(1949). „ GrandGrand synthesessyntheses——GeneralGeneral systemssystems theorytheory ((BertalanffyBertalanffy,, 1969)1969) andand biologybiology (Miller,(Miller, 1978).1978). „ PerceptualPerceptual controlcontrol theorytheory (Powers,(Powers, 1973).1973). „ ComputerComputer modelingmodeling (Holland,(Holland, 1992).1992).

Fragmented knowledge

„ AA toptop flightflight medicalmedical educationeducation ignoresignores corecore evolutionaryevolutionary principlesprinciples

‹ GroupGroup selectionselection

‹ KinKin selectionselection

‹ CoCo--evolutionevolution

‹ TradeTrade--offsoffs

‹ LifeLife historyhistory theorytheory

‹ ProximateProximate vs.vs. evolutionaryevolutionary explanationsexplanations

Evolutionary Q. about disease

„ WhyWhy hashas naturalnatural selectionselection leftleft usus vulnerablevulnerable toto disease?disease?

„ NotNot justjust whywhy somesome peoplepeople getget sick,sick, butbut whywhy naturalnatural selectionselection hashas leftleft usus allall withwith bodiesbodies thatthat areare vulnerablevulnerable toto diseasedisease

„ SixSix possiblepossible reasonsreasons 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 shapedNesse, for QRB, R/S, March not 2005 health 6Df d ffi Genetic “Quirks”

„ HarmlessHarmless inin aa naturalnatural environmentenvironment „ CauseCause diseasedisease inin novelnovel environment.environment.

‹ AtherosclerosisAtherosclerosis

‹ MyopiaMyopia

‹ DrugDrug abuseabuse Hygiene Hypothesis

„ LackLack ofof exposureexposure toto pathogenspathogens deprivesdeprives immuneimmune systemsystem ofof inhibitoryinhibitory componentscomponents „ RapidlyRapidly increasingincreasing immuneimmune diseasesdiseases (Rook)(Rook)

‹ TypeType II diabetesdiabetes

‹ CrohnCrohn’’ss diseasedisease

‹ AsthmaAsthma „ AcuteAcute lymphoblasticlymphoblastic leukaemialeukaemia (Greaves)(Greaves) Streptococcal infection

„ StrepStrep antigensantigens mimicmimic ourour proteinsproteins „ RheumaticRheumatic fever,fever, scarletscarlet fever,fever, OCDOCD

Malaria in melanesia 4. Constraints

„ PathPath dependencedependence

‹ JustJust likelike ourour computercomputer keyboardskeyboards „ HappenstanceHappenstance

‹ MutationsMutations Terrestrial Whales I = (IRYh - IRYa) / IRYh

Defenses & suffering in AA today! Shivering-Unpleasant but useful How much shivering is best? JustJust right?right?

TooToo littlelittle TooToo muchmuch

Selection is everywhere

„ Whenever variation influences prevalence

‹ Coins in a jar

‹ Programs on TV

‹ Products in the grocery store

‹ What politicians say „ Genes in organisms? Special kind:

‹ NATURAL selection 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 morgani praedicta Angraecum sesquipedale The Star Orchid of Madagascar Awe at the body’s perfection

„ TheThe eyeeye „ TheThe heartheart „ TheThe nephronnephron „ RegulationRegulation ofof clottingclotting Horror at the body’s flaws: You could do better in one afternoon!

„ EliminateEliminate thethe appendixappendix „ TakeTake outout thethe wisdomwisdom teethteeth „ TurnTurn thethe eyeeye insideinside outout „ MakeMake bonesbones strongerstronger „ ImproveImprove immuneimmune responsesresponses „ MakeMake bloodblood clotclot aa bitbit moremore slowlyslowly „ LetLet thethe heartheart getget bloodblood fromfrom itsits chamberschambers „ InstallInstall aa zipperzipper soso babiesbabies cancan exitexit easily!easily! Why has natural selection left the body so vulnerable?

PartsParts ofof thethe bodybody OthersOthers areare botchedbotched areare exquisiteexquisite Why?

Depression is simple

„ LifeLife situationsituation „ HowHow youyou thinkthink aboutabout thethe situationsituation „ HowHow thethe brainbrain isis workingworking

Disease and evolution

„ DiseaseDisease isis notnot shapedshaped byby naturalnatural selectionselection „ ButBut vulnerabilityvulnerability toto diseasedisease hashas been.been. „ NaturalNatural selectionselection cancan helphelp explainexplain maladaptationmaladaptation asas wellwell asas adaptationadaptation New Questions About Disease

„ NotNot whywhy oneone personperson getsgets sicksick „ ButBut whywhy wewe allall shareshare vulnerabilitiesvulnerabilities „ WhyWhy didndidn’’tt naturalnatural selectionselection dodo better?better?

‹ JustJust becausebecause itit isis tootoo weak?weak? „ Yes,Yes, butbut alsoalso fivefive otherother kindskinds ofof explanationsexplanations DEFENSE REGULATION

„ Pain,Pain, fever,fever, cough,cough, nausea,nausea, anxiety,anxiety, etc.etc. oftenoften seemsseems excessiveexcessive „ WeWe cancan usuallyusually blockblock themthem safelysafely „ DidDid selectionselection makemake aa mistake?mistake? BP, Genes, Latitude and Environmental change Young, et al., PLOS 2006 Two Kinds of Explanation Needed

““NoNo biologicalbiological problemproblem isis solvedsolved untiluntil bothboth thethe proximateproximate andand thethe evolutionaryevolutionary causationcausation hashas beenbeen elucidated.elucidated. Furthermore,Furthermore, thethe studystudy ofof evolutionaryevolutionary causescauses isis asas legitimatelegitimate aa partpart ofof biologybiology asas isis thethe studystudy ofof thethe usuallyusually physicophysico-- chemicalchemical proximateproximate causes.causes.”” E.E. Mayr,Mayr, 19821982 TheThe GrowthGrowth ofof BiologicalBiological ThoughtThought Tinbergen’s 4 Questions Organized

Proximate Evolutionary

Transition over time Ontogeny Phylogeny

Cross Selective section Mechanism Advantage

New Question