Darwinian MedicineBasic theory with Practical

Uses for Public Health

150 Years after The Origin

Evolution just now being Evolution just now being applied in many areas of applied in many areas of medicinemedicineA historical transition in A historical transition in how we understand how we understand diseasedisease

On the Aims and Methods of EthologyNiko Tinbergen, 1983

A Recent FloweringA Recent Flowering

Recent and Upcoming Meetings

Humboldt University, BerlinHumboldt University, BerlinYork Hull Medical SchoolYork Hull Medical SchoolUniversity of CopenhagenUniversity of CopenhagenNESCENT meeting at DukeNESCENT meeting at DukeAmerican Institute for Biological SciencesAmerican Institute for Biological SciencesAmerican Physiological SocietyAmerican Physiological SocietyUniversity of Arizona University of Arizona Wissenschaftskolleg zu BerlinWissenschaftskolleg zu BerlinAmerican Clinical Epidemiology SocietyAmerican Clinical Epidemiology SocietyNational Academy Sackler SymposiumNational 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, 1794Darwin, 1794

Erasmus DarwinErasmus DarwinOpening paragraph ofOpening paragraph of ZoonomiaZoonomia,,

E Conchis Omnia (Everything From Shells! )Erasmus Darwin 1731-1802

Origins of evolution in medicine

Erasmus DarwinErasmus Darwin——PhysicianPhysicianRobert DarwinRobert Darwin——PhysicianPhysicianCharles DarwinCharles Darwin——Medical school dropoutMedical school dropout

Because he hated geology!Because he hated geology!

What is Darwinian Medicine?

Darwinian (Evolutionary) Medicine

The enterprise of using the basic The enterprise of using the basic science of evolutionary biology in the science of evolutionary biology in the services of medicine and public health services of medicine and public health

Darwinian Medicine—NOT!Not radical in any wayNot radical in any wayNot about improving the speciesNot about improving the speciesNot opposed to ordinary medicineNot opposed to ordinary medicineNot a method of practiceNot a method of practiceNot a source of quick curesNot a source of quick curesNot just about modern diseases Not just about modern diseases Not just about the value of defensesNot just about the value of defenses

Evolution is a basic medical science Evolution is a basic medical science with many untapped applicationswith many untapped applications

Don’t Doctors Know Evolution?

No, not even the basicsNo, not even the basics

Evolutionary Biology Faculty in Medical Schools

9876543210

30

20

10

0

Std. Dev = 1.76

Mean = 1

N = 33.00

Selection is everywhereExplanations based on history

Your penny jarYour penny jarWhat grocers stockWhat grocers stockWhat is on TVWhat is on TVWho becomes an academicWho becomes an academicWho is here today!Who is here 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 orchidsare fertilised by insects. London, John Murray, 1862.

Angraecum sesquipedale The Star Orchid of Madagascar

Why would an orchid have

A spur 30 cm. long?

Xanthopan morganii praedicta

Four lines of work1.1. Infection and fast evolution Infection and fast evolution

Still being developed Still being developed

2.2. Constructing phylogeniesConstructing phylogeniesEstablished, new applicationsEstablished, new applications

3.3. Evolutionary geneticsEvolutionary geneticsSome old, much that is newSome old, much that is new

4. Why selection left our bodies vulnerableNew questions just being asked

1. Studies of Fast Evolution

Pathogen evolutionPathogen evolutionImmune system Immune system Cancer clonesCancer clones

Last Week’s JAMA—Fatal Threats MRSA MRSA ((KlevansKlevans, et al., JAMA), et al., JAMA)

9% resistant9% resistant10% mortality rate in hospital10% mortality rate in hospital18,650 deaths/year 18,650 deaths/year vsvs AIDS 12,500AIDS 12,500

Strep. Strep. PneumPneum. Untreatable . Untreatable ((PichicheroPichichero, JAMA), JAMA)Because of vaccine?Because of vaccine?Emergence of these nonEmergence of these non--PCV7 strains appears to have occurred PCV7 strains appears to have occurred as a consequence of as a consequence of replacement replacement of PCV7 strains of PCV7 strains

Avoiding the e-wordAntonovics, PLOS Biology, 2007

2. Constructing Phylogenies

Levels of selectionLevels of selectionPleiotropyPleiotropyQuirks that Interact with environmentsQuirks that Interact with environmentsVariation Variation

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

Levels of selectionLevels of selectionPleiotropyPleiotropyQuirks that Interact with environmentsQuirks that Interact with environmentsVariation Variation

Antagonistic Pleiotropy Blasco, 2005

Pleiotropy Telomere length Cawthon et al., Lancet, 2003

Crespi- Sig. Sel for Schiz genes ProcRoyalSoc 2007

Quirks

Not disease genes, just variations that Not disease genes, just variations that interact with environments to cause interact with environments to cause diseasediseaseMyopiaMyopiaApo E 4Apo E 4

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

““ The answer, the answer, what is the The answer, the answer, what is the answer? The answer, the answer, what answer? The answer, the answer, what is the answer?...is the answer?...

No, no thatNo, no that’’s not it. s not it.

What is the question?What is the question?””

Why has natural selection left the body so vulnerable?

Parts of the body Parts of the body are exquisiteare exquisite

Others are botched Others are botched

Why?

The Old Answer: Natural selection is just too weak to make the body better.

The New Answer

There are There are six reasonssix reasons why natural why natural selection leaves the body selection leaves the body vulnerable to diseasevulnerable to disease

Six Reasons Why Diseases Exist

Selection is slow1. Mismatch: body in a novel environment 2. Competition with fast evolving organisms

Selection is constrained3. Every trait is a trade-off4. Constraints on natural selection

We misunderstand5. Organisms shaped for R/S, not health6. Defenses and suffering

Breast Cancer Breast Cancer MUCH more common nowMUCH more common nowHormone exposureHormone exposure

400+ cycles now, about 110 then400+ cycles now, about 110 thenNight light exposureNight light exposure

1. Mismatch

Atheroma

Cholesterol levels

Modern American 200Modern American 20020 pre20 pre--industrial 131industrial 1315 hunter5 hunter--gatherer 123gatherer 123Rural Chinese 127Rural Chinese 127

•• Eaton, et al. Eaton, et al.

Myopia

Copyright ©2005 BMJ Publishing Group Ltd.

Summers, R W et al. Gut 2005;54:87-90

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).

2. Competition with other organisms

Mostly covered Mostly covered alredyalredy——Fast SelectionFast Selection

Eco-Evoapproach to pathogensPallen, Nature 2007

Gout Uric Acid Concentration/SMR vs. MLSP

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0 10 20 30 40 50 60 70 80 90 100

Years

Uri

c A

cid/

SMR

(mg/

100m

l)/(c

al/g

/day

)3. Every trait is a trade-off

Most genes are tradeMost genes are trade--offsoffs

Why does the body make bilirubin?

Why Bilirubin?Sedlak and Snyder, Pediatrics, 2004

More Bili Fewer Heart Attacks

Bili and Antioxidant in NeonatesHammerman et al., 1998

Why is there Aging?

Some genes that cause ageing have no Some genes that cause ageing have no selective cost in the wildselective cost in the wildOthers offer advantages early in life Others offer advantages early in life when selection is strongerwhen selection is stronger

Implication: Disrupting aging associated Implication: Disrupting aging associated genes is likely to cause problemsgenes is likely to cause problems

If mortality stayed at early adulthood rates throughout life

4. Constraints

Path dependencePath dependenceBlind spotBlind spotDangerous childbirth pathwayDangerous childbirth pathway

MutationsMutationsHuntingtonHuntington’’s diseases diseaseMuscular dystrophyMuscular dystrophy

Path Dependence

The vulnerable sex

Sex mortality ratioSex mortality ratio% males who die in a year% males who die in a year

----------------divided bydivided by--------------% females who die in a year% females who die in a year

M.R. > 1.0 means that proportionately M.R. > 1.0 means that proportionately more males than females are dying more males than females are dying

5. Health is not selection’s goal

2000 U.S. Mortality from All Causes and theMale:Female Mortality Ratio (M:F MR)

All causes

1

10

100

1000

10000

< 11 - 45 - 910 - 1415 - 1920 - 2425 - 2930 - 3435 - 3940 - 4445 - 4950 - 5455 - 5960 - 6465 - 6970 - 7475 - 79

Age

Mor

talit

y R

ate

(per

100

,000

)

1

1.5

2

2.5

3

M:F

MR

MaleFemaleM:FMR

0

1

2

3

4

5

6

0 to

4

5 to

9

10 to

14

15 to

19

20 to

24

25 to

29

30 to

34

35 to

39

40 to

44

45 to

49

50 to

54

55 to

59

60 to

64

65 to

69

70 to

74

75+

Age Group

M:F

Mor

talit

y R

atio

Australia

Belguim

Canada

Colombia

El Salvador

Finland

France

Greece

Ireland

Italy

Japan

Norway

Poland

Singapore

Russia

Spain

Sweden

Switzerland

Ukraine

USA

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

Cardiovascular Disease

26%

Non-Auto Accidents10%

Suicide9%

Auto Accidents9%

Malignant Neoplasms

8%

Other23%

Homicide7%

Cerebrovascular Disease

1%

Liver Disease & Cirrhosis

3%

Congenital Abnormalities

2%

Pneumonia & Influenza

1%

Diabetes Mellitus1%

Hypertension0%

Kruger and Nesse, 2006

M:F MR East Germany/M:F MR West GermanyBefore and After Unification

0.85

0.9

0.95

1

1.05

1.1

1.15

1980-1984 1985-1989 1990-1994 1995-1999

DefectsDefectsSeizuresSeizuresCancerCancerParalysisParalysisJaundiceJaundiceInjuryInjury

DefensesDefensesFeverFeverCoughCoughPainPainFatigueFatigueAnxietyAnxiety

6. Defenses and suffering

Defenses and Suffering

Why are defenses Why are defenses aversive?aversive?Why so much Why so much unnecessary pain and unnecessary pain and suffering?suffering?

If the immediate and direct purpose of If the immediate and direct purpose of our life is not suffering, then our our life is not suffering, then our existence is the most illexistence is the most ill--adapted to its adapted to its purpose in the world.purpose in the world.

Schopenhauer, 1851Schopenhauer, 1851

Smoke Detector Principle Nesse, 2005

Express response whenever Express response whenever CR< CH * CR< CH * p(Hp(H))

Many false alarms expected from the Many false alarms expected from the normal systemnormal system

The Smoke Detector PrincipleFalse alarms are NormalFalse alarms are NormalThis is why we can block pain, cough This is why we can block pain, cough and nausea safelyand nausea safely(Except for 1 time out of 1000!)(Except for 1 time out of 1000!)

Implication: It should be safe to block Implication: It should be safe to block much suffering, but we must THINKmuch suffering, but we must THINK

Six Reasons Why Diseases Exist

Selection is slow1. Mismatch: body in a novel environment 2. Competition with fast evolving organisms

Selection is constrained3. Every trait is a trade-off4. Constraints on natural selection

We misunderstand5. Organisms shaped for R/S, not health6. Defenses and suffering

What Evolution Offers Public Health

Established methodsEstablished methodsNew research methodsNew research methodsNew research questionsNew research questionsA feeling for the organismA feeling for the organism

There is no normal genomeThere is no normal genomeThe body is not a machineThe body is not a machine

The Body is NOT a Machine

No designNo designNo blueprintsNo blueprintsNo normal genomeNo normal genomeSelection left the body Selection left the body full of maladaptations full of maladaptations as well as adaptationsas well as adaptations

So Many Missing Studies

Wise to block symptoms of influenza?Wise to block symptoms of influenza?Vaccine influences on virulenceVaccine influences on virulenceRhinorrhea a defense, or for virus?Rhinorrhea a defense, or for virus?Wisdom teeth, why?Wisdom teeth, why?Fast sperm Fast sperm →→ short life?short life?Lights for babies?Lights for babies?Risks of central heating?Risks of central heating?

Next Steps for Evolution and Public Health

Fast growth but dispersed communityFast growth but dispersed communityA textbook and a journalA textbook and a journalA web resourceA web resourceTraining programsTraining programsResearch FundingResearch Funding

New Resources in New Media

Just completed!Just completed!

A complete course3838 talks with slidesMount on a server

Leading authoritiesUp to the minute

INTERESTING!

http://EvolutionAndMedicine.org

Public Health

A practical field, and a good thing tooA practical field, and a good thing tooHow can we improve health now?How can we improve health now?

But little evolutionary basic scienceBut little evolutionary basic science

Bimodality Bias

Evaluations are usually bimodalEvaluations are usually bimodalWe judge thing, people, and groups as We judge thing, people, and groups as GOOD or BADGOOD or BADFor evolutionary reasons that go back to For evolutionary reasons that go back to bacteria going towards or awaybacteria going towards or awayFIGHT Bimodality Bias!FIGHT Bimodality Bias!DonDon’’t judge whole fields t judge whole fields Assess one hypothesis Assess one hypothesis at a time at a time

Signals of Recent Selection

Prevalent mutations with high linkage Prevalent mutations with high linkage disequilibriumdisequilibrium

ADHADH——Ken KiddKen KiddLactaseLactase——in herdersin herdersDRD4DRD4--7Rpt7Rpt----MoyzisMoyzisG6PD/ CD4OLG6PD/ CD4OL——LanderLander--MalariaMalariaApo E? Apo E? ——Sapolsky and Finch Sapolsky and Finch BDNF??BDNF??——Sen/Nesse DepressionSen/Nesse Depression

A Biological View of the Body

Medicine is still fleeing vitalismMedicine is still fleeing vitalismThe metaphor of body as machine rose The metaphor of body as machine rose with Descartes and peaked with with Descartes and peaked with SchrSchröödingerdinger’’s s ““What Is Life?What Is Life?””But it is seriously misleadingBut it is seriously misleading

No blueprint, just genes with variationNo blueprint, just genes with variationNot optimal, not one aspectNot optimal, not one aspectNot for health, but reproductionNot for health, but reproduction

Politics

RightRight——Creationists who fear evolution Creationists who fear evolution will undermine morality will undermine morality LeftLeft——vivid memories of eugenics and vivid memories of eugenics and fears that explanations for bad behavior fears that explanations for bad behavior will be used to justify it will be used to justify it

Dangers and Opportunities

MediaMediaPoliticsPoliticsMedicineMedicineFunding agenciesFunding agenciesBimodality biasBimodality bias

Media

ControversyControversyCuresCuresBizarre ideas make good memesBizarre ideas make good memesFast, New, News Now!Fast, New, News Now!

Dangers and OpportunitiesEvolutionary biologists deeply involvedEvolutionary biologists deeply involved

Although wary of applied scienceAlthough wary of applied scienceMedical researchersMedical researchers

Who love the power of evolutionary theoryWho love the power of evolutionary theoryDoctors and NursesDoctors and Nurses

Who value Who value ““a feeling for the organisma feeling for the organism””Curious people everywhere who want to Curious people everywhere who want to understand why diseases existunderstand why diseases exist

Main Points

Evolutionary Medicine is not one thingEvolutionary Medicine is not one thingIt is a basic science for medicineIt is a basic science for medicineSuggests new studies, not new curesSuggests new studies, not new curesMany applications, not just oneMany applications, not just one

Examples from four main areasExamples from four main areasIt kills the false analogy of body as machine It kills the false analogy of body as machine We can help it grow up healthyWe can help it grow up healthy

Outline

Origins and current floweringOrigins and current floweringFour main lines of workFour main lines of workKiller the analogy of body as machineKiller the analogy of body as machineOpportunities and dangersOpportunities and dangersWhat we can do to foster hybrid vigorWhat we can do to foster hybrid vigor

The Long Eclipse

In FlexnerIn Flexner’’s time (1910) s time (1910) evolution was dismissedevolution was dismissedThe Synthesis brought us pop geneticsThe Synthesis brought us pop geneticsPrevious applications mostly fast Previous applications mostly fast evolution and physiology/anatomyevolution and physiology/anatomyNew studies of adaptation finally New studies of adaptation finally brought more evolution to medicine. brought more evolution to medicine.

Disease and evolutionDisease is Disease is notnot shaped by natural shaped by natural selectionselectionBut But vulnerabilityvulnerability to disease has been.to disease has been.Natural selection can help explain Natural selection can help explain maladaptation as well as adaptationmaladaptation as well as adaptation

Two Complementary Explanations

1.1. ProximateProximate explanations are about explanations are about how a trait workshow a trait works..

2.2. EvolutionaryEvolutionary explanations are about explanations are about how a trait increases fitnesshow a trait increases fitness..

Phyloproteonomics Abu-Asab, 2006

Levels of selection

Haig Haig Parent Offspring ConflictParent Offspring ConflictComplications of pregnancyComplications of pregnancy

Modern environments and disease

See Mismatch section belowSee Mismatch section below……

Constructive Engagement

Understanding a proposal in depthUnderstanding a proposal in depthInhibiting global approval or criticismInhibiting global approval or criticismSaying what is right and what is wrong Saying what is right and what is wrong in detail, with suggestions for data that in detail, with suggestions for data that would settle the question would settle the question This goes against human nature! This goes against human nature!

Published by AAAS

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

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

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

25516120N =

BDNF Genotype

Val/ValVal/MetMet/Met

Mea

n N

euro

ticis

m +

/- 1

SE

M

95

85

75

65

N=20 N=161 N=255

p=0.0057

Neg

ativ

e A

ffec

t Sco

re

Table 2.Table 2. Human genes identified that influence HIV infection and diseaseHuman genes identified that influence HIV infection and disease. . Gene Gene productsproducts Allele(sAllele(s)) EffectEffect Barriers to retroviral infectionBarriers to retroviral infection TRIM5 SPRY species TRIM5 SPRY species specific Infection resistance, specific Infection resistance, capsidcapsid specific ABOBEC3G Polymorphisms specific ABOBEC3G Polymorphisms Infection resistance, Infection resistance, hypermutationhypermutation Influence on HIVInfluence on HIV--1 infection1 infectionCoreceptor/ligandCoreceptor/ligand CCR5 32 homozygous Infection CCR5 32 homozygous Infection CCL2, CCLCCL2, CCL--7, CCL11 7, CCL11 Infection Infection (MCP1, MCP3, (MCP1, MCP3, eotaxineotaxin), H7 Cytokine ), H7 Cytokine ILIL--10 5'A dominant 10 5'A dominant Infection Infection Influence on development of AIDSInfluence on development of AIDS Coreceptor/ligandCoreceptor/ligand CCR5 32 CCR5 32 heterozygous Disease progression heterozygous Disease progression CCR2 164 dominant Disease CCR2 164 dominant Disease progression progression CCL5 (RANTES) ln1.1c dominant Disease CCL5 (RANTES) ln1.1c dominant Disease progression progression CCL3L1 (MIP1 ) Copy number Disease progression CCL3L1 (MIP1 ) Copy number Disease progression DCDC--SIGN Promoter variant Parenteral infection Cytokine SIGN Promoter variant Parenteral infection Cytokine ILIL--10 5'A dominant 10 5'A dominant Disease progression Disease progression IFNIFN-- 179T dominant Disease progression 179T dominant Disease progression Innate Innate KIR3DS1 (with KIR3DS1 (with HLAHLA--Bw4Bw4) 3DS1 ) 3DS1 epistaticepistatic Disease progression Disease progression Adaptive Adaptive HLAHLA--A, HLAA, HLA--B, HLAB, HLA--C Homozygous Disease progression C Homozygous Disease progression HLAHLA--B*5802, HLAB*5802, HLA--B*18B*18 CodominantCodominant Disease progression Disease progression HLAHLA--B*35B*35--PxPxCodominantCodominant Disease progression Disease progression HLAHLA--B*27B*27 CodominantCodominant Disease Disease progression progression HLAHLA--B*57, HLAB*57, HLA--B*5801B*5801 CodominantCodominant Disease progression Disease progression

Adaptive

Disease progression 3DS1 epistaticKIR3DS1 (with HLA-Bw4)

Innate

Disease progression 179T dominant IFN-

Disease progression 5'A dominant IL-10

Cytokine

Parenteral infection Promoter variant DC-SIGN

Disease progression Copy number CCL3L1 (MIP1 )

Disease progression ln1.1c dominant CCL5 (RANTES)

Disease progression 164 dominant CCR2

Disease progression 32 heterozygous CCR5

Coreceptor/ligand

Influence on development of AIDS

Infection 5'A dominant IL-10

Cytokine

(MCP1, MCP3, eotaxin), H7

Infection CCL2, CCL-7, CCL11

Infection 32 homozygous CCR5

Coreceptor/ligand

Influence on HIV-1 infection

Infection resistance, hypermutationPolymorphisms ABOBEC3G

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 Futurewww.EvolutionAndMedicine.org

Olin Hall, Carleton College, 1967Olin Hall, Carleton College, 1967

Sophomore invertebrate biology Why is there aging?

Highly heritableHighly heritableBig differences in lifeBig differences in life--span in closely span in closely related speciesrelated speciesSo, why isnSo, why isn’’t life longer?t life longer?

Maybe to ensure a turnover of Maybe to ensure a turnover of individuals so the species can individuals so the species can evolve?evolve?

Not a theory but a principle

IFIF individuals vary on a trait that individuals vary on a trait that influences the number of offspringinfluences the number of offspringAnd that variation is passed onAnd that variation is passed onTHENTHEN the group will change over timethe group will change over time

ADAPTATIONADAPTATION: Individuals get better: Individuals get betterSPECIESSPECIES: New species split off from old: New species split off from old

Breeding

Natural Selection

Honeycreepers

Two Kinds of Explanation

““No biological problem is solved until both the No biological problem is solved until both the proximate and the evolutionary causation has proximate and the evolutionary causation has been elucidated. Furthermore, the study of been elucidated. Furthermore, the study of evolutionary causes is as legitimate a part of evolutionary causes is as legitimate a part of biology as is the study of the usually biology as is the study of the usually physicophysico--chemical proximate causes.chemical proximate causes.””

E. Mayr, 1982 E. Mayr, 1982 The Growth of Biological ThoughtThe Growth of Biological Thought

Two Complementary Explanations

1.1. ProximateProximate explanations are about explanations are about how a trait workshow a trait works..

2.2. EvolutionaryEvolutionary explanations are about explanations are about how a trait increases fitnesshow a trait increases fitness..

Disease and evolutionDisease is Disease is notnot shaped by natural shaped by natural selectionselectionBut But vulnerabilityvulnerability to disease has been.to disease has been.Natural selection can help explain Natural selection can help explain maladaptation as well as adaptationmaladaptation as well as adaptation

Darwinian MedicineNot radical in any wayNot radical in any wayNot opposed to allopathic medicineNot opposed to allopathic medicineNot a method of practiceNot a method of practiceJust a basic medical science Just a basic medical science whose power is just being recognizedwhose power is just being recognized

Medical school

Why is there aging? Why is there aging? Things wear out, obviously!Things wear out, obviously!And, natural selection isnAnd, natural selection isn’’t that greatt that greatStop asking questions and memorize Stop asking questions and memorize more!more!

Hanging out with evolutionarybiologistsWhy do organisms do what they do?Why do organisms do what they do?Why is there sex at all?Why is there sex at all?Why are some species social?Why are some species social?FINE QUESTIONS!!FINE QUESTIONS!!

I ask a biologist: “Why is there aging?”

ColleagueColleagueBobbi Low Bobbi Low replies: replies:

““WHAT!!! WHAT!!! You have You have

never read never read Williams Williams 1957?!!!1957?!!!””

What about my lovely model?

““DonDon’’t you even t you even know the know the

problem with problem with group group

selection?selection?””

Some General PrinciplesImperfections cannot be eliminated because Imperfections cannot be eliminated because natural selection is too weak and randomnatural selection is too weak and randomSelection shapes traits to benefit the speciesSelection shapes traits to benefit the speciesPathogens evolve to coPathogens evolve to co--exist with hostsexist with hostsNatural selection shapes health and longevityNatural selection shapes health and longevityGenetic disease results from mutations that Genetic disease results from mutations that natural selection cannatural selection can’’t eliminatet eliminateAging results because body parts wear outAging results because body parts wear outNatural selection cannot influence anything Natural selection cannot influence anything after reproduction endsafter reproduction ends

Current Views

Imperfections are present Imperfections are present for 6 reasonsfor 6 reasonsNatural selection shapes traits Natural selection shapes traits for genesfor genesPathogens evolve Pathogens evolve to maximize replicationto maximize replicationNatural selection shapes the body to Natural selection shapes the body to maximize maximize reproductive successreproductive successCommon genetic disease results mainly from Common genetic disease results mainly from quirks quirks interacting with novel environmentsinteracting with novel environmentsAging results because of Aging results because of pleiotropy pleiotropy Natural selection Natural selection continues after reproductioncontinues after reproduction

Pain

EXPERIENCE means something is EXPERIENCE means something is wrongwrongCAPACITY is usefulCAPACITY is usefulCongenital absence VERY rare Congenital absence VERY rare

35 in USA35 in USAWhy? Lack of pain causes early deathWhy? Lack of pain causes early death

Fixed defenses

SkinSkinInnate immune responsesInnate immune responsesStomach acidStomach acidEar waxEar waxCells shed steadilyCells shed steadily

Inducible Defenses(Tollrian, Harvell, Clark, Dill, Lima, Pulliam, et al.)

Latent traits expressed only in response Latent traits expressed only in response to a cue associated with a dangerto a cue associated with a danger

Developmental changesDevelopmental changes——size, shapesize, shapeSustainedSustained——tanning, callus formationtanning, callus formationTemporaryTemporary——Physiological defensesPhysiological defensesEmotionsEmotions——Adjust body to situations Adjust body to situations with adaptive challengeswith adaptive challenges

DaphniaDifferent morphology induced by exposureto chemical cues from predator

The Ecology and Evolution of Inducible Defensesby Ralph Tollrian

Stress

Too much cortisol is badToo much cortisol is badToo little is fatalToo little is fatal

AddisonAddison’’s diseases disease

If stress is so useful, why not express it all the time?

Many of us DO! However…It consumes energyIt decreases ability to do other thingsIt 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.

FeverA Defense that A Defense that fights infectionfights infectionEvidenceEvidence

Blocking fever Blocking fever can slow can slow recoveryrecoveryDoes Does increasing fever increasing fever help?help?

"La "La FiFiËËvrevre" by Matthew J. " by Matthew J. KlugerKluger, , La La RechercheRecherche 12: 68812: 688--696, 1981. 696, 1981.

Diarrhea

Clears pathogens and toxinsClears pathogens and toxinsBlocking diarrhea causes complications Blocking diarrhea causes complications in Shigellosis infectionin Shigellosis infection

––DupontDupont HL, HL, HornickHornick RB: RB: Adverse effect of Adverse effect of LomotilLomotiltherapy in shigellosis. therapy in shigellosis. JAMAJAMA1973; 226: 15251973; 226: 1525--1528 1528

Anxiety

Really useful to escape and avoid danger!Really useful to escape and avoid danger!People complain about too much anxiety People complain about too much anxiety What about hypophobics?What about hypophobics?

Fear of Heights at 18 vs. Severe Falls in ChildhoodPoulan, et al., 1998

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

Fall with severe injury (hypophobia?) n=60 No fall with severe injury (fearful?) n=789

% w

ith M

ild o

r Se

v. H

t. Fe

ar a

t 18 Fear of

Heights

The Clinical Illusion(that Defenses are Defects)

Clinicians are prone to think that Clinicians are prone to think that defenses are the problem because:defenses are the problem because:

Defenses are expressed when there Defenses are expressed when there is a problemis a problemThey are painfulThey are painfulBlocking them is often safeBlocking them is often safe

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

Pain or suffering of any Pain or suffering of any kind, if long continued, kind, if long continued, causes depression and causes depression and lessens the power of lessens the power of action; action;

yet it is well adapted to yet it is well adapted to make a creature guard make a creature guard itself against any great itself against any great or sudden evil. or sudden evil.

Charles Darwin, Charles Darwin, 1887, pp. 511887, pp. 51--5252

The First Noble Truth

Life Is SufferingLife Is Suffering

The Mystery about Defenses

Natural selection should shape near-optimal defense regulation mechanismsBut we are plagued by excess anxiety, pain and sadness, & other defensesAnd we know, from general medicine, that they often can be blocked safelyWhy are defenses expressed excessively?

How Should Defense Regulation Have Been Shaped by Natural Selection?

Monitor cues associated with dangerMonitor cues associated with dangerIf the cost of the defense < harm reduction, If the cost of the defense < harm reduction, express defense.express defense.Express allExpress all--oror--none defense iff: none defense iff:

C(D) < C(D) < C(HC(HNoDNoD) ) -- C(HC(HwDwD))

What if the Cue is Unreliable?Signal detection analysis needed:Signal detection analysis needed:

Cost of false alarmCost of false alarmCost of missed alarmCost of missed alarmCost of Harm if Defense (correct response)Cost of Harm if Defense (correct response)Probability that Harm is present (S/N ratio)Probability that Harm is present (S/N ratio)

Express defense wheneverExpress defense whenever

C(D) < pH ((C(D) < pH ((C(HC(HNoDNoD) ) -- C(HC(HwDwD))))

At what p(Harm) is Defense Expression Worthwhile?

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1 5 9 13 17 21 25 29 33

Ratio of Cost of Harm to Cost of Defense

P H

arm

at w

hich

Def

ense

Exp

ress

ion

is

Wor

thw

hile 2:12:1

5:15:120:120:1

Should you flee from a noise?

Is it a monkey?Is it a monkey?…… or a tiger?!!or a tiger?!!Cost of fleeing= 200 caloriesCost of fleeing= 200 caloriesCost of not fleeing if a tiger= 200,000 caloriesCost of not fleeing if a tiger= 200,000 caloriesRatio is 1000:1Ratio is 1000:1Optimum: Flee whenever p (tiger) > 1/1000Optimum: Flee whenever p (tiger) > 1/1000

999 /1000 panic attacks will be 999 /1000 panic attacks will be unnecessary, unnecessary, but perfectly normalbut perfectly normal

““Few failures are as unforgiving Few failures are as unforgiving as failure to avoid a predator. as failure to avoid a predator. Being killed greatly decreases Being killed greatly decreases future fitnessfuture fitness””

Lima and Dill, 1989, p. 619Lima and Dill, 1989, p. 619

Signal Detection TheoryGreen and Swets, 1966

Correct Correct RejectionRejection

Missed Missed RespResp. . (False negative, (False negative, Type II error)Type II error)

Decision: Decision:

Do not RespondDo not Respond

False AlarmFalse Alarm(False Positive, (False Positive, Type I error)Type I error)

HitHit(Correct (Correct detection)detection)

Decision: Decision:

RespondRespond

Signal:Signal:

AbsentAbsentSignal: Signal:

PresentPresent

Signal comes from real danger

Signal comesfrom noise

0---------False Alarms-----→1.0

1.0 …………

……

…….0.5………………

………….0

d′=0

d′=2d′=1

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

HitsHits

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?

Optimal Defense depends on how Harm Optimal Defense depends on how Harm declines with increasing Defensedeclines with increasing DefenseFind point of minimal costFind point of minimal cost

0

1

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3

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5

1 21 41

C(H)C(D)C(Tot)

At cost minimumC(D) = C(H)

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

0

1

2

3

4

5

1 21 41

C(H)C(D)C(Tot)

At optimum, C(D)is greater than C(H)

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 readilyPositive 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 thresholdAny hint of danger releases a panic responseWhen you have recently been the object of a predator attack, agoraphobia is useful indeed!

Immune responses

One exposure induces an responseOne exposure induces an responseSecond exposure arouses faster Second exposure arouses faster stronger responsestronger responsePathological extreme: Anaphylaxis Pathological extreme: Anaphylaxis

Nausea and Vomiting

One exposure to novel taste/odor and toxin One exposure to novel taste/odor and toxin conditions nauseaconditions nauseaSDP explains generalization to related odorsSDP explains generalization to related odorsRepeated exposure increases sensitivityRepeated exposure increases sensitivityExample: Conditioned nausea and vomiting Example: Conditioned nausea and vomiting in chemotherapyin chemotherapy

Depression

First episode 80% precipitated by life eventFirst episode 80% precipitated by life eventBy the fourth episode, precipitants are no By the fourth episode, precipitants are no more common in depressives than controlsmore common in depressives than controlsKindling is a neurological metaphorKindling is a neurological metaphorBut this may represent positive feedback, with But this may represent positive feedback, with decreased motivation arising ever more decreased motivation arising ever more quickly in response to unpropitious situationsquickly in response to unpropitious situations

ImplicationsA theoretical foundation for general medicineA theoretical foundation for general medicine

But most of the research has yet to be doneBut most of the research has yet to be doneEssential foundation for pharmacologyEssential foundation for pharmacology

Pharmacological utopia possible?Pharmacological utopia possible?

Pharmacological Utopia?

Most Suffering is normal but unnecessaryMany false alarmsRepeated arousal changes thresholdModern environment relatively safe

So we should be able to safely block most defenses and sufferingExcept for the one time in a hundred, when the defense will essential!

Medicine uses some evolution

Antibiotic resistanceAntibiotic resistanceEvolutionary geneticsEvolutionary geneticsHuman phylogenyHuman phylogeny

But much is missing

CoCo--evolution and arms racesevolution and arms racesSubtle evolutionary geneticsSubtle evolutionary geneticsEvolution and behaviorEvolution and behaviorEvolution and developmentEvolution and developmentAsking why natural selection has left the Asking why natural selection has left the body so vulnerable body so vulnerable

Percent of schools that include topic in medical curriculum (n=55)Nesse & Schiffman, 2000

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tance

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etics

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se genes

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l. bal.

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electio

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o. arm

s race

s

Mismatch

of body-en

vir.

Design tra

de-offs

Comparativ

e anatomy

Defense

regulat

ion

Life history

traits

Path dep

endence

Human phylogenyKin sele

ction

Proximate

ultimate

distinct

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!

Eliminate the appendix Eliminate the appendix Take out the wisdom teeth Take out the wisdom teeth Turn the eye inside outTurn the eye inside outMake bones strongerMake bones strongerImprove immune responsesImprove immune responsesMake blood clot a bit more slowlyMake blood clot a bit more slowlyInstall a zipper so babies can exit more Install a zipper so babies can exit more easily!easily!

An Example—The Eye

→An organ of extreme perfection?→Or, a design so poor that no one would want credit?

1. Upper eyelid 1. Upper eyelid 2. Lower eyelid 2. Lower eyelid 3. Lateral angle 3. Lateral angle 4. Medial angle 4. Medial angle 5. Lacrimal 5. Lacrimal

carunclecaruncle6. 6. LimbusLimbus7. Iris 7. Iris 8. Pupil 8. Pupil 9. Lacrimal 9. Lacrimal

papilla papilla 10 Sclera10 Sclera

First half of medical school:An organ of perfection

In the Clinic: A botched design

••GlaucomaGlaucoma••CataractsCataracts••MyopiaMyopia••PresbyopiaPresbyopia••IritisIritis••Corneal cloudingCorneal clouding••Retinal detachmentRetinal detachment

1. Mismatch

Our bodies were never designed to cope Our bodies were never designed to cope with this novel environmentwith this novel environmentSelection is slowSelection is slowThe mismatch explains most chronic The mismatch explains most chronic disease disease Our fulfilled desires are killing usOur fulfilled desires are killing us

5. Health is not selection’s goalSelection maximizes reproductive success, NOT health, longevity, & happiness

AgeingAgeingThe feeble sexThe feeble sex

“The human mind treats a new idea the way the body treats a strange protein; it rejects it.”

Peter Medawar

Origins of Control Theory

Erwin Erwin ShrShröödingerdinger’’ss classic classic ““What is Life?What is Life?””how organisms avoid entropy by using how organisms avoid entropy by using energy to create and maintain order 1944)energy to create and maintain order 1944)Weiner expanded the basic principle of Weiner expanded the basic principle of feedback control into cybernetics (1948) feedback control into cybernetics (1948) Shannon and Weaver codified information Shannon and Weaver codified information theory (1949). theory (1949). Grand synthesesGrand syntheses——General systems theory General systems theory ((BertalanffyBertalanffy, 1969) and biology (Miller, 1978). , 1969) and biology (Miller, 1978). Perceptual control theory (Powers, 1973). Perceptual control theory (Powers, 1973). Computer modeling (Holland, 1992). Computer modeling (Holland, 1992).

Fragmented knowledge

A top flight medical education ignores A top flight medical education ignores core evolutionary principles core evolutionary principles

Group selectionGroup selectionKin selectionKin selectionCoCo--evolutionevolutionTradeTrade--offsoffsLife history theory Life history theory Proximate vs. evolutionary Proximate vs. evolutionary explanationsexplanations

Evolutionary Q. about disease

Why has natural selection left us Why has natural selection left us vulnerable to disease?vulnerable to disease?

Not just why some people get sick, but Not just why some people get sick, but why natural selection has left us all with why natural selection has left us all with bodies that are vulnerable to diseasebodies that are vulnerable to disease

Six possible reasonsSix possible reasons

Six Reasons Why Diseases ExistSelection is slow

1. Mismatch: body in a novel environment

2. Competition with fast evolving organisms

Selection is constrained3. Every trait is a trade-off4. Constraints on natural selection

We misunderstand5. Organisms shaped for R/S, not

health6 D f d ff i

Nesse, QRB, March 2005

Genetic “Quirks”

Harmless in a natural environmentHarmless in a natural environmentCause disease in novel environment.Cause disease in novel environment.

AtherosclerosisAtherosclerosisMyopiaMyopiaDrug abuseDrug abuse

Hygiene Hypothesis

Lack of exposure to pathogens deprives Lack of exposure to pathogens deprives immune system of inhibitory componentsimmune system of inhibitory componentsRapidly increasing immune diseases (Rook)Rapidly increasing immune diseases (Rook)

Type I diabetesType I diabetesCrohnCrohn’’s diseases diseaseAsthmaAsthma

Acute Acute lymphoblasticlymphoblastic leukaemialeukaemia (Greaves)(Greaves)

Streptococcal infection

Strep antigens mimic our proteinsStrep antigens mimic our proteinsRheumatic fever, scarlet fever, OCDRheumatic fever, scarlet fever, OCD

Malaria in melanesia

4. Constraints

Path dependencePath dependenceJust like our computer keyboardsJust like our computer keyboards

HappenstanceHappenstanceMutationsMutations

Terrestrial Whales

I = (IRYh - IRYa) / IRYh

Defenses & suffering in AA today!

Shivering-Unpleasant but useful

How much shivering is best?

Too muchToo muchToo little Too little

Just right?Just right?

Selection is everywhere

Whenever variation influences prevalenceCoins in a jarPrograms on TVProducts in the grocery storeWhat politicians say

Genes in organisms? Special kind:NATURAL selection

Darwin: On the various contrivances by which British and foreign orchidsare fertilised by insects. London, John Murray, 1862.

Angraecum sesquipedale The Star Orchid of Madagascar

Why would an orchid have

A spur 30 cm. long?

Xanthopan morgani praedicta

Awe at the body’s perfection

The eyeThe eyeThe heartThe heartThe nephronThe nephronRegulation of clottingRegulation of clotting

Horror at the body’s flaws: You could do better in one afternoon!

Eliminate the appendix Eliminate the appendix Take out the wisdom teeth Take out the wisdom teeth Turn the eye inside outTurn the eye inside outMake bones strongerMake bones strongerImprove immune responsesImprove immune responsesMake blood clot a bit more slowlyMake blood clot a bit more slowlyLet the heart get blood from its chambersLet the heart get blood from its chambersInstall a zipper so babies can exit easily!Install a zipper so babies can exit easily!

Why has natural selection left the body so vulnerable?

Parts of the body Parts of the body are exquisiteare exquisite

Others are botched Others are botched

Why?

Depression is simple

Life situationLife situationHow you think about the situationHow you think about the situationHow the brain is workingHow the brain is working

Disease and evolutionDisease is Disease is notnot shaped by natural shaped by natural selectionselectionBut But vulnerabilityvulnerability to disease has been.to disease has been.Natural selection can help explain Natural selection can help explain maladaptation as well as adaptationmaladaptation as well as adaptation

New Questions About Disease

Not why one person gets sickNot why one person gets sickBut why we all share vulnerabilitiesBut why we all share vulnerabilitiesWhy didnWhy didn’’t natural selection do better?t natural selection do better?

Just because it is too weak?Just because it is too weak?Yes, but also five other kinds of Yes, but also five other kinds of explanationsexplanations

DEFENSE REGULATION

Pain, fever, cough, nausea, anxiety, etc. Pain, fever, cough, nausea, anxiety, etc. often seems excessiveoften seems excessiveWe can usually block them safelyWe can usually block them safelyDid selection make a mistake?Did selection make a mistake?

BP, Genes, Latitude and Environmental change Young, et al., PLOS 2006

Two Kinds of Explanation Needed

““No biological problem is solved until both the No biological problem is solved until both the proximate and the evolutionary causation has proximate and the evolutionary causation has been elucidated. Furthermore, the study of been elucidated. Furthermore, the study of evolutionary causes is as legitimate a part of evolutionary causes is as legitimate a part of biology as is the study of the usually biology as is the study of the usually physicophysico--chemical proximate causes.chemical proximate causes.””

E. Mayr, 1982 E. Mayr, 1982 The Growth of Biological ThoughtThe Growth of Biological Thought

Tinbergen’s 4 Questions Organized

Proximate

Evolutionary

Transition over time

Ontogeny

Phylogeny

Cross section

Mechanism

Selective Advantage

New Question