Darwinian Medicine - World Health Organization...Origins of Darwinian Medicine "The purport of the...
Transcript of Darwinian Medicine - World Health Organization...Origins of Darwinian Medicine "The purport of the...
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
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)
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?
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
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
2
3
4
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
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Antibiotic
resis
tance
Virulence
evolutio
n
Population gen
etics
Sel. fo
r disea
se genes
Mutation se
l. bal.
Levels of s
electio
n
Host-path
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