Evolution: Medicine's Missing Basic Science Prof. Randolph ..."Evolution: Medicine's Missing Basic Science" Prof. Randolph M. Nesse The screen versions of these slides have full details

"Evolution: Medicine's Missing Basic Science"

Prof. Randolph M. Nesse

The screen versions of these slides have full details of copyright and acknowledgements 1

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Randolph M. Nesse, M.D.

The University of Michigan

"Evolution: Medicine's MissingBasic Science"

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Medicine Uses Some Evolution

• Antibiotic resistance

• Evolutionary genetics

• Human phylogeny




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But Much Is Missing

• Co-evolution and arms races

• Subtle evolutionary genetics

• Evolution and behavior

• Evolutionary epidemiology

• Asking why natural selection has left the body so vulnerable

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Some General Principles?

• Imperfections cannot be eliminated because natural selection is too weak and random

• Selection shapes traits to benefit the species

• Pathogens evolve to co-exist with hosts

• Natural selection shapes health and longevity

• Genetic disease results from mutations that natural selection can’t eliminate

• Aging results because body parts wear out

• Natural selection cannot influence anything after reproduction ends

They are all false

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General Principles Corrected

• Imperfections are present for 6 reasons

• Natural selection shapes traits for genes

• Pathogens evolve to maximize replication

• Natural selection shapes the body to maximize reproductive success

• Common genetic disease results mainly from quirks interacting with novel environments

• Aging results because of pleiotropy

• Natural selection continues after reproduction




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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%

Antibiot ic resistance

Vir ulence evolution

Population genetics

Sel. for disease genes

Mutation sel. bal.

Levels of selection

Host-patho. arms races

Mism

atch of body-envir.

Design trade-offs

Comparative anatomy

Defense r egulation

Life history tr aits

Path dependen ce

Human p hylogeny

Kin selection

Proximate ultimate dis...

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Evolutionary Biology Facultyin Medical Schools

9876543210

30

20

10

0

Std. Dev = 1.76

Mean = 1

N = 33.00

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Gertrude Stein on Her Deathbed

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

No, no that’s not it

What is the question?”




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Why Has Natural Selection Left the Body So Vulnerable?

Parts of the body are exquisite Others are botched

WHY?

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The Old Answer: Natural Selection Is Just Too

Weak to Make the BodilyMachine Better

Flaws are inevitable because natural

selection is a random process

of limited power

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The New Answer

There are six reasons why natural selection leaves

the body vulnerable to disease




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Disease and Evolution

Disease is not shaped by selection

But vulnerabi li ty to disease is

Natural selection can help explain

maladaptation as well as adaptation




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An Example: the Eye

• An organ of extreme perfection?

• Or, the exemplar of selection’s limits?

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1. Upper eyelid

2. Lower eyelid

3. Lateral angle

4. Medial angle

5. Lacrimal caruncle

6. Limbus

7. Iris

8. Pupil

9. Lacrimal papilla

10. Sclera

11. Plica semilunaris

First Half of Medical School:An Organ of Perfection

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In the Clinic: a Botched Design

•Glaucoma•Cataracts•Myopia•Presbyopia•Iritis•Corneal clouding•Retinal detachment




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You Could Design a Better Bodyin One Afternoon!

• Eliminate the appendix

• Take out the wisdom teeth

• Turn the eye inside out

• Make bones stronger

• Improve immune responses

• Make blood clot a bit more slowly

• Install a zipper so babies can exit more easi ly!

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Natural Selection

When heritable variations

in a trait influence

reproductive success, the trait wi ll inevitably

change over the generations

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Two Kinds of Explanation

“No biological problem is solved unti l both the proximate and the evolutionary causation has been elucidated; Furthermore, the study of evolutionary causes is as legitimate a partof biology as is the study of the usuallyphysico-chemical proximate causes”

E. Mayr, 1982 The Growth of Biological Thought




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Two Complementary Explanations

• Proximate explanations are about howa trait works

• Evolutionary explanations are about howa trait increases fitness

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Tinbergen’s 4 QuestionsOrigins of Darwinian Medicine

1. Immediate causes

2. Developmental causes

3. Function4. Evolutionary origins

Tinbergen, 1963

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Tinbergen’s 4 Questions Organized

New Question

Proximate Evolutionary

Transition over time Ontogeny Phylogeny

Cross section Mechanism Selective advantage




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Four questions about

honeycreeper beaks

1. Mechanism

2. Ontogeny

3. Phylogeny

4. Selection

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Darwin: On the Various Contrivances by Which Britishand Foreign Orchids Are Fertilised by Insects;

London John Murray, 1862

Angraecum sesquipedaleThe Star Orchid of Madagascar

Xanthopan morganii praedicta

Why would an orchidhave a spur 30 cm long?

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Darwinian Medicine

• Noting radical or alternative about it

• Not opposed to allopathic medicine

• Not a method of practice

• Just applying a basic medical science whose power is just being recognized




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How Is Evolution Usefulfor Medicine?

• Established contributions• antibiotic resistance

• genetics

• physiology

• Asking new research questions

• A deeper feeling for the organism• the analogy of body as machine is wrong

• the body is a bundle of evolved tradeoffs

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Direct Applications in the Clinic?

• Medicine is suspicious of theory

• Direct applications mostly unwise

• But evolution inspires new research with major clinical implications

• And understanding that the body as a bundle of tradeoffs shaped by selection, fundamentally changes doctors understanding of why disease exists

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Evolution and Medicine - Branches

• Genetics and pathogen evolution• Stearns, Ebert et al.

• Anthropology• Trevathan et al.

• Genetic indicators of selection• Wallace et al.

• Why selection leaves us vulnerable• Nesse, Williams et al.




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Evolutionary Q. About Disease

• Why has natural selection left us vulnerable to disease?

• Not just why some people get sick

• Why has natural selection left us all with bodies that are vulnerable to disease

• Six possible reasons

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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-off

4.Constraints on natural selection

We misunderstand5.Organisms shaped for R/S, not health

6.Defenses and suffering




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1. Mismatch

• Our bodies were never designed to cope with this novel environment

• Selection is slow

• The mismatch explains most chronic disease

• Our fulfi lled desires are ki lling us

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Atheroma

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Cholesterol Levels

• Modern American 200

• 20 pre-industrial 131

• 5 hunter-gatherer 123

• Rural Chinese 127

Eaton, et al.,




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Breast Cancer• Much more common now

• Hormone exposure• 400+ cycles now, about 110 then

• Night light exposure

• blind Norwegians

• melatonin actions

• nurses study

• new rat studies

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Genetic “Quirks”

• Harmless in a natural environment

• Cause disease in novel environment• atherosclerosis

• myopia

• drug abuse

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Myopia




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

25516120N =

BDNF Genotype

Val/ValVal/MetMet/Met

Mean Neuroticism +/- 1 SEM

95

85

75

65

N = 20 N = 161 N = 255

p = 0.0057Negative affect score

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Hygiene Hypothesis

• Lack of exposure to pathogens deprives immune system of inhibitory components

• Rapidly increasing immune diseases (Rook)• type I diabetes

• Crohn’s disease

• asthma

• Acute lymphoblastic leukemia (Greaves)

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Signals of Recent Selection

• Prevalent mutations with high linkage disequi librium

• ADH — Ken Kidd

• Lactase — in herders

• DRD4-7Rpt — Moyzis

• G6PD/ CD4OL — Lander-Malaria

• Apo E? — Sapolsky and Finch

• BDNF?? — Sen/Nesse Depression




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BP, Genes, Latitude and EnvironmentYoung et al., PLOS 2006

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2.Competition with Other Organisms

• Pathogens evolve faster

• Also predators and conspecifics

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Streptococcal Infection

• Why not better defenses?

• Streptococci antigens mimic our proteins

• Rheumatic fever, scarlet fever, OCD




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Antibiotic Resistance Profiling of 480 Soil-Derived Bacterial Isolates

V. M. D'Costa et al.,Science 311:374 -377 (2006)

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Virulence

• Selection not for benignness

• Virulence maximizes spread

• Vectors increase virulence• mosquitoes — malaria• impure water — cholera• human hands!!

Anderson, May Ewald, Ebert, Levin, et al.

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3. Every Trait Is a Trade-Off




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Malaria in Melanesia

50Copyright©1997 by the National Academy of Sciences

Alpha + Thalassemia Protects Against Malaria

Allen, S. J. et al., (1997) Proc. Natl. Acad. Sci. USA 94:14736-14741

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Uric Acid Concentration/SMR vs. MLSP

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0 20 40 60 80 100

Years

Uric Acid/SMR

(mg/100ml)/(cal/g/day)

Gout




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Why Bilirubin?Sedlak and Snyder, Pediatrics, 2004

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4. Constraints

• Path dependence

• Mutation

• Weakness of selection

• Happenstance

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Terrestrial Whales




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Path Dependence

Vitreous chamber

Conjunctiva

Cornea

Anterior chamber

Iris

Blind spot

Optical nerve

Fovea

Neuralretina

Retinal pigment epithelium

ChoroidScleraEpidermis

of eyelid

Copyright 1997 The Anatomy Project

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5. Health Is Not Selection’s Goal

• Selection maximizes reproductive success not health, longevity and happiness

• Reproduction trumps all

• senescence

• the feeble sex

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Senescence and Pleiotropy

• Some genes that cause aging have no selective cost in the wi ld

• Others offer advantages early in life when selection is stronger




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I = (IRYh - IRYa) / IRYh

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Force of Selection Against Senescence• Dall sheep .86• Waterbuck .64 • Impala male .69• Buffalo male .79• Caribou .05• Himalayan Thar .18• Zebra male .41• Black rhinoceros .24• Hippopotamus .75• African elephant .40• Herring gull .04• Lapwing .06• Great tit male .26 • American Mallard -.03• Blue jay .02• Lake trout .22• Sessile rotifer .60• Barnacles .57• Human, USA, 1970 .85

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If Mortality Stayed at EarlyAdulthood Rates Throughout Life




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The Vulnerable Sex

• Consider the mortality ratio

• percent of males who die in a year--------divided by--------

percent of females who die in a year

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

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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 G roup

M:F Mortality Ratio

Australi a

Belgu im

Canada

Colomb ia

El Salvado r

Fi nland

France

Greece

Irelan d

It aly

Japan

Norway

Po land

Si ngapore

Russia

Sp ain

Sweden

Sw itzerland

Ukrain e

USA

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Developmental Pleiotropy a Prediction

• Only .0001% of sperm ferti lize an egg

• Only 20% of ferti lized eggs go to term

• A mutation that gave a tiny incremental advantage at these stages would spreadeven if i t caused disease• sperm motility, fertilization advantage

• implantation advantage ( HLA-diabetes)




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6. Defenses and Suffering

Nausea, vomiting, diarrhea, fever, coughfatigue, anxiety are painful but useful responses

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Pain or suffering of any kind, if long continued, causes depression and lessens the power of action; yet it is well adapted to make a creature guard itself

against any great or sudden evi lCharles Darwin, 1887, pp. 51-52

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Defenses vs. Defects

• Defects• seizures

• cancer

• paralysis

• jaundice

• injury

• Defenses• fever

• cough

• pain

• fatigue

• anxiety




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Defense Regulation

• Pain, fever, cough, nausea, anxiety, etc.often seems excessive

• We can usually block them safely

• Did selection make a mistake?

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“The Smoke Detector Principle”Optimal Defense Regulation

• Monitor cues associated with danger

• If the cost of the defense is less than the expected reduction in harm from the danger then it is worth expressing the defense

• Express defense if:

C(D) < C(HsD) - C(HwD)

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What If the Cue Is Unreliable?

• Signal detection analysis needed:• cost of the defense (C(D) = cost of false alarm)

• cost of harm if no defense

• cost of harm if defense (correct response)

• probability that harm is present (S/N ratio)

• Express defense whenever

C(D) < pH ((C(HNoD) - C(HwD))




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Signal comes from real danger

Signal comesfrom noise

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Optimal Response Threshold

p(x|s) p(n) v(rej.) + v(f.a.)p(x|n) p(s) v(hit) + v(miss)

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Should You Flee from a Noise? It Could Be a Monkey… or a Lion!!

• Cost of fleeing = 200 calories

• Cost of not fleeing if tiger = 200,000 kcal

• Optimal: flee whenever p tiger > 1/1000

• 999/1000 panic attacks wi ll be unnecessarybut perfectly normal




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

Lima and Dill, 1989, p. 619

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Panic Disorder

• A fight-flight response false alarm

• the smoke detector principle

A dysregulated defense




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The Smoke Detector Principle

• Optimal regulation system expresses many normal false alarms

• This is why we can block defenses safely

• (except for that one time out of a thousand!)

• Also: pain, fever, vomiting, fatigue, etc.

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A Conclusion About Defenses:Most Human Suffering Is Normal but Unnecessary

Except for one time in a thousand,

when the defense is essential!

This explains how generalmedicine is possible!




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Six Reasons for Vulnerability

1. Mismatch: body in a novel environment

2. Competition with fast evolving organisms

3. Every trait is a trade-off

4. Constraints on natural selection

5. Organisms shaped for R/S, not health

6. Defenses and suffering

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Main Conclusions

• Evolution is as essentialto medicine as physicsis for engineering

• The body is not a machine but a soma shapedby selection

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Some of Many Implications

• No normal genome

• Need explanations for universals• not just for individual differences

• Expect poor design everywhere

• But recognize that what you think is poor design may well be exquisite

• Studying evolution is great fun!




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Overall Conclusion

Nesse, Omenn, StearnsScience, 2006

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The State of Darwinian Medicine• Many conferences and new books

• Lectures now avai lable

• But no training programs yet

• Little research funding in the USA

• And medical curricula don’t includemedicine’s most basic science

• A field ready to flower — and about time!

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http://EvolutionAndMedicine.org




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Evolution: Medicine's Missing Basic Science Prof. Randolph ..."Evolution: Medicine's Missing Basic Science" Prof. Randolph M. Nesse The screen versions of these slides have full details

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