Why We Get SickThe New Science of

Darwinian MedicineFundación Ciencia y Evolución

Santiago de Chile

Randolph Nesse

The University of Michigan

Ideographic

MedicineEvolutionary

Biology

The Gap

On the Aims and

Methods of Ethology

Niko Tinbergen, 1983

A Recent Flowering

Recent Meetings

• Humboldt University

• York Hull Medical School

• University of Copenhagen

• NESCENT meeting at Duke

• American Institute for Biological Sciences

• American Physiological Society

• University of Arizona

• Berlin Institute for Advanced Study

• American College of Epidemiology

• National Academy Sackler Symposium

• Fundación Ciencia y Evolución, Santiago de Chile

Evolution in 2 Minutes

Selection happens

• When members of a group vary

• And those variations influence survival or

reproduction

• the group WILL CHANGE OVER TIME.

• Selection is not a theory,

it is a theorem!

Examples of selection

• Your penny jar

• What is on television

• Products on the grocer’s shelf

• Who is here today!

Natural Selection

When inherited

variations in a trait

influence the

number of

offspring, the trait

will change over

the generations.

Natural Selection

When inherited

variations in a trait

influence the

number of

offspring, the trait

will change over

the generations.

Dogs from Wolves in a Blink

Darwin: On the various contrivances by which British and foreign orchids

are 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

Ideographic

Deep time

1 mm of dust each year

How long does it take to fill the canyon?

Just one million years

What selection explains

• Adaptation-Darwin’s BIG discovery

• Why bodies work pretty well

• Individuals whose bodies worked better

than average had more offspring, so over

time the average bodies work better and

better

The body’s perfection

• The eye

• The heart

• The nephron

• Regulation of clotting

1. Upper eyelid

2. Lower eyelid

3. Lateral angle

4. Medial angle

5. Lacrimal aruncle

6. Limbus

7. Iris

8. Pupil

9. Lacrimal papilla

10. Sclera

11. Plica semilunaris

An organ of perfection

A botched ―design‖

•Blind spot

•Vessels block light

•Nearsightedness

•Lens gets clouded

•Lens gets stiff

•Retinal detachment

•Glaucoma

You could design a better body!

• Eliminate wisdom teeth

• Eliminate the appendix

• Make bones stronger

• Improve immune responses

• Make blood clot more slowly

• Make coronary arteries bigger

• Install a zipper so babies can exit easily!

If it is easy to improve the body,

why didn’t natural selection do

it long ago?

Two Kinds of Explanation Needed

―No biological problem is solved until both the

proximate and the evolutionary causation has

been elucidated. Furthermore, the study of

evolutionary causes is as legitimate a part of

biology as is the study of the usually physico-

chemical proximate causes.‖

E. Mayr, 1982

The Growth of Biological Thought

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?”

Why has natural selection left the

body so vulnerable?

Parts of the body

are exquisiteOthers are botched

Why?

The Old Answer: Natural selection is

just too weak to make the body better.

The New Answer

• There are six reasons why natural

selection leaves the body vulnerable

to disease

Six Reasons Why Diseases Exist

Selection is slow

1. Mismatch: body in a novel environment

2. Competition with fast evolving organisms

Selection is constrained

3. Every trait is a trade-off

4. Constraints on natural selection

We misunderstand

5. Organisms shaped for R/S, not health

6. Defenses and suffering

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, 1794

Erasmus Darwin

Opening paragraph of Zoonomia,

E Conchis Omnia (Everything From Shells! )

Erasmus Darwin 1731-1802

Origins of evolution in medicine

• Erasmus Darwin—Physician

• Robert Darwin—Physician

• Charles Darwin—Medical school dropout– Because he hated geology!

Darwinian (Evolutionary) Medicine

• The enterprise of using the basic science

of evolutionary biology in the services of

medicine and public health

Darwinian Medicine—NOT!

• Not a method of practice

• Not radical in any way

• Not about improving the species

• Not opposed to ordinary medicine

• Not a source of quick cures

• Not just about modern diseases

• Not just about the value of defenses

Evolution: A basic science for medicine

Four lines of work in

evolutionary medicineNesse & Stearns, 2008

1. Infection and fast evolution

2. Constructing phylogenies

3. Evolutionary genetics

4. Why selection left our bodies vulnerable

1. MISMATCH

• Atherosclerosis

• Breast cancer

• Allergy

• Autoimmune diseases

Atheroma

Cholesterol levels

• Modern American 200

• 20 pre-industrial 131

• 5 hunter-gatherer 123

• Rural Chinese 127

– Eaton, et al.

Quirks

• Harmless genetic variations that cause

disease in modern environments

Myopia

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

Avoiding the e-word

Antonovics, PLOS Biology, 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

/SM

R (

mg

/100m

l)/(

cal/

g/d

ay)

3. Every trait is a trade-off

Most genes are trade-offs

Why does the body make bilirubin?

More Bili Fewer Heart Attacks

Why Bilirubin?Sedlak and Snyder,

Pediatrics, 2004

Why is there Aging?Williams 1957

• Selection cannot eliminate genes that

cause problems after wild individuals die

• Selection will increase the frequency of

genes that give advantages in youth,

even if those genes eventually kill us all

If mortality stayed at

early adulthood rates throughout life

4. Constraints

• Things selection just cannot do

– Path dependence

– Mutations

Path Dependence

Mutation

• Mutations happen

• Takes time to purge them

• Random factors can make deleterious

mutations more common

The vulnerable sex

• Sex mortality ratio=

% Males who die in a year

--------divided by--------

% Females who die in a year

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

5. Health is not selection’s goal

0

1

2

3

4

5

6

0 to

4

5 to

9

10 t

o 1

4

15 t

o 1

9

20 t

o 2

4

25 t

o 2

9

30 t

o 3

4

35 t

o 3

9

40 t

o 4

4

45 t

o 4

9

50 t

o 5

4

55 t

o 5

9

60 t

o 6

4

65 t

o 6

9

70 t

o 7

4

75+

Age Group

M:F

Mo

rtal

ity 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

• Defects

– Seizures

– Cancer

– Paralysis

– Jaundice

– Injury

• Defenses

– Fever

– Cough

– Pain

– Fatigue

– Anxiety

6. Defenses and suffering

Defenses

and Suffering

• Why are defenses

aversive?

• Why so much

unnecessary pain and

suffering?

Pain or suffering of any

kind… is well adapted to

make a creature guard

itself against any great

or sudden evil.

Charles Darwin,

1887, pp. 51-52

If the immediate and direct purpose of

our life is not suffering, then our

existence is the most ill-adapted to its

purpose in the world.

Schopenhauer, 1851

Cold coming soon in Santiago!

How much shivering is best?

Too muchToo little

Just right?

Using drugs to block defenses

• If natural selection is so great, why doesn’t

blocking normal defenses cause great

harm?

The Smoke Detector Principle

• False alarms are Normal

• This is why we can block pain, cough

and nausea safely

(Except for that 1 time in 1000!)

Panic and Agoraphobia

• Panic is a false alarm fight-flight response

• The experience of panic seems to down-regulate

the panic threshold

• Any hint of danger releases a panic response

• When you have recently been the object of a

predator attack, agoraphobia is useful indeed!

Why isn’t the Body better?

There are six good evolutionary reasons

1. Infection

2. Mismatch

3. Trade-offs

4. Constraints

5. Selection is for reproduction not health

6. Defenses and the smoke detector principle

Conclusion

Evolutionary

biology

is a crucial

basic science

for medicine