Evolution and Defense Regulation:

1

• Evolution and Defense Regulation
• How Much Suffering is Enough?
• Randolph Nesse
• Saturday Morning Physics
• February, 2006

2
Gary Larson
3
Defenses suffering in AA today!
www.noaa.gov
4
Shivering-Unpleasant but useful
http//www.physoc.org/publications/pn/issuepdf/58/
26-27.pdf
5
How much shivering is best?
Just right?
Too much
Too little
6
Olin Hall, Carleton College, 1967
http//northfield.org/blogimages/winterarb1w400.jp
eg
7
Sophomore invertebrate biology Why is there aging?

• Highly heritable
• Big differences in life-span in closely related
  species
• So, why isnt life longer?
• Maybe to ensure a turnover of individuals so the
  species can evolve?

8
Medical school

• Why is there aging?
• Things wear out, obviously!
• And, natural selection isnt that great
• Stop asking questions and memorize more!

9
Hanging out with evolutionary biologists

• Why do organisms do what they do?
• Why is there sex at all?
• Why are some species social?
• FINE QUESTIONS!!

10
My Q Why is there aging?
WHAT!!! You have never read Williams 1957?!!!

• Bobbi Low
• replies

Photo courtesy of Bobbi Low
11
Natural Selection

• When heritable variations in a trait influence
  reproductive success, the trait will inevitably
  change over the generations.

www.nap.edu
12
Selection is everywhere

• Whenever variation influences prevalence
• Coins in a jar
• Programs on TV
• Products in the grocery store
• What politicians say
• Genes in organisms? Special kind
• NATURAL selection

13
Darwin On the various contrivances by which
British and foreign orchids are fertilised by
insects. London, John Murray, 1862.
Why would an orchid have A spur 30 cm. long?
Xanthopan morgani praedicta
Angraecum sesquipedale The Star Orchid of
Madagascar
14
Awe at the bodys perfection

• The eye
• The heart
• The nephron
• Regulation of clotting

15
Horror at the bodys flaws You could do better
in 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
• Let the heart get blood from its chambers
• Install a zipper so babies can exit easily!

16
Why has natural selection left the body so
vulnerable?

• Parts of the body are exquisite

• Others are botched

Why?
17
Disease and evolution

• Disease is not shaped by natural selection
• But vulnerability to disease has been.
• Natural selection can help explain maladaptation
  as well as adaptation

18
Darwinian Medicine

• Not radical in any way
• Not a method of practice
• Just adding a basic science to medicine

19
(No Transcript)
20
(No Transcript)
21
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

22
New Questions About Disease

• Not why one person gets sick
• But why we all share vulnerabilities
• Why didnt natural selection do better?
• Just because it is too weak?
• Yes, but also five other kinds of explanations

23
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

24
For Lumpers 3 Reasons for Vulnerability
April 2nd

• 1. Selection is slow
• Mismatch
• Competition
• 2. Selection is constrained
• Trade-offs
• Constraints
• 3. We misunderstand
• Organisms maximize R/S, not health
• Defenses and suffering

TODAY
25
6. Defenses and suffering

• Latent capacities, shaped by selection, expressed
  only when needed
• Expression is regulated by a system that monitors
  cues associated with threats
• Nausea, vomiting, diarrhea, fever
• Cough, fatigue, anxiety, jealousy

26
Defenses vs. Defects

• Defects
• Seizures
• Cancer
• Paralysis
• Jaundice
• Injury

• Defenses
• Fever
• Cough
• Pain
• Fatigue
• Anxiety

27
DEFENSE REGULATION

• Pain, fever, cough, nausea, anxiety, etc. often
  seems excessive
• We can usually block them safely
• Did selection make a mistake?

28
Defenses and Suffering

• Why are defenses aversive?
• Motivates escape and avoidance
• What if pain did not hurt?

www.apocalipsis.org/ artwork/durer-07.jpg
29
Pain

• EXPERIENCE means something is wrong
• CAPACITY is useful
• Congenital absence VERY rare
• 35 in USA
• Why? Lack of pain causes early death

30
Fixed defenses

• Skin
• Innate immune responses
• Stomach acid
• Ear wax
• Cells shed steadily

31
Inducible Defenses(Tollrian, Harvell, Clark,
Dill, Lima, Pulliam, et al.)

• Latent traits expressed only in response to a cue
  associated with a danger
• Developmental changessize, shape
• Sustainedtanning, callus formation
• TemporaryPhysiological defenses
• EmotionsAdjust body to situations with adaptive
  challenges

32
Daphnia Different morphology induced by
exposure to chemical cues from predator The
Ecology and Evolution of Inducible Defenses by
Ralph Tollrian
http//www.bookhq.com/compare/0691012210.html
http//biol.lancs.ac.uk/bs/mainimg/Tollrian.jpg
33
Stress

• Too much cortisol is bad
• Too little is fatal
• Addisons disease

34
If stress is so useful, why not express it all
the time?

• Many of us DO! However
• It consumes energy
• It decreases ability to do other things
• It damages tissues!
• Why? Because it is precisely those changes that
  damage tissues that must be packaged away in an
  emergency kit, to be opened only when the costs
  are worth it.

35
Fever

• A Defense that fights infection
• Evidence
• Blocking fever can slow recovery
• Does increasing fever help?

"La FiËvre" by Matthew J. Kluger, La Recherche
12 688-696, 1981.
http//www.pbs.org/wgbh/evolution/library/10/4/l_1
04_04.html
36
Diarrhea

• Clears pathogens and toxins
• Blocking diarrhea causes complications in
  Shigellosis infection
• Dupont HL, Hornick RB Adverse effect of Lomotil
  therapy in shigellosis. JAMA 1973 226 1525-1528

37
Anxiety

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

38
Fear of Heights
39
The First Noble Truth

• Life Is Suffering

40

• 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

http//www.cancellieri.org/images/schopenhauer202
.jpg
41
(No Transcript)
42

• 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 evil.
• Charles Darwin,
• 1887, pp. 51-52

http//pages.britishlibrary.net/charles.darwin3/ml
etters_images/darwin1.jpg
43
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
http//www.harvardmagazine.com/lib/03ma/images/wil
.jpg
44
The Clinical Illusion(that Defenses are Defects)

• Clinicians are prone to think that defenses are
  the problem because
• Defenses are expressed when there is a problem
• They are painful
• Blocking them is often safe

45
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

http//www.flickr.com/photos/druggedmoon/45411126/
46
The Mystery

• Natural selection should shape near-optimal
  defense regulation mechanisms
• But we are plagued by excess anxiety, pain and
  sadness, other defenses
• And we know, from general medicine, that they
  often can be blocked safely
• Why are defenses expressed excessively?

47
How Should Defense Regulation Have Been Shaped
by Natural Selection?

• Monitor cues associated with danger
• If the cost of the defense is less than the
  expected reduction in harm from the danger, then
  expressing the defense is wise.
• Express all-or-none defense iff
• C(D) lt C(HNoD) - C(HwD)

48
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 missed alarm)
• Cost of Harm if Defense (correct response)
• Probability that Harm is present (S/N ratio)
• Express defense whenever
• C(D) lt pH ((C(HNoD) - C(HwD))

49
At what p(Harm) is Defense Expression Worthwhile?
21
51
201
50
Should you flee from a noise?

• Is it a monkey? or a tiger?!!
• Cost of fleeing 200 calories
• Cost of not fleeing if a tiger 200,000 calories
• Ratio is 10001
• Optimum Flee whenever p (tiger) gt 1/1000
• 999 /1000 panic attacks will be unnecessary,
  but perfectly normal

51
(No Transcript)
52

• Few failures are as unforgiving as failure to
  avoid a predator. Being killed greatly decreases
  future fitness
• Lima and Dill, 1989, p. 619

53
The Smoke Detector Principle

• Normal systems have many false alarms
• Much suffering is normal but unnecessary
• So it can be blocked safely
• Except for the rare instances when this causes
  catastrophe!
• Nesse 1990, 1994, 2005

54
Signal Detection Theory Green and
Swets, 1966
55
Signal comes from real danger
Signal comes from noise
56
(No Transcript)
57
Signal Detection Theory To get high detection
you have to accept many false alarms
Hits
58
Optimal Response Threshold
p(xs) p(n) v(rej.) v(f.a.) p(xn)
p(s) v(hit) v(miss)
59
(No Transcript)
60
What if the Defense is Expressed in Gradations?

• Then the optimal Defense expression depends on
  how Harm declines with increasing Defense
• Find the point where total cost is minimized

61
At cost minimum C(D) C(H)
CD LD0.05, CH 1/(LD0.1).
62
B) CD 1LD0.05, CH1/(LD0.1
63
Regulation of DefensesThe Perils of Positive
Feedback

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

64
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!

65
Immune responses

• One exposure induces an response
• Second exposure arouses faster stronger response
• Pathological extreme Anaphylaxis

66
Nausea and Vomiting

• One exposure to novel taste/odor and toxin
  conditions nausea
• SDP explains generalization to related odors
• Repeated exposure increases sensitivity
• Example Conditioned nausea and vomiting in
  chemotherapy

67
Depression

• First episode 80 precipitated by life event
• By the fourth episode, precipitants are no more
  common in depressives than controls
• Kindling is a neurological metaphor
• But this may represent positive feedback, with
  decreased motivation arising ever more quickly in
  response to unpropitious situations

68
Implications

• A theoretical foundation for general medicine
• But most of the research has yet to be done
• Essential foundation for pharmacology
• Pharmacological utopia possible?

69
Pharmacological Utopia?

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

70
The Future
71
What actions would bring the full power of
evolutionary biology to bear on human disease?
We suggest three. First, include questions about
evolution in medical licensing examinations this
will motivate curriculum committees to
incorporate relevant basic science education.
Second, ensure evolutionary expertise in agencies
that fund biomedical research. Third, incorporate
evolution into every relevant high school,
undergraduate, and graduate course. These three
changes will help clinicians and biomedical
researchers understand that both the human body
and its pathogens are not perfectly designed
machines but evolving biological systems shaped
by selection under the constraints of tradeoffs
that produce specific compromises and
vulnerabilities. Nesse, Omenn, Stearns,
Science, 2006
72
Take-home points

• Defense capacities are useful
• The Clinicians Illusion
• The Smoke Detector Principle
• Evolutionary biology is incredibly cool!

73
(No Transcript)
74
(No Transcript)
75
The human mind treats a new idea the way the
body treats a strange protein it rejects it.
Peter Medawar
Gary Larson
76
(No Transcript)
77
Origins of Control Theory

• Erwin Shrödingers classic What is Life? how
  organisms avoid entropy by using energy to create
  and maintain order 1944)
• Weiner expanded the basic principle of feedback
  control into cybernetics (1948)
• Shannon and Weaver codified information theory
  (1949).
• Grand synthesesGeneral systems theory
  (Bertalanffy, 1969) and biology (Miller, 1978).
• Perceptual control theory (Powers, 1973).
• Computer modeling (Holland, 1992).