thanks for your interest in my lecture on evolution and
DESCRIPTION
TRANSCRIPT
•Thanks for your interest in my lecture on evolution and medicine. I began giving a version of this to our 1st y ear students at UNC in 2008.
•Be sure to click through the presentation in the “slide show” mode. It will make the most sense this way as you see the animations.
•If you want to see the notes that accompany many of the slides you’ll need to look through the presentation slide by slide, not in the “presentation” mode.
•We use an “audience response system” and for this lecture, just out of interest, I usually would ask the students at the start if they’d ever had a course on evolutionary biology. Predictably, most had not. You can see those slides at the end in the “extra slides” section.
•Thanks again, and enjoy! Please contact me with any questions,
James P. Evans MD, Ph.DEditor-in-Chief; Genetics in MedicineProfessor of Genetics and Medicine
University of North Carolina at Chapel HillCB#7264
Chapel Hill, NC 27599-7264T: (919) 966-2007F: (919) 966-4151
From Darwin to Pharmacogenomics
The Emergence of Evolutionary Medicine
Jim Evans MD, Ph.D
1st year Medical School
Block 1
University of North Carolina at Chapel Hill
Paraphrasing Theodosius Dobzhansky
“Nothing in medicine makes sense except in the light of evolution”
1973
Evolution and Medicine
• Evolutionary considerations answer many of the “why” questions in Medicine
• Explaining the deep underlying principles that have shaped us and thus result in health or sickness– Illustrates the importance of “biological
history”
• As genetics increasingly permeates medicine we use evolutionary principles routinely
The interpretation of
genetic data hinges on
evolutionary evidence
Will accelerate as sequencing is
applied more generally
“completely conserved in mouse, rat, rabbit, dog, horse, armadillo, elephant, opossum, lizard and puffer fish”
The Theory of Evolution by Natural Selection
• Proposed in 1859 by Charles Darwin and Alfred Russel Wallace to explain the diversity and exquisite adaptations exhibited by life on earth– Existence of inter-individual variation within any
population– Selection by the environment for fittest organisms
which then differentially reproduce– Heritability of variations
• Posits common descent with natural selection as a driving force in speciation
"How stupid of me not to have thought of that." -T.H. Huxley
The Explanatory Power of Darwin’s Theory
• Key pieces of evidence included:– Homologous structures
in different organisms – Similarities in embryos– Artificial selection (e.g.
pigeons and dogs)– Geographical
distribution of species
Predictions• Discovery of
intermediate fossil forms• Archyopteryx • Tiktaalik roseae
• The age of the earth• Modern Genetics
– The mechanism underlying heredity had to be compatible with particulate inheritance & subject to selective pressures
– Genetics represents a grand fulfillment of predictions inherent in evolutionary theory
Genetic Similarity Reveals Common Descent
• Identical Twin– 100%
• Un-related individual– 99.9%
• Chimpanzee– 98%
• Broccoli– 67%
Evolution and Medicine• Numerous prosaic
examples of evolutionary processes relevant to medicine– The (micro) evolution of
bacterial antibiotic resistance• Clear implications for antibiotic
use in– Clinical activity– Farming
– The evolution of resistance to anti-HIV agents within an individual
– Human cancer as a microcosm of selection and evolutionary change
Three Phases of Human EvolutionR
ate
of E
volu
tiona
ry C
hang
e
There exist important contemporary medical implications for all phases of evolution
~4,000,000,000 BP ~1,000,000 BP ~100,000 BP
Phase 1: Structural Evolution
• Our bodies evolved structurally in ways that are not necessarily optimal to health
• Such design flaws exist because of the necessary constraints of evolution’s mechanism– Evolution works on a pre-existing substrate – Does not see the big picture– Does not plan for the future– New adaptations are rarely “optimal”, they
must only be better
What Would You Do Next?
1) Get another length of hose?
2) Go back around the tree?
Adapted from Alan R. Rogers
Evolution chose option 1
Evolution Explains Human Anatomy
• During evolution testes moved from abdomen to scrotum
• Went down “wrong” side of ureter
Adapted from Alan R. Rogers
Our Evolutionary Legacy Creates Problems
Medical Implications of Evolution’s 1st Phase
The Structural Level• You engage in a life-threatening event
several times each minute– Swallowing is hazardous due to the risk of
aspiration– 5-10% of community acquired pneumonia
results from aspiration– Our common ancestor with the African
lungfish developed an air opening at the top of the snout, leading to a common opening with the food passageway
– Respiratory and food passages remain shared at their proximal extent
• Aspiration pneumonia is a 400 my old legacy of our evolutionary past
• Another such example is shared orifices for reproductive and excretory purposes
• Low back pain– 80% of US population will experience at least one
prolonged episode of severe low back pain– A direct result of our evolutionary history– It was advantageous for us to walk upright
• Freeing the forelimbs• Range of vision• Communication cues?
– However the resultant mechanical stresses result in a high rate of injury and pain
Some Medical Implications of Evolution’s 1st Phase
Medical Implications of Evolution’s 1st Phase
• Evolution explains adaptive & maladaptive responses – Congestive Heart Failure– Retention of sodium is a key
mechanism that increases CO via Starling forces
– However, as CHF progresses, this response becomes maladaptive
• We intervene with this evolutionarily programmed (mal)adaptattion with diuretics, etc.
• Appendicitis– Each year in the US 250,000
people require appendectomy– Appendicitis was a uniformly
fatal disease prior to the modern era
– Little evidence for useful function
– Evolutionary remnant– Evolutionary considerations
also explain the persistence of the appendix…
Medical Implications of Evolution’s 1st Phase
Medical Implications of Evolution’s 1st Phase
The Molecular and Cellular Level
• Cancer and Aging as “Rival Demons”1
– Our defenses against cancer and our susceptibility aging represent an evolutionary tradeoff
• The evolution of metazoans with renewable cells required mechanisms to strictly regulate cell growth– These mechanisms protect against cancer and
developmental problems– But their legacy is senescence and aging
• Mouse line with increased p53 activity demonstrating lower tumor rates but 2-=30% shorter lifespan2
1Judith Campisi; Nature Reviews 3:339; 20032Tyner; Nature 415:45; 2002
• Childbirth: A classic evolutionary trade-off– A very risky endeavor prior to the modern era– The human female’s pelvic structure is barely
sufficient for safe childbirth• We see an evolutionary trade-off between the
maximal size of the birth canal (& thus head size) that still retains pelvic integrity
• The result was a stunning rate of maternal/infant mortality in the era before modern obstetrics– Counterbalanced only by the selective advantages of
a large brain• But for the intervention of modern medicine we
have likely reached the limit of head size
Medical Implications of Evolution’s 1st Phase
Evolution’s 2nd PhaseThe Emergence of Cognition and Emotion
• The emergence of sophisticated cognition allowed – Nimble response to the environment
• Forgoing the need for rote programs & enhanced flexibility
– Ability to alter the environment• Through tool use • The eventual development of technology• Now on a global – and dangerous - scale
Evolution’s 2nd PhaseThe Emergence of Cognition and Emotion
• The evolution of emotion was a corollary of cognition– Emotions are potent
evolutionary mechanisms to drive reproductively successful behavior
• Anxiety • Lust• Fear • Love for mate and
offspring
nucleusaccumbens
hippocampusstriatum
frontalcortex
substantianigra/VTA
Adapted from Donald R. Vereen, M.D., M.P.H., NIDA
Dopamine Pathways Represent the Principal “Pleasure” System of the Brain
Dopamine Pathways Represent the Principal “Pleasure” System of the Brain
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ScrScrBasFemale
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SEX
Natural Rewards Elevate
Dopamine Levels ~100%
Comings (1987) pointed out that the limbic system has been
characterized as controlling the 4 F's--fight, flight, feeding, and
sexual activity
Medical Implications of Evolution’s 2nd Phase
• Psychiatric illnesses– Anxiety, “neuroses”, obsessive compulsive disorders,
phobias– Corollaries in other mammals
• The same pharmacologic agents active in, e.g. dogs with anxiety disorders illustrate common neurochemical pathways and the continuity between humans and other animals
• Direct result of the evolution of higher cognition and emotions
• Clear selective pressures leading to heightened anxiety, obsessive behavior, etc.
Medical Implications of Evolution’s 2nd Phase
• Reward pathways, being biochemical, are susceptible to manipulation by– Naturally occurring substances– Synthetic substances
Synergism Between Evolution of Synergism Between Evolution of Cognitive & Emotional CapacitiesCognitive & Emotional Capacities
• The rise of cognitive prowess eventually lead to technologies capable of artificially triggering our evolved emotional reward pathways– Ethanol (9,000 BCE)– Heroin (1860’s)– Crack cocaine (1980’s)
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% o
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AccumbensAccumbens COCAINECOCAINE
00100100200200300300400400500500600600700700800800900900
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00 11 22 33 44 5 hr5 hrTime After AmphetamineTime After Amphetamine
% o
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as
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DADA
AccumbensAccumbensAMPHETAMINEAMPHETAMINE
Source: Di Chiara and ImperatoSource: Di Chiara and Imperato
Substance Abuse Costs the US More than $484
Billion per Year
Costs of this Evolutionary Synergy
• Diabetes costs society $131.7 billion annually• Cancer costs society $171.6 billion annually
Medical & Societal Burden of Our Ability to Manipulate Evolved Reward Pathways– Direct causation of
disease• Cigarettes• Ethanol• Other substances
– Indirect causation• Trauma• Role in crime• Domestic Violence
– Addiction• To substances• To activities (e.g. gambling)
The combination of our highly evolved cognitive abilities
along with the existence of evolved chemical emotional reward pathways result in a modern
public health burden of immense proportion
"A hen is only an egg's way of making another egg."
Samuel Butler
Evolution’s Second Phase Influences our Definition of Disease
• Natural selection is not concerned with your happiness or health
• A single, very narrow priority– Reproductive fitness– No necessary match between the optimal
evolutionary strategy our ancestors unwittingly pursued and our own (or their) happiness
• Unhappiness, suffering and pain (physical or emotional) are transparent to the sieve of natural selection unless they affect reproductive success
• Morning sickness in pregnancy
As Physicians We Commonly Work Against Evolution
• Heightened anxiety, worry, discomfort were all likely adaptive in our evolutionary past
• As physicians we sometimes “work against” evolution in order to minimize suffering and enhance quality of life even at the expense of an individual’s evolutionary fitness– As we may do when we prescribe anti-anxiety agents– As we certainly do each time we prescribe birth control
• We are not obligated to adhere to an “evolutionary imperative”
…and that’s okay
Evolution’s 3rd PhaseThe Emergence of Culture
• At some point in the last 100,000 years humans developed strong “culture”– Complex group activities that vary
geographically and are transmitted non-biologically (now mostly symbolically)
• Including technology, art, decoration, science, moral systems, religion and characteristic behaviors and habits
• Cultural evolution is far faster than biological evolution– And more powerful
Evolution’s 3rd PhaseThe Emergence of Culture
• Human health is now highly dependent upon culture and in some sense, we are freed from proximal biological & evolutionary constraints– Myopia was a severe detriment to fitness prior to the
rise of glass grinding technology– Childhood infectious diseases are now of little
significance • If you happen to live in a culture with access to vaccines
• Leading to the oft-heard but nonsensical claim that human evolution is “dead”
• Evolution is faster & less predictable now due to the complex interplay between culture and biology
Medical Implications of Evolution’s 3rd Phase
The Clash of Evolution & Culture• Neel’s “Thrifty Gene
Hypothesis”– Certain human alleles
emerged to maximize metabolic efficiency & food searching behavior
• In times of abundance these alleles predispose their carriers to diseases caused by excess nutritional intake, such as obesity & DM
• Populations with a history of food scarcity may harbor more such thrifty alleles than other populations
Worldwide Prevalence of Diabetes 2000 and 2010
Calories are Cheap– The average citizen of NC earns
$30,553/yr– The price of a Hardee’s Monster
Thickburger© is $5.59– It takes 21 minutes to earn one
• It supplies almost a day’s worth of calories• Never in the history of our species have
calories been so cheap• It is engineered to appeal to our evolutionarily
derived compulsion to seek concentrated fat, salt, carbohydrates and protein
• And we don’t even have to leave our car to get it
Disease as a clash between our evolutionary past and our cultural present
1417 calories
A Similar Clash Can Be Observed in Other Disorders
– Lactose tolerance/intolerance– Hypertension– Coronary Artery Disease– Breast Cancer– HIV & emerging infectious diseases– ADHD
• Prevalence reaches 18% in populations world-wide• Very strong genetic component• Predisposing genetic variants are frequent and fixed in some
populations• Attributes which may have been driven evolutionarily but are
now not adaptive to our cultural milieu– Hyperactivity vs. hypoactivity– Multi focus (“attention”) vs. mono-focus
Evolution and Individualized Medicine Variation as a linchpin of Evolutionary Theory
and Modern Medicine
• Darwin overturned “essentialist” thought in biology– Fixed species modeled on an archetypical
ideal• He pointed to the importance of
variation• This insight is now highly relevant to
modern medicine– The differences that we observe account
for differential disease susceptibility, drug response, etc. as well as being the raw material of evolutionary change
• Individualized Medicine seeks to harness this variation towards better health
Variation in ActionPharmacogenomics and Tamoxifen
• Tamoxifen is a “pro-drug”– It requires metabolism to
its active form, endoxifen– This metabolism is largley
carried out by Cyp2D6– Many inactive or less
active alleles of CYP2D6 exist in the population
– Those individuals who are “intermediate metabolizers” have lower levels of endoxifen
CYP2D6 and Clinical Outcomes
• Data are not yet definitive
• But strongly suggest a relationship between tamoxifen response and outcome
Kaplan-Meier estimates of (A) relapse-free time, (B) disease-free survival, and (C) overall survival for patients with the CYP2D6*4 genotype
Goetz: J Clin Oncol, Volume 23(36).December 20, 2005.9312-9318
Evolution Reveals our Collective Family History
• Modern genetics illustrates the importance of a patient’s family history to guide
• Diagnosis• Risk of disease• Therapy
• Human evolution represents the deep “family history” of our species
• As such it contains important insights for medicine
We shall not cease from exploration, and the end of all our exploring will be to arrive where we started and know the place for the first time.
TS Eliot, 1942
Little Gidding
Understanding Our Collective Family Tree
THE FOLLOWING ARE EXTRA SLIDES TO CONSIDER
Only answer if you were a biological sciences major:
During my undergraduate education I had a course in evolutionary biology
Yes N
o
50%50%1. Yes
2. No
Only answer if you were not a biological sciences major:
During my undergraduate education I had a course in evolutionary biology
Yes N
o
50%
50%
1. Yes
2. No
• “An unfortunate compartmentalization has … hindered persons in medicine…from attaining the ... knowledge of genetics, mutatis mutandis, has hindered geneticists from mastering the necessary human subject” – Muller (1951)
• “The logic of disease must be developed in an evolutionary context and the possibility of doing so is vastly better now than it was in Garrod’s day” – Childs (1999)
Evolution and Medical Education
Medical Evolutionary Biology
(Evolutionary/Darwinian Medicine)
• Evolutionary principles unify molecular, biochemical, epigenetic, morphological and environmental variations that influence human health (and disease)
• Medical insights will illuminate both evolutionary biology, genetics and profoundly influence the future of medical practice
“It is in this indirect sense that our DNA is a coded description of the worlds in which our ancestors survived…We are digital archives of the African Pliocene, even of Devonian seas; walking repositories of wisdom out of the old days. You could spend a lifetime reading in this ancient library and die unsated by the wonder of it.”
Richard Dawkins; Unweaving the Rainbow, 1998
CFTR
Phylogenetic Relationship of the CFTR Gene Sequence
20 kb
Chimpanzee
Gorilla
Orangutan
Baboon
Macaque
Vervet
Marmoset
Squirrel Monkey
Lemur
Galago
Armadillo
Rabbit
Cow
Pig
Horse
Cat
Dog
Bat
Hedgehog
Rat
Mouse
Opossum
Monodelphis
Wallaby
PlatypusChicken
Courtesy: Eric Green (2007)
Before…the universe was filled with activity, none of which was purposeful. Atoms spun, and light beams whizzed through space. Flowers opened and closed, single celled animals replicated, and sponges fed. None of this activity, though, had a point. And yet somehow, in the midst of all this pointless activity, there arose collection of atoms capable of forming goals and striving toward them. At last, there was meaning in the universe—not meaning in the cosmic sense, perhaps, but meaning nonetheless.
From On Desire
William B. Irvine
The Evolution of Emotion
Individual Variability in Warfarin Dose
Warfarin maintenance dose (mg/day)
SENSITIVITYSENSITIVITY
CYP2C9 coding SNPs
RESISTANCERESISTANCE
VKORC1 coding SNPs
0.5 5 15
Fre
qu
ency
Common Common VKORC1VKORC1 non- non-coding SNPscoding SNPs
Adapted from Rettie and Tai, Molecular Interventions 2006
(*3/*3)
Group A Haplotypes
Group BHaplotypes
Warfarin FDA package insert
Rewritten in October 2007 to include information about increased sensitivity to warfarin associated with CYP2C9
and VKORC1 genetic variants
Sconce, et al. Blood 2005
Warfarin dosing algorithm (based on age, height, CYP2C9 and VKOR)
Evolution and MedicineMany physician scientists have made fundamental
contributions to both genetics and evolution
Friedrich Meischer Louis Pasteur Ernst Haeckel William Osler Oswald Avery Carl Landsteiner Lionel Penrose James Neel Alexander Flemming Harry Harris
Luca Cavalli – Sforza David Weatherall Victor McKusick
Alfred Knudson Arno MotulskyBarton Childs
Charles Scriver Randolph Nesse John Bell and others…
Yet, evolutionary thinking has remained largely isolated from medical practice