2400: evolution and medicine

fever

evolved as a defense mechanism to fight infection by pathogens

endotherm

maintain a stable internal body temp by generating heat through metabolism

ectotherm

animals that rely on external sources like the sun to regulate body temps

inducing fever

the desert iguanas induces fever behaviorally in response to bacterial infection

endothermic and ectothermic vertebrates induce fevers to respond to infections

fever in humans

costs of running a fever

• increased metabolic rate

  • 2-3 degree C rise = 20% increase

  • shivering = up to 6x metabolic rate

patients who receive fever reducing drugs recover less quickly

why is fever beneficial?

H1: higher temps may harm the pathogen more than the host

H2: higher temps reduce growth rates of microorganism- doesn’t apply to all bacteria

H3: fever triggers the expression of heat shock proteins, which stimulates immune cell activity and helps cells deal with intracellular damage

why are fevers so common?

smoke detector principle

• must be very sensitive to keep body safe

why are we vulnerable to disease?

1. we’re locked in a coevolutionary arms race with pathogens, and they evolve more rapidly

2. nat selection has not had enough time to catch up with environmental change

3. the laws of physics and biology impose trade-offs on what an organism can do

4. nat selection lacks foresight, we are stuck with relics of our past

5. nat selection favors reproductive success, even at the expense of vulnerability to disease

6. some defenses (fever, nausea, anxiety) are unpleasant but they’re beneficial adaptations rather than maladies

thicker bone structure would result in less breaks, but at cost of speed and nimbleness

evolutionary body plans not well suited to bipedal locomotion- eg spinal column holds weight

coevolutionary arms race: pathogens-host

pathogens typically have large pop sizes with shorter generation times

leading to more genetic variation via mutation for natural selection to act on

immune strategies

host pops could never keep up via adaptive substitution rates so it has relied on diff strategies:

1. detecting characteristic components of pathogens

2. finding infected cells

3. creating variation through sexual reproduction

detecting characteristic components of pathogens

pathogens have essential highly conserved components known as pathogen-associated molecular patterns (PAMPs)

our immune system uses pattern recognition receptor molecules to detect these PAMP’s

finding infected cells

what makes viruses difficult to find?

1. have few conserved external structures

2. many were produced by budding from host cell- wrapped in a membrane layer structurally the same as the host cell

3. replicate within a host cell- need to find infected host cells in addition to the free virus

distinctive characteristics the immune system can target:

• form double stranded RNA during replication

• viral nucleic acids

• viral coat proteins

• etc

hosts learn to detect pathogen cues throughout their lifetime

the immune system produces an enormous, highly diverse repertoire of T cells that recognize infected cells and B cells

V(D)J recomb

clonal selection

clonal expansion

V(D)J recombination

variable-diversity-joining rearrangement

mechanism of somatic recomb that occurs only in developing immune cells

• creates millions of diff receptors by combining a small number of subunits in diff ways

clonal selection

a process to produce a large repertoire of immune receptors via somatic recomb

clonal expansion

an antibody binds to an antigen and it begins to proliferate rapidly

creating variation through sexual reproduction

sexual reproduction generates large amounts of variation

if pathogens are transmitted vertically:

• asexual reproduction- identical genotypes- more susceptible to pathogens

• sexual reproduction - diff genotypes- less susceptible to pathogens

pathogens have evolved counter measures

1. avoid detection

2. sabotage or deceive the immune system

human immunodeficiency virus

poxviruses

some bacteria

human immunodeficiency virus

downregulates the major histocompatibility complex (MHC) that helps recognize t=infected cells

induces programmed death in uninfected cells

poxviruses

produce enzymes that degrade the immune systems chemical signals that control replication and migration of cells to fight infection

produce decoy receptors to divert signals from true agents

some bacteria

tap into inhibitory pathways to control the hosts inflammatory response

secrete enzymes that degrade immune signaling molecules

normal looking pathogen phylogeny

immune response generates lifelong immunity

pathogens cannot evolve escape variants that can dodge immune memory

chronogram shows longer branch lengths, with older nodes

cactus shaped pathogen phylogeny

immune response does not generate lifelong immunity

pathogen generates escape variants capable of reinfecting an ind

short branches with recent nodes

single trunk with twiggy spines branching off

evolution of virulence

early theories:

• pathogens should evolve to reduce virulence and minimize the cost imposed on their host

• killing their host is not in their “evolutionary interest” as it need the host to reproduce and spread

virulence

the degree of harm a pathogen causes its host

can be measured as the fraction of infected inds that die- infection mortality rate

case study: myxoma virus in australian wild rabbits

19th century- wild rabbits were introduced to australia but they had devastating effects on the ecosystem

1950’s- introduced the myxoma virus to control rabbit pop

myxoma dropped from 99% to 60% in the wild, still extremely virulent

in the lab, mortality rate slightly decreased with time (90%-60%), but was still high

epizootic

a disease outbreak

trade-off theory of virulence

rapid exploitation kills the host decreasing transmission

grow too slowly and immune system will clear you quicker

best applied on a case-to-case basis

consider:

1. vertical vs horizontal transmission

   1. some empirical support

2. multiplicity of infection (multiple strains = variation in virulence)

   1. some empirical support

3. mode of transmission: direct vs vector

   1. lacks support

covid-19 pandemic

what should we have anticipated for the virulence of this pathogen?

• transmission occurs within the first 1-2 weeks of infection

• symptoms occur after ~2 weeks

• death typically occurs several weeks later

selection for increased virulence more likely

2020-2022 virulence stable

omicron and delta variants had increased virulence

caveat- difficult to measure virulence- treatment got better with time

biggest drive of reduced fatality rates in humans associated with immune system learning rather than nat selection on either the virus or the host

top causes of mortality in humans

1. automobile accidents

2. poisoning

3. falls

4. choking

phylogenetic constraint and choking vulnerability

why did we evolve to have such an unfortunate intersection between the trachea and esophagus?

epiglottis as a safety mechanism but still not ideal

benefits of current structure:

• mouth provides a backup airway if nose is clogged

• facilitates complex vocalizations (human speech)

consequences of phylogenetic constraint

lungs arose early in primitive fish to trap gas bubbles by gulping via mouth

tetrapods- gills were lost die to the evolution of lungs

lungs developed from the esophageal tissue and could not be decoupled

phylogenetic constraint in dogs vs humans

dogs can eat and breathe at the same time bc their soft palate and epiglottis meet

human trade off

• a descended larynx in humans enables human speech (needs air to create sound)

• a descended larynx in humans exacerbates choking hazard

humans are vulnerable to choking, could be worse

octopus brain wraps around esophagus

each bit of food must pass through the middle of the brain

each bite can have disastrous consequences if too big

senescence

the decline in the physical functioning or performance of living organisms with age

similar structures are seen as fertility declines with age

it is a general phenomenon among multicellular organisms

rate-of-living hypothesis

senescence is an unavoidable consequence of accumulated physical wear and tear

two predictions:

1. if selection has done everything possible to slow senescence, there is little to no genetic variability in the senescence rate

2. strong inverse correlation between metabolic rate and life span across species

if selection has done everything possible to slow senescence, there is little to no genetic variability in the senescence rate

evidence contradicts this!

identified longevity mutations that slow senescence in various model organisms (APOE2 allele in humans)

life span is a heritable trait

there is considerable genetic variations

strong inverse correlation between metabolic rate and life span across species

high metabolic rates → increase in oxidative stress → intracellular damage

skepticism:

1. longevity mutants

2. within a species longevity and metabolic rate are not associated

3. exercise increases metabolic rate but doesn’t decrease longevity

4. ex. birds typically have longer life spans than mammals of comparable metabolic rate

early vs late mutations

average reproductive success is proportional to the average reproductive life span

inds with late-acting mutations have higher reproductive success than inds with early-acting mutations

deleterious mutations acting early in life will be under stronger selection

deleterious mutations acting late in life will be under weaker selection

mutation accumulating hypothesis

for late-life traits, selection is not strong enough to purge deleterious traits

deleterious mutations build up in genomes

predicts genes expressed early in life are under stronger selection than those expressed later in life

antagonistic pleiotropy hypothesis

a gene that provides an advantage early in life has deleterious effects later in life (or vice versa)

antagonistic pleiotropy

testosterone:

• early/mid life: boosts muscle mass, immune function, competitive ability, and reproductive success- all things selection loves

• late life: associated with increased risk of prostate cancer and cardiovascular disease

p53:

• early life: aggressively suppresses cancer by triggering cell death in damaged cells- clearly beneficial

• late life: same aggressiveness may contribute to tissue aging by eliminating too many stem cells over time, reducing the body’s ability to repair itself

1925: The state of Tennessee v. John Thomas Scopes

1925- a high school teacher was accused of violating the Butler Act, a law which outlawed the teaching of human evolution in public schools

scopes was a teacher represented by the american civil liberties union and defended by Clarence Darrow

william jennings bryan, a 3-time presidential candidate and former secretary of state, argued for the prosecution

scopes lost and was fined $100

became famous bc:

• staged acts to bring attention to the town (monkeys)

• Darrow took unorthadox step of calling Bryan, counsel for the prosecution, as a witness to question him on the Bible as an expert

• darrow embarrassed bryan and got him to contradict himself

• teaching of evolution continued to be prohibited in some states for many years

1968: Epperson v Arkansas

1927: “unlawful” for any teacher to say that evolution from animals was real in public school

1958: soviets launch sputnik and congress passes the national defense education act, promoted a textbook teaching evolution

1968: teacher Susan epperosn from little rock wanted to use new textbook

in 1968, US Supreme court unanimously ruled in this case that laws prohibiting teaching evolution violated the establishment clause of the 1st amendment