Evolutionary Medicine PDF

VL 1 Evolution in action -> Pathogen and tumor evolution is ongoing and somewhat predictable “Could this virus mutate and kill 90% of the population? Probably” - Can’t kill too fast in order to spread - Virus adapts to become successful at both: → Virulence/ transmission tradeoff...

VL 1 Evolution in action -> Pathogen and tumor evolution is ongoing and somewhat predictable “Could this virus mutate and kill 90% of the population? Probably” - Can’t kill too fast in order to spread - Virus adapts to become successful at both: → Virulence/ transmission tradeoff (Bad transmission if too low virulence, because not enough replications) - Vaccines, social distancing, etc. affect viral evolution - Bacteria: Selection and adaptation happens very fast (Short generation time) - Antibiotics already existed in nature (fungi, mold) “Always finish the full course of antibiotics” - ??? - Kills all, but selects for resistance more! → Resistant grow and take over (Usually have cost in the mix with non-resistance types bc of additional enzymes) - Some bacteria give their drug-resistance to other bacteria, causing more problems - Alternatives: Fecal transplant therapy, drug cocktails (diff. Antibiotics, overlapping), better use in hospitals, phage therapy (use viruses that stick to bacteria; viruses evolve even quicker than bacteria) - Same process in cancer (Chemotherapy can select for resistance)  - Resistance clumps not targeted by chemotherapy - Alternative treatment: Adaptive therapy (Control, not eliminate) - Evolution in action: Adaptive immune response Many lymphocytes with highly variable receptors are generated (--> Largest library in the universe) When a pathogen/ foreign antigen arrives look for the cell with just the right receptor → If respond, allowed to replicate → Highly specific attack thanks to variation and selection! - Breast cancer risk about 100 times higher!! (Due to lactation and pregnant period → Evolutionary mismatch) - Paleopathology: Agriculture: Was bad for health at first (Narrow diet (-> deficiencies); Malnutrition, relying on only very few species, especially weather; more infectious diseases (People live more densely) - → From acute to chronic disease (More hygienic life, less opportunity to learn for immune system (more autoimmune disorder)) What does evolution add to medicine? Usually: Proximate level - How does the mechanism work? Intervene with mechanism. But: Ultimate level - WHY/ Where does it come from (history)? What is it good for (function)? - Myopia (nearsightedness) not very prevalent in hunter-gatherers, but now (artificial light, indoors) BUT: It is inheritable and only expresses in the modern lifestyle!!!  - Fever - we think of it as a disease but actually raises body temp. slow pathogene replication - Iguanas (cold blooded) injected with bacteria - Raise body temp. With heat lamp - Treat with antipyretic (unable to raise temp) - More likely to die! - Similar found in rabbits → CHANGE in body temp is important! - !!!Heat Trial (2015) - Patients with fever assigned acetaminophen - No clear benefits with fever!! - → Smoke detector principle: Our bodies tend to overreact! - Error 1: False alarm - smoke detector goes off falsely - Error 2: Fail to alarm - smoke detector goes NOT go off despite fire - Error 2 >>>> Error 1 → Evolutionary adapted - → Reducing fever often not harmful; also applies to mental health - Evolution is all about reproductive success, not survival (healthy, well-being, etc.) - Survive into adulthood, ggf. post-reproductive years to help grandkids - Male reproductive effort is often concentrated in young adulthood, at the expense of longevity (in comparison to women who don’t die off as quickly → If they stay healthy for longer they can achieve more reproductive success) Woman play the long game vs. men earlier on - Trade off: Reproduction vs. maintenance = Ageing (Evolution favors reproduction) - Force of selection declines with age, once we start reproducing → “Selection shadow” (Things happening in old age not as visible to evolution) → Natural selection favors a limited lifespan  → Antagonistic pleiotropy: Alleles that are beneficial early in life will spread even if detrimental later in life (e.g. many oncogenes) VL 2 - Evolutionary Theory, Adaptation and Selection, Micro- and Macroevolution - Microevolution = How organisms become adapted to their environments (changes with one species) - Macroevolution = Origins of species, diversity of life (e.g. hereditary tree) - Evolution = Changes in traits over generations - Variation among individuals - Variation influences survival and reproduction - Variation is heritable (genetic basis) - → Natural selection - → Adaptations (design) - Source of variation: Mutation and recombination (meiosis) → Mutation is random, selection not! - Selection = “Survival of the fittest” (-> Fittest: Best adapted to environment) - Selection pressures: Predators, disease & parasites, access to food, access to mates - Adaptation = An inherited trait that makes an organism more fit in its environment; has arisen due to selection - Convergent evolution = Similar selection pressures produce similar adaptations, though not always by the same means (evidence for adaptation by natural selction) - Currency of adaptation: Fitness=Expected reproductive success of an individual with a specific trait, relative to other members of the population. --> Fitness depends on environment: Local adaptation and mismatch (in space) - E.g.: Skin color dark along equator: Save melanin production if not needed + Vit. D production (even if well protected enough production along equator) - Liver enzyme production thorough CYP2D6 gene → Duplications: Higher frequency of liver enzyme → Different in different populations → Medical consequences: Medication metabolism - Why do traits not change all the time? - Existing variants well adapted to their environment - Only adaption to change in environment -  - Adaptation: - !!!Medicine: More for physiology (e.g. at the moment adapting to temp. in room) - Evolution: To environment - Evolution hard to see when long generation times → Comparative methods, genetics, fossil record, laboratory studies → E.coli 8760 generations/year - Balanced selection = Heterozygous advantage - E.g.: Sickle-cell anemia: - Heterozygous: Changed hemoglobin structure, Less prone to Malaria, no sickle cell-anemia - Homozygous: Sickle Cell-anemia, few malaria resistance, short life expectancy —> It’s all about passing your genes on! Selection will be ongoing as long as people vary in how many kids they have!! - Sexual selection: Trade-off with immune system  - Male-male competition: High testosterone levels -> Chance for prostate cancer increases - Modern human environment is very dependent on culture/ technology (Insulation from climate, food production (fermentation), removed parasites (immune system less trained), repair bodies, increase physical performance, etc.) - Intervenience natural selection: 98% reach reproduction period, increase infertile gene (assisted reproduction technology) → Accumulation less favorable genes, diseases, increased intragroup variability !!!NOT all evolutionary change due to selection, not all traits adaptations → BY CHANCE, TOO!!! VL 3 - Evolutionary Medicine: Plasticity and life history Developmental plasticity = Different species able to react within their genetic makeup in different ways to environmental conditions. (Narrow reaction norm, broad reaction norm, alternative trajectories(worker/queen bees) - Reaction norm = Expresses the phenotype as a function of the environment; makes the variation you observe in a population - Plasticity changes over multiple generations (e.g. 10-year old boys in Brandenburg smaller possibly due to physical activity, nutrition, migration) - - Epigenetics - Reasons: Turn genes on & off during development - Mechanism for predictive adaptive response (“epigenetic memory”) - Mostly get erased in early zygote (“imprinted” genes stay) - Developmental plasticity: Programming according to expected environment (Optimal environment: Investment in longevity; Threatening environment: Altered reproductive strategy(early), ensure survival to birth, adjustments to resist threatening and difficult environment) → Tradeoff btw. Immediate survival and future health (Birth weight = high mortality/ morbidity)  - Holländischer Hungerwinter - Epigenetic transmission through generations!!! - - →Risk of disease accumulate over time!! - Dual burden in developing countries: Usually: - Less disease, more food —> 1) Taller population  - Too much to eat → 2) Obesity - BUT: Third world countries both!!! - Life history theory: Two main strategies - Small, lots of offspring(few survive), reproduce early, die young vs. grow slow&big, reproduce late, invest in offspring, live long → Timing of events in the lifespan → Increasing body mass (also brain size) comes with longer life! (& later reproduction) - - Human life history - Long investment in skills, multiple stacked offspring, supplemented by parents & grandparents - Demographic transition - - Switzerland: More middle-age people than young people - Antagonistic pleiotropy = Genetic variants that are beneficial at young age, but increase the risk of disease at older age. (e.g. cancer, cystic fibrosis, coronary heart disease, Alzheimer, Huntington’s disease) - Costs and benefits within transition to modernity VL 4 - Human Evolution and Human Biological Variation - Charles Darwin: - Right: - Humans evolved in Africa - Humans are one species - Unique traits: Bipedalism((Two legs), technology, large brains, small canines - Wrong: - Unique traits evolved at the same time - There are distinct races - Europeans are superior to other races, men to women → Human origin as field of study → Science is done by people (many biases!!!) → Knowledge improves as more evidence accumulates - Humans share many traits with other mammals (e.g. hair, life birth, gastation); All primates: e.g. Hands (hold on to branches), larger brains, slower life histories Uniquely human: No tails, sleep in nests, etc.k HUMANS ARE PRIMATES! - Human Evolution is not linear -> Many small, slow steps! Process never necessarily lead to our species! -Upright walking proceeds brain expansion! - Different homini species co-existed! - Svante Pääbo: 2022 Nobel Price in Medicine: “For his discovery concerning the genomes of extinct(ausgestorben) hominis and human evolution” (e.g. discovered entirely new species Denisova” - Method: Extract DNA from remains -> Sheds different view on history of coexistence - What made the Genus Homo? - Humans had to deal with fluctuating temperatures for most of human history -> Genetic inheritance isn’t useful when environment is constantly changing! (Listen to elderly people how to live!) -> Development of certain traits: - Cooperative breeding (impossible to raise child alone) - Allows for high human fertility despite slow development - BUT: Hard to raise child alone -> Post-partum depression, selective neglect, infanticide, etc. - Cumulative culture - Omnivorous, extractive diet ( = Consume variety of food sources) → More complex sociality (Social, cognitive changes-> Vulnerable to certain diseases!) → Response to variability depending on time scale: Long (many gens): Genetic adaption Fast ( Self-medication (BUT: Vulnerable to addiction!) & COOPERATION - African Americans are more likely to die at early ages from all causes!! Not genetic! - Out-of-Africa: ca. 100`000 years ago - !!!Humans share >99% of the genome with each other & chimps; 50% with bananas - As humans expanded across globe -> Some local genetic adaptation due to new selection pressures, e.g. pathogens. Diet, altitude, UV radiation, etc. - Genetic information can be used to reconstruct population history/ ancestry; BUT: Most variation neutral (most mutations: silent without function); AND: continuous variation going in different directions !!!! Variation within >>>>> btw. Populations!!! - Most adaption was cultural, not genetic (e.g- build iglu) - Race as a social construct; BUT: Racism cause health disparities (e.g. psychological stress, socio-economic deprivation, health inequity, e.g. vicarious racism->shortened telomeres) ASK: WHAT IS THE ENVIRONMENT OF THESE PEOPLE LIKE? - Health disparities in other species: e.g. stress-eating, higher inflammation in subordinate monkeys (but NOT if dominant animal) - Obesity paradox: Poor people who face food scarcity - Overeat more! - Lifetyme exposure to Testosterone -> Prostate cancer risk - Population differences in T levels -> Prostate cancer Envrioment -> Biology -> Health - People living in worse neighboorhood reproduce earlier, age faster - Also here: Immigrants from low-income countries at greater risk for being overweight - Envriomental causes e.g. trauma, stress, migration, discrimination, current poverty/ social status, developmental mismatch (over- -> undernutrition)  - Epigenetic inheritance, maternal effects -> Takes several gens to adapt → Environment has stronger effect on health than genetic ancestry!!! → Public health interventions >> new medicines —> Public health = Politics