Chapter 18 -- Evolutionary Medicine p. p. 605

ZIMMER and EMLEN FREEMAN and HERRON

Insights from evolutionary biology can inform medical research.

"The substantial benefits of evolutionary studies of disease will be realized only if they become central to medical curricula, an advance that may at first require the establishment of one or more research centers dedicated to the further development of Darwinian medicine."

George Williams and R. M. Nesse 1991. The dawn of Darwinian Medicine. Quarterly Review of Biology.  66:1-22.

 

 

  1. Figure 14.1: Map of Central London & Cholera Epidemic
  2. The germ theory of disease was one of the most important breakthroughs in medicine.
    1. Louis Pasteur, 1858:  diseases were caused by microorganisms
  3. Germ Theory and Understanding the Evolution of Disease
    1. Disease could be treated by fighting the invading pathogen
    2. These changes brought about a dramatic improvement in the treatment of disease
    3. By the end of the 1960's the medical community considered infectious disease would be conquered.

18.1 How Diseases Are Born p. 607

  • New human diseases emerge through the evolutionary shift of pathogens from animal hosts.
 

Host Shifting p. 609

  • Shifting from one host to another may require a suite of mutations and more than a single influx of alleles – an evolutionary pathway that we may be able to exploit for our benefit.
 
Evolution Within p. 611
  • Viruses and other pathogens respond to natural selection at a rapid rate. Pathogen evolution can be measured even within a single host.
 
18.2 The Evolution of Virulence p. 613
  • The harm that pathogens cause is under selection.
  • Pathogens must trade off the rate at which they replicate inside a host, and how easily they can be transmitted from one host to another.
14.3 EVOLVING PATHOGENS: VIRULENCE
  1. virulence describes the effect a pathogen has on its host.
  2. Three models have been proposed to account for the evolution of virulence.
  3. The coincidental evolution hypothesis
  4. virulence is not a direct target of selection.
    1. it is a result of selection acting on the pathogen in a different environment. (e.g., tetanus)
    2. The short-sighted evolution hypothesis
      1. traits that enhance within-host fitness may be detrimental to transmission of the pathogen
      2. The trade-off hypothesis
        1. pathogens should evolve to where its costs to the host are balanced by its capacity to propagate itself to other hosts
        2. Transmission Rate Hypothesis (Paul Ewald)
          1. High transmission rate favors high virulence
          2. Low transmission rate requires low virulence
        3. Natural selection should strike an optimal balance between the costs and benefits of harming hosts
        4. Experimental evolution: evolution of virulence
          1. E. coli as the host and a virus (phage f1) as the pathogen
          2. Phage f1 produces lasting, non-lethal infections in E. coli, but slows growth rate
          3. The phage can be transmitted either horizontally or vertically
          4. Messenger et al. (1999) manipulated the study system
            1. Some cultures had 1-day vertical transmission phases coupled with a short horizontal phase
            2. Some cultures had 8-day vertical transmission phases coupled with a short horizontal phase
          5. Figure 14.14 A trade-off between the virulence and within host reproductive rate of a virus that infects E. coli
          6. Fig. 14.15 Virulence in Human Pathogens
            1. Diseases carried from host to host by insects (malaria) are on average more virulent than directly transmitted diseases (colds, flu).
            2. Fig. 14.16 The virulence of intestinal bacteria, as a function of tendency toward waterborne transmission
The Ever-Evolving Flu p. 615
  • Influenza rapidly evolves each year, and processes such as reassortment give rise to new genotypes.
  1. 14.1 Evolving Pathogens
    1. Pathogens have evolved in response to the selection pressures imposed by medicine.
    2. there is strong selection imposed by host's immune system for parasites that can evade detection.
  2. The evolution of flu viruses
    1. the Influenza A virus is responsible for annual flu epidemics and pandemics
    2. Influenza virus is a retrovirus with a genome of 8 RNA strands
    3. The strands can reassort
  3. The evolution of antigenic sites
    1. Hemagglutinin is the main target of our immune system.
  4. Flu Virus Evolution
    1. New genes through reassortment
    2. New alleles through mutation
  5. A phylogenetic analysis of frozen flu samples
    1. Figure 14.5a: The molecular evolution of Influenza A hemagglutinin gene over a 20-year period
  6. Flu Virus Evolution
    1. Since flu is an RNA virus, mutation frequency is higher than for a DNA virus
    2. Most strains represented extinct side branches on the phylogeny (Fig. 14.5b)
  7. Knowledge of Flu Evolution & Vaccines
    1. successful strain would have had more mutations in its antigenic versus non-antigenic sites (Fitch et al)
    2. Over 75% of the amino acid replacements in surviving lineages were in antigenic (hemagglutinin) sites (versus <50% in extinct).
  8. A typical pattern observed in most protein coding genes
    1. Evidence for the neutral model
      1. "silent" substitution rates are higher than "replacement" substitution rates.
      2. Fig. 7.21: Among 331 mutations observed in hemagglutinin Influenza A alleles: 58% were silent, 42% were replacement
  9. Evidence for positive selection among the 331 mutations in the hemagglutinin alleles
    1. positive selection occurs when the rate of replacement substitution exceeds the rate of silent substitution.
    2. positive selection is attributed to the action of selection favoring amino acid replacements.
    3. in Influenza A, there are 18 hemagglutin codons exhibiting higher ratios of silent to replacement mutations
    4. These 18 codons are in antigenic sites
    5. this allows us to predict surviving strains and thus make flu vaccines
  10. Positive selection in the hemagglutinin gene
    1. Figure 14.6 Predicting which lineages of flu will survive to cause future epidemics
      1. Usually, it is the lineage with the most amino-acid replacements in its hemagglutinin antigenic sites (indicated by colored dots). Redrawn from Bush (2001).
The 1918 Flu p. 617
  • About 50 million people died from a massive flu pandemic in 1918.
  • Evolutionary biology helps explain why it was so virulent and helps scientists prepare for new pandemics.
  1. Origins of pandemic flu strains
    1. If a host becomes infected with two different flu strains these strains could swap RNA strands
    2. Figure 14.7 A phylogeny of flu viruses based on the nucleoprotein gene (important for host recognition).
      1. for each viral strain shows the host species from which it was isolated, the year, and the type of hemagglutinin and neuraminidase it carries.
      2. Codes show that they have different neuraminidases and hemagglutins
  2. Are viruses "swapping" genes?
    1. Novel Hemagglutinin often associated with pandemics
    2. Prior to the pandemic of 1968, no H3 hemagglutins were ever observed in human flu strains
  3. Origin of Pandemic Flu Strains
    1. Flu strains 'swap' chromosomes
    2. 14.8 A phylogeny of flu virus hemagluttinin genes
    3. Some recent work on Influenza A: recreating the 1918 Spanish Flu virus Ghedin et al. 2005; Taubenberger et al. 2005)
Resurrecting a Monster p. 618
  • Understanding the path to virulence is the key to some epidemics, and it may be locked in their evolutionary history.
 
18.3 Molded by Parasites p. 620
  • Humans have evolved defenses against many diseases.
  • Studying these defenses can provide clues about how to fight these diseases more effectively.

 
18.4 Evolution’s Drug War p. 623
  • The invention of antibiotics has given rise to strong selection for resistant bacteria.
 
Silver Bullets p. 623
  • The rapid evolution of resistance to antibiotics raises concerns about whether new drugs will be able to remain effective for long.
14.2 Evolving Pathogens: Antibiotic Resistance
  1. Antibiotics are chemicals that kill bacteria by disrupting particular biochemical processes.
  2. An evolutionary perspective suggests that antibiotics should be used judiciously
  3. Sources of antibiotic resistance:
    1. Mutation to create new resistance alleles
    2. Horizontal transfer of resistance genes.
    3. Significant Antibiotic Resistance of Some Example Bacterial Strains
    4. Evidence of evolution as a result of antibiotic use
      1. CDC Tuberculosis study (page 539)
      2. Icelandic penicillin study (Fig. 14.11)
      3. Costs of resistance to bacteria
        1. Resistance imposes a cost on bacteria.
        2. If the cost is high, non-resistant bacteria should have an advantage
        3. Costs of resistance suggest that suspending use of an antibiotic might allow populations to evolve to a non-resistant state again.
        4. Resistant bacteria may also evolve ways to reduce or eliminate the costs of resistance (Schrag et al., 1997)
      4. Schrag et al. (1997)
        1. Experiment tested competition between two strains in the absence of the antibiotic over the short term and after the resistant strain had reproduced for many generations (Fig. 14.12)
        2. Studied streptomycin sensitive E. coli and screened for resistant mutants.
        3. Point mutations in gene rpsL coding for that ribosomal protein can confer resistance.
        4. In the first set of experiments in which streptomycin resistant strains were compared with genetically manipulated non-resistant strains a short time after the mutation, resistant strains were at a disadvantage and sensitive strains grew better.
        5. Resistant strains allowed to evolve for many generations and then tested against streptomycin senistive strains, developed mutations that compensated for costs of streptomycin resistance
        6. there is no guarantee that bacterial populations can be restored to vulnerability by withdrawing an antibiotic from use.
        7. Thus, steps to avoid bacteria developing resistance need to be taken.
        8. Guidelines for Antibiotic Use
        9. Society's ongoing struggle against infectious disease
          1. Carl Nathan. 2004. Antibiotics at the crossroads. Nature 431, 899-902
18.5 Human Variation and Medicine p. 628
  • Recognizing and understanding the incredible variation in human populations that has resulted from drift and natural selection may be crucial to treatment of diseases and genetic disorders.
 
Sick from Sexual Conflict p. 630
  • Evolutionary conflicts between parents can lead to a number of genetic disorders through defects in genetic imprinting.
 
Old Age: Evolution’s Side Effect p. 630
  • Medical researchers seeking to slow the effects of old age are investigating the evolution of senescence in humans and other species.
 
18.6 The Natural Selection of Cancer p. 631
  • Cancer cells experience a form of natural selection in which cells compete with one another for resourses and rapid growth.
  • The human body has evolved a wide range of defenses against cancer.
 
18.7 Mismatched with Modern Life p. 634
  • The environment of modern humans has changed with great speed, and the human body has not had enough time to adapt completely to the new conditions.
  • Autoimmune disorders, such as allergies and asthma, may result from an evolutionary mismatch between the human body and modern life.

  1. 14.5 THE ADAPTATIONIST PROGRAM APPLIED TO HUMANS
  2. We can use the adaptationist program (Ch. 10) to study human physiological and behavioral traits relevant to medicine and public health.
  3. Adaptation to What Environment?
    1. Humans were hunter-gatherers until the beginning of agriculture about 10,000 years ago.
    2. Effects of novel behaviors: dietary diseases
      1. Fig. 14.21, A typical hunter-gatherer diet versus a typical modern American diet
      2. There are few ways in which our bodies have adapted to post-hunter-gatherer lifestyles.
      3. Myopia
        1. Nearsightedness is at least partly heritable.
        2. Data from Inuits suggest that myopia associated with lots of reading during childhood (p. 553).
      4. Applying adaptationist thinking to humans: Breast Cancer
        1. About 1 in 8 North American women develops breast cancer, some of whom die while in their child-bearing years.
        2. Like myopia, breast cancer has both genetic and environmental components.
        3. why hasn't selection eliminated genes that cause the disease or selected for individuals resistant to environmental effects that induce cancer?
          1. Breast cancer may be caused by a pathogen
          2. Breast cancer, like myopia, may be a disease of civilization
        4. Mice carry a virus called Mouse Mammary Tumor Virus (MMTV) that causes the mouse equivalent of breast cancer.
          1. In an analysis of 314 breast tissue samples (Wang et al. 1995), 38.5% of cancer tissue samples contained DNA sequences similar to MMTV, but only 1.9% of normal breast tissue samples did.
          2. Geographical level analysis looking at incidence of breast cancer in relation to distribution of the mouse Mus musculus and Mus domesticus (Stewart et al., 2000) (Fig. 14.22).
          3. On average, rates of breast cancer are higher in countries occupied by Mus domesticus.
          4. MMTV has not been isolated from breast tumors and possible route of infection is unknown.
          5.  MMTV cannot account for more than 40% of breast cancer cases
        5. Breast cancer as a disease of civilization.
          1. Monthly menstrual cycle of most modern/western women is considered normal.
          2. However, epidemiological evidence suggests monthly menstrual cycles may increase the risk of breast cancer.
          3. Menstrual cycling appears to elevate risk of cancer because combination of estrogen and progesterone stimulates cell division in cells lining milk ducts. More cell division increases chance of mutations.
          4. Fig. 14.24. In hunter-gatherer societies, most women are pregnant or breast feeding, not cycling continuously like in industrialized societies (From Strassmann, 1999))
          5. Figure 14.24a: Most Dogon women had relatively few menstrual cycles during a two-year period.
          6. At any given time less than 30% of Dogon women are undergoing menstrual cycling.
          7. Over the course of her reproductive lifetime a Dogon woman experiences about 100 cycles as compared to the approximately 300 cycles of a North American woman.
          8. Figure 14.24b
          9.  Women 20-35 spend little time menstruating.
          10. W. African women have 1/12 rate breast cancer as American women.
From Famine to Feast p. 636
  • Obesity is the result of our physiology—adapted to surviving on scarce food supplies—being plunged into the food-rich environment of modern life.
 
18.8 Evolutionary Medicine: Gloom and Hope p. 639
  • Many insights from evolutionary medicine are sobering reminders of the limits to repairs we can make to the human body.
  • But they also provide some reasons for hope, such as the ability to discover new drug targets by exploring the evolutionary history of our genes.
 
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