Category Archives: evolution


Plague Dialogues: Monica Green and Boris Schmid on Plague Phylogeny (I)

In keeping with this blog’s goal to be a meeting ground for interdisciplinary discussions, I’ll be hosting a series of dialogues between scholars in the humanities and sciences. If you would like to be involved in one of these dialogues, please use the contact form on the about page.

On behalf of today’s participants, I invite you to post comments on this dialogue or on twitter.

Monica H. Green (, @MonicaMedHist ) is a historian of medieval medicine. An elected Fellow of the Medieval Academy of America, she teaches both global history and the global history of health. She was the editor in 2014 of Pandemic Disease in the Medieval World: Rethinking the Black Death, the inaugural issue of a new journal, The Medieval Globe.

Boris Schmid (@BorisVSchmid) is a theoretical biologist at the University of Oslo, Norway, and specializes in disease ecology and epidemiology. He recently described a link between climate fluctuations in medieval Central Asia and what looks like repeated introductions of plague into Europe’s harbors, a hypothesis that can be tested by the analysis of ancient DNA samples of Y. pestis. He works in a multidisciplinary team of theoreticians, archeologists, microbiologists and historians, led by Nils Chr. Stenseth.

“Tiny Changes with Huge Implications: Counting SNPs in Plague’s History”


I’d like to raise the question of SNPs and why understanding them is so important for those keeping an eye on the “plague aDNA debates.” SNPs – single nucleotide polymorphisms, one of the smallest levels of genetic change you can document on a genome — are critical to the evolutionary, and historical, story of Yersinia pestis (the causative agent of plague), because Y. pestis in fact has been proven to change so little over time. Nucleotide changes are a normal part of evolution. They just happen. But they don’t necessarily happen at the same rate in all organisms, or even necessarily at the same rate in the same species in all circumstances. On top of that, sudden proliferation of an organism — say, in the context of an epidemic in the case of pathogenic organisms — may increase the rapidity with which a random evolutionary change gets fixed in a population. (See Cui et al. 2013)

In the case of Y. pestis, it’s actually been shown to be “genetically monomorphic.” That’s another way of saying, it doesn’t change very much or very often. Within its core genome (the common set of genes shared by all Y. pestis bacteria), most any Y. pestis cell you find is going to look pretty much like every other one across much of its ±3.5 million nucleotides, differentiated only by a few dozen or a few hundred different SNPs (Achtman 2012). So when a ‘C’ (cytosine) in one position on the genome changes to a ‘G’ (guanine) or ’T’ (thymine) or ‘A’ (adenine), that can actually be a historically significant change. And when that new SNP suddenly shows up in a whole population, that’s a sign that something major has happened. That’s what Cui et al. 2013 talked about in the “Big Bang” they posited for the later medieval period: the old Branch 0 of Y. pestis (see fig. 1) suddenly split into four new branches, each characterized by a different SNP signature. And the sequencing in 2011 of the first three Y. pestis genomes from the London Black Death cemetery (Bos et al. 2011; I’ll want to talk about the 4th genome, London 6330, later), made clear that that split did indeed happen quite suddenly. The split happens (presumably somewhere in western China or central Eurasia) and then, “two SNPs later,” Y. pestis shows up in London. Given the distances involved in transmitting this single-celled organism — several thousands of kilometers —  and the fact that there are no airplanes in the 14th century to account for rapid dissemination, that’s quite significant.

Cui et al 2013 fig S3B Minimum spanning tree, with SNP counts (post-polytomy branches only)
Fig. 1: Cui et al 2013 fig S3B Minimum spanning tree of relationships between 133 core genomes of Y. pestis based on 2298 SNPs. Detail to show post-polytomy branches (the “Big Bang”), at the middle of the tree. Branch 0 is the vertical stem below that. New aDNA work in 2016 has added additional sub branches just after the polytomy on Branch 1 (upper left).



The mutation rates of bacteria is indeed a topic with quite some nuance, and one that is worth delving into in order to understand the slew of aDNA plague papers that are currently coming online.

The rate at which plague accumulates new point mutations has been calculated from the plague outbreaks in Madagascar (Morelli 2010) to be on average of 1 mutation for every 100 million nucleotides copied (Cui 2013). While that sounds like a very uncommon event, it really is not, given the length of its genome – a single bacterium that is replicating itself would after 4 generations (so roughly 7 hours within a human (Chauvaux 2007)) be a small colony of 16 bacteria, with a total of 105 million nucleotides of core genome copied, and therefore most likely already with 1 SNP among them. But here we are comparing two different things – the mutation rate used by Morelli and Cui is valid for the amount of variation you’d expect to accumulate in each surviving lineage of plague during an epidemic; many of the mutations that were generated are lost again simply because those bacteria were not the ones that continued the epidemic.

Bos (2011) notices with surprise that the plague at the time of the Black Death differed just 97 SNPs from CO92 (a sample collected from a human patient in 1992 in Colorado, and the plague strain that by convention is used as a baseline against which to compare other plague strains). So that is 1 accumulated mutation every 6.6 years, counting from 1348 to 1992. That compares pretty well to the mutation rate in a plague focus we in Oslo are currently studying, where we see an accumulation of mutations along each lineage of about 1 mutation every 8 years. Continuing with our back-of-the-envelope calculation, this “two SNPs later” since the sudden divergence of plague into 4 lineages puts the date of the “Big Bang” at just 10-20 years prior to the arrival of the Black Death in Europe in 1347. There are some caveats that come with this analysis, notably that the rate at which mutations are accumulated can be quite slower in some branches of plague (up to 6-fold, Cui 2013), but for now let us continue with a simplistic 1 new SNP being fixed into a plague lineage approximately every 7 years.

With that 1 SNP per 7 years rate in mind, let’s look at the stylized version of the evolution of Yersinia pestis, recently presented by Johannes Krause (fig. 2 below), with the recently published medieval plague sequences (and now the new publication from Spyrou et al. 2016), and see what it tells us in terms of the history of plague.

Fig. 2: A simplified diagram of the “Big Bang” (polytomy) proposed by Cui et al. 2013, where plague split up into its 4 branches in the 13th or 14th century. Branch 1 is the lineage responsible for both the Second (medieval) Pandemic in western Eurasia and Africa and the Third (modern, global) Pandemic. Moving along Branch 1 from the initial split, two SNPs after the “Big Bang,” we see the introduction of the Black Death into Europe (the red-darkred circle). In our discussion, we call the branch leading to Marseille (the grey circle) “Branch 1A”; the branch leading to the rest of Branch 1 we call “Branch 1B.” (Source: Krause 2016.)



Thanks, Boris, for laying out these calculations. So, we’ve established that, even though Y. pestis is genetically monomorphic—that it doesn’t have sex and doesn’t even often switch genetic material laterally—that it does have a tendency to develop random mutations over time. Par for the course for basic biology. I’d like to return now to a point I already made, which is more historical: “And when that new SNP suddenly shows up in a whole population, that’s a sign that something major has happened.” The big question we’re looking at with the Black Death strain and the “founding” of Branch 1 of the Y. pestis phylogenetic tree is: how did one—just one—Y. pestis cell get its SNP profile to be the founder of the whole lineage that caused millions of deaths in the first wave of the Black Death? This seems to be a classic “founder effect” scenario, the Mitochondrial Eve of this new phase of plague history. (And yes, I know that Y. pestis doesn’t have mitochondria.) Granted, we only have fully sequenced aDNA from two Black Death sites: London and Barcelona. But Spyrou et al. report that the Barcelona sample is identical in every respect with the three London Black Death genomes that were sequenced in 2011.

Let us assume then, for the moment, that our historical sources are correct that the famous outbreak of plague in Caffa in 1346 (the bodies being hurled over the walls) caused a single chain of events that carried our one strain of Y. pestis all the way to Barcelona and London within a two-year period. Presumably, if we had samples from all the other places plague struck in those brutal first years as it spread from the Black Sea to the Mediterranean—Alexandria, Aleppo, Almeria, etc., etc.—they would all have the same SNP signature that Haensch et al. 2010 reported from sample SNP typing for Hereford (UK) and Saint-Laurent-de-la-Cabrerisse (France), and that Seifert et al. 2016 reported, also from sample SNP typing, for Manching-Pichl (Bavaria). None of those sites are as precisely dated as the first three genomes sequenced from the East Smithfield cemetery in London (which is dated from documentary records to late 1348 to 1350). But for the sake of argument let’s assume that they are, in fact, all first outbreak burials. So all those human deaths are caused by an identical organism, moving into new vulnerable hosts at the same time.

But now we have to ask: what happened after the Black Death? What was Y. pestis’s next stage of evolution? The samples we have thus far, whether whole genome sequences or just SNP profiles, are all taken from human bodies. But humans are not natural carriers of plague. Every aDNA sample found thus far is probably a dead end, literally: the end of the line for the unique SNP profile (if it had one) of the Y. pestis that infected that individual. It died with them. If we’re going to look for what sustained plague, what allowed it to focalize and continue replicating for centuries thereafter, then we need to look at what plague strains survived in rodent populations.


The question of where plague’s reservoir was in medieval Eurasia is indeed the question that, as a biologist, I was eager to work on, Monica. Validation of any theory of how plague has moved across Eurasia in the past would have to come from the analysis of the SNPs that plague gathered along the way. However, the interpretation of those medieval SNPs turns out to less clear-cut than most of us had anticipated, as we will discuss in the next blog post.


Achtman, M. (2012). Insights from genomic comparisons of genetically monomorphic bacterial pathogens. Philosophical Transactions of the Royal Society B: Biological Sciences, 367(1590), 860–867.

Bos, K. I., Schuenemann, V. J., Golding, G. B., Burbano, H. A., Waglechner, N., Coombes, B. K., et al. (2011). A draft genome of Yersinia pestis from victims of the Black Death. Nature, 478(7370), 506–510.

Chauvaux, Sylvie, Marie-Laure Rosso, Lionel Frangeul, Céline Lacroix, Laurent Labarre, Angèle Schiavo, Michaël Marceau, et al. 2007. “Transcriptome Analysis of Yersinia Pestis in Human Plasma: An Approach for Discovering Bacterial Genes Involved in Septicaemic Plague.” Microbiology 153 (Pt 9): 3112–3124

Cui, Y., Yu, C., Yan, Y., Li, D., Li, Y., Jombart, T., et al. (2012). Historical variations in mutation rate in an epidemic pathogen, Yersinia pestis. Proceedings of the National Academy of Sciences, 110(2), 577–582.

Haensch, S., Bianucci, R., Signoli, M., Rajerison, M., Schultz, M., Kacki, S., et al. (2010). Distinct Clones of Yersinia pestis Caused the Black Death. PLoS Pathogens, 6(10), e1001134.

Krause, Johannes (4-12-2016)  Oral Presentation #S577:  Ancient pathogen genomics: what we learn from historic pandemics. European Congress  of Clinical Microbiology and Infectious Diseases

Seifert, L., Wiechmann, I., Harbeck, M., Thomas, A., Grupe, G., Projahn, M., et al. (2016). Genotyping Yersinia pestis in Historical Plague: Evidence for Long-Term Persistence of Y. pestis in Europe from the 14th to the 17th Century. PLoS ONE, 11(1), e0145194–8.

Spyrou, M. A., Tukhbatova, R. I., Feldman, M., Drath, J., Kacki, S., de Heredia, J. B., et al. (2016). Historical Y. pestis Genomes Reveal the European Black Death as the Source of Ancient and Modern Plague Pandemics. Cell Host and Microbe, 19(6), 874–881.

Keeping Bronze Age Yersinia pestis in Perspective

Graphic abstract from ____
Graphic abstract from Rasmussen et al, 2015.

The latest plague news to splash across headlines is the discovery of Yersinia pestis aDNA in seven Bronze Age remains from Eurasia.  The most important findings in this new study are not anthropological; they are evolutionary. This paper allows us to drop a couple more evolutionary mile markers. Finding  7% of the tested remains  (7 out of 101) positive for plague is surprising, but I’m not yet ready to believe that it was endemic over such a huge area scattered over 2000 years. Not yet anyway.

The new phylogenetic tree places Y. pestis in humans since the Bronze Age and the origin of the species as far back 50,000 years ago.  It also opens up questions on the original reservoir species and the location of the birth of the species, although central Asia is still the most likely location.

Stretching out the Yersinia pestis tree. Blue arrows are gains and red arrows are losses. (Rasmussen et al, 2015)


So let’s look at the genetic results in three areas highlighted by Rasmussen et al: flea transmission, Pla activity, and suppression of the immune response stimulating flagellin production. These traits are critical to producing bubonic plague as we know today.

Late phase flea transmission of modern Yersinia pestis is dependent on the ability to survive in and colonize the flea. The Bronze Age strains have all of the plasmids and virulence genes of modern strains except one, the ymt gene that encodes the murine toxin. The basic tool set of modern strains also have deactivated or knocked-out the protein products of three ancestral genes that hinder Yersinia pestis biofilm formation. Remnants of these genes persist as pseudogenes in modern strains. (A pseudogene is the corpse of a former gene.) This genetic combination allows Y. pestis to survive in the mid-gut of the flea, persist longer and form a biofilm; a necessity for late phase flea transmission. However, as Monica Green reminded me,  ymt is not required for early phase flea transmission, dirty-needle style (Johnson et al, 2014). In fact, since Y. pestis does not need to persist long or multiply at all, there are no known genes needed to be present or absent for early phase transmission.  As I recently reviewed, early phase transmission is very common and effective (see Eisen, Dennis & Gage, 2015). Based on the dates of their samples, they estimate that ymt was gained in about 1000 BC. In the RISE509 strain from Afanasievo Gora in southern Siberia, the pde3 is inactive but the other two, pde2 and rcsA, are still functional. Taken together this genetic combination should allow early phase flea transmission but not late phase flea transmission that requires biofilm formation. They are still mid-way in developing late phase flea transmission. This makes sense for a microbe being transmitted dirty-needle style, providing the opportunity for natural selection to develop late phase transmission bit by bit. While early phase transmission can support regional epizootics and epidemics,  late phase flea transmission is probably important for long distance transmission by fleas in grain or textiles, or by sea.

The recent discovery of the Pla gene in Citrobacter koseri and Escherichia coli, other enteric opportunistic flora, but not found in Yersinia pseudotuberculosis, suggests that lateral gene transfer  brought the plasmid to the young Y. pestis while still in the enteric environment (Hänsch et al, 2015) . This is consistent with Y. pestis Pla and Salmonella enterica PgeE both evolving from the same ancestral omptin ancestor in an enteric environment (Haiko et al, 2009).  This suggests that Y. pestis may have remained an enteric organism for some time after it split from Y. pseudotuberculosis.

Six of seven Bronze Age Y. pestis strains contain the Pla gene required for deep tissue invasion and bubo formation. Rasmussen et al (2015) suggest that the strain lacking the Pla gene has lost it and that this gene has been lost more than once in the phylogenetic tree. In other words, Pla was present in the common ancestral strain. However, to support development of bubonic plague Pla needed to gain a mutation at position 259 that these strains lack (Haiko et al, 2009). So the Pla gene without the mutation at position 259 can support pneumonic plague but not bubonic in the Pestoides F strain (0.PE2) of Y. pestis (Zimbler et al, 2015).  On the other hand, Sebbane et al (2006) showed that strains completely lacking Pla can still develop primary septicemic plague following flea transmission. They can envision an “evolutionary scenario in which plague emerged as a flea-borne septicemic disease of limited transmissibility”(Sebbane et al, 2006).  Without the polymorphism at position 259, bubo formation should be retarded, if not suppressed.

A third genetic difference of possible significance is the apparent ability to produce flagellin, a major activator of the human innate immune system. Modern Y. pestis strains have deactivated the production of flagellin by a frameshift mutation in the regulatory gene flhD. The Bronze Age strains lack this frameshift and so presumably had normal flagellin production. However, Y. pseudotuberculosis and  Y. enterocolitica down regulate production at mammalian body temperatures. If the ancestral Y. pestis did also then its possible that it wasn’t a factor in human infections.  Experimentally recreating the regulatory environment from  Y. pseudotuberculosis would be much more difficult than simply inserting an intact copy of the gene in a modern strain of Y. pestis.

Predicting the impact of these ancestral genes is highly conjectural. This combination of genes has never been studied together. Since these strains were isolated from human remains we can assume that there is a path for transmission and pathogenesis. The reliance on early phase flea transmission, the less virulent pla allele and the possible production of flagellin suggest that Bronze Age local (dermal) infections from flea bites would be less virulent (more survivable). Interestingly, these milder local infections may have been immunogenic.

As Y. pestis moved away from an enteric lifestyle, producing a septicemia was necessary for either flea transmission or development of a secondary pneumonia with aerosol transmission. I find it hard to believe that Bronze Age Siberia or Estonia had a large enough population for sustained pneumonic transmission. Since Pulex irritans can transmit Y pestis without development of a biofilm, there is no reason to see humans as a dead-end to flea transmission even as early as the Bronze Age.

Humans could have also contracted septicemic plague by ingesting infected meat. Although natural ingestion infections are very rare today, this mode remains effective. A village size outbreak could easily occur from sharing a large infected animal as happened in Afghanistan in 2007. In that outbreak a single infected camel shared among two villages produced 83 probable cases of plague with 17 deaths, a case fatality rate of 20.5%. (Leslie et al, 2011).  Last but certainly not least, the further back we go in Yersinia pestis‘ evolution the more likely ingestion is to be a mode of transmission like its ancestor Yersinia pseudotuberculosis.

Its takes more than good transmission to cause a demographic changing epidemic over large areas like the Eurasian continent. It also requires a fairly high human density and good trade or communication routes. Humans play the the most important role in transmitting plague of pandemic size. I can’t say if the cultural factors that make such large epidemics possible were in place in Bronze Age Eurasia.

Let’s keep things in perspective before we conjure up the specter of virgin soil epidemics of plague in the Bronze Age. Yersinia pestis is the kind of over achiever that may have been a player in Bronze Age demographics but it would be nice to have a lot more evidence before jumping to that conclusion.


Rasmussen, S., Allentoft, M. E., Nielsen, K., Orlando, L., Sikora, M., Sjögren, K.-G., et al. (2015). Early Divergent Strains of Yersinia pestis in Eurasia 5,000 Years Ago. Cell, 163(3), 571–582.

Eisen, R. J., Dennis, D. T., & Gage, K. L. (2015). The Role of Early-Phase Transmission in the Spread of Yersinia pestis. Journal of Medical Entomology, tjv128–10.

Johnson, T. L., Hinnebusch, B. J., Boegler, K. A., Graham, C. B., MacMillan, K., Montenieri, J. A., et al. (2014). Yersinia murine toxin is not required for early-phase transmission of Yersinia pestis by Oropsylla montana (Siphonaptera: Ceratophyllidae) or Xenopsylla cheopis (Siphonaptera: Pulicidae). Microbiology, 160(Pt_11), 2517–2525.

LESLIE, T., WHITEHOUSE, C. A., YINGST, S., BALDWIN, C., KAKAR, F., MOFLEH, J., et al. (2011). Outbreak of gastroenteritis caused by Yersinia pestis in Afghanistan. Epidemiology and Infection, 139(5), 728–735.

Sebbane, F., Jarrett, C. O., Gardner, D., Long, D., & Hinnebusch, B. J. (2006). Role of the Yersinia pestis plasminogen activator in the incidence of distinct septicemic and bubonic forms of flea-borne plague. Proceedings of the National Academy of Sciences of the United States of America, 103(14), 5526–5530.

Zimbler, D. L., Schroeder, J. A., Eddy, J. L., & Lathem, W. W. (2015). Early emergence of Yersinia pestis as a severe respiratory pathogen. Nature Communications, 6, 1–10.

Hänsch, S., Cilli, E., Catalano, G., Gruppioni, G., Bianucci, R., Stenseth, N. C., et al. (2015). The pla gene, encoding plasminogen activator, is not specific to Yersinia pestis. BMC Research Notes, 1–3.

Haiko, J., Kukkonen, M., Ravantti, J. J., Westerlund-Wikstrom, B., & Korhonen, T. K. (2009). The Single Substitution I259T, Conserved in the Plasminogen Activator Pla of Pandemic Yersinia pestis Branches, Enhances Fibrinolytic Activity. Journal of Bacteriology, 191(15), 4758–4766.

An Unnatural History of Emerging Infections

Unnatural HistoryRon Barrett and George Armelagos. An Unnatural History of Emerging Infections. Oxford University Press, 2013 (e-book)

This is not a traditional review. In keeping with this blog’s function as my shared file cabinet, this post will be something like a précis /notes with a few of  my comments in italics.

Medical anthropologists Ron Barrett and George Aremelagos argue that there have been common factors in the disease ecology that has governed all three main epidemiological transitions in human health. They argue that there is nothing fundamentally new about the driving factors of the current ecology of emerging and re-emerging infectious diseases. In all three transitions, human factors have created the ecology for acute infectious disease to thrive.

Concept: “syndemics: interactions between multiple diseases that exacerbate the negative effects of one or more diseases” (p. 10). Examples: co-infections of HIV, and combinations of infection and chronic respiratory disease (asthma etc).

Metaphor: “seed and soil” where the microbe is the seed and the ecology is the soil. Historically used by physicians who accepted Germ theory but practiced environmental medicine (sanitarians) especially in the gap between the beginning of germ theory and the availability of antibiotics. I really like this metaphor; it still works today. 

Prehistoric baseline

  • Important as our evolutionary context, first 100,000 years of human history. (that’s about 90% of total human history). At its peak only 8 million people globally; small, nomadic groups  rarely in contact.
  • Temporary shelter and carried little with them to carry vectors (or fomites?). Hunter gatherers maintained near zero population growth. More diverse nutrition but could not support large groups. Little hierarchy within the group so few inequalities (at least not consistently detectable in the osteological record.)
  • Nutrition is closely tied to immunological competence.  Protein deficiencies reduces competence to the level of AIDS patients. Nomads can move to find better nutrition, avoiding ‘famine foods’. Diets higher in lean meats and  fiber, but low in carbohydrates.
  • Too small to support acute epidemics (ran out of hosts too soon) but at an increased risk for parasites. Heirloom parasites like pin worms and lice; souvenir parasites picked up while foraging like ticks and tapeworms. Mostly chronic infections that could remain with the nomads until they could be transmitted to new groups.  New zoonoses that can be passed human to human contracted from hunting would ‘flash out’ in a small group. Groups too small for diseases like measles, smallpox or influenza.

First epidemiological transition – Agricultural revolution

  • The first transition comes with people settle down and form villages.  Settlement and agriculture allow populations to grow large enough to support acute epidemic disease and animal domestication brings humans in prolonged contact with animals sparking some important zoonotic diseases.
  • They note that agriculture and settlement begin in multiple parts of the world independently but not at the same time. It took about 9000 years for 99.99 % of the population to shift to farming and domestic animals as their primary nutrition source. Once the shift to agriculture comes, there is no going back.  They debate which comes first, settlement or agriculture, but they note that in the end for heath it doesn’t matter. (The length of time here has important implications for the incomplete nature of the second transition.)
  • Decrease in overall health seen in all societies that shifted to agriculture. Correlations between more/better grave goods and better health; ie. social inequity was bad for health as early as the neolithic. Very high childhood mortalities bring the overall lifespan down considerably. Settlement increased densities of humans and newly domestic animals making conditions ripe for the first acute epidemics and zoonotic transfers. Most zoonotic transfers in this period come from domestic animals.
  •  Nutrition suffers with settlement. Reliance on a monoculture makes them vulnerable to bad years and nutritional deficiencies of essential nutrients not found in the monoculture.  There is a general reduction in stature, increase in signs of anemia, and increase in osteological signs of infection. Examples: Nubia and Dickson Mounds, IL, USA. Correlation of age with skeletal pathologies shows that is health declines are not due to the ‘osteological paradox’ (more pathologies in stronger people because they survive what would have killed others).

Second epidemiological transition – Industrial revolution

  • Transition marked by decreasing deaths due to infectious disease and an increase in chronic diseases. Increasing life expectancy due in large part to decreasing childhood mortality. Total human population soars.
  • Germ theory vs. Sanitation reform: Germ theory is associated with quarantine tied to power of the church and state. (??) Sanitary reform has greater success in controlling diseases like cholera and food-bourne diseases. Sanitary reformers focused on building infrastructure, improving living conditions and personal hygiene. “Germ theorists had begun a revolution in medical thinking, but in the realm of medical practice, they could do little more than agree with existing recommendations of the miasmists.” “with the exception of a few vaccines and surgical asepsis, Germ Theory offered little…until well into the 20th century”. Not surprising that germ theory didn’t make much difference until antibiotics came along. 
  • McKeown Thesis: “identifies nutrition as the primary determinant in the decline of infection-related mortality” Improved nutrition best explains increasing population growth in different countries in a short time period; improved agricultural methods and transport of food. Urban growth with industrialization increased crowding and decreasing sanitation leaving nutrition as the cause for decreasing infectious disease. Correlation between increasing height and decreasing infant mortality, increasing maternal height (indicating good nutrition) increased indicators of infant health so that improving nutrition improved health from generation to generation.
  • McKeown’s critics: error rates in bills of mortality obscure particularly respiratory infections in the elderly. They also believe that he underestimates the significance of smallpox vaccination in decreasing death rates. Greatest criticism is that McKeown places too much emphasis on nutrition over non-medicinal factors.
  • “Comparing the Agricultural Revolution with the Industrial Revolution, we find the same human determinants of infectious disease: a) subsistence, via its affects on nutritional status and immunity; b) settlement, via its effects on population densisty, living conditions, and sanitation; and c) social organization, via distributions of these resources and their differences within and between groups…. As such, the First and Second Transition could be seen as two sides of the same epidemiological coin with human actions as the basic currency.” (p. 61)
  • Second transition is incomplete in many countries. Only seven nations began the transition before 1850 and 17 more by 1900 with most transitioning after World War II. “The ‘low mortality club’ consisted of richer nations whose life expectancies converged at around 75 years old at the turn of the millennium. The ‘high mortality club’ consisted of poorer nations whose life expectancies converged at the same time around 50 years of age.” (p. 66)  The poorer nations have relied more heavily on vaccines and drugs as a buffer against living conditions to achieve the transition. Drug resistant pathogens removes this buffer for poorer nations. High childhood moralities continued in the poorer countries for the same reasons as in the first transition.
  • Chronic diseases make people susceptible to different infections. example: diabetes + TB, infectious diseases causing cancer: HPV, H. pylori, EBV (lymphoma).
  • Developed world vulnerable to “reimportation epidemics” from poorer nations with agents like smallpox (prior to eradication). Increased speed of air travel allows people to travel between high and low disease areas during the incubation period through entry ports without detection.

Third epidemiological transition (current)

  • Convergence of chronic and infectious diseases in a global human disease ecology marks the Third epidemiological transition.
  • Human health determinants remain subsistence, settlement and social organization.
  • 335 novel pathogens discovered 1940-2004, mostly after 1980, 60% of which are zoonoses and 70% of those come from wild animals. With long exposure to zoonoses from domestic animals it makes sense for most new pathogens today to come from wild animals; also due to encroachment and habitat destruction.
  • Challenges of new zoonotic pathogens: establishing animal to human  transmission, then human to human transmission, and finally human population to population. Chatter is a pathogen trying to establishing the animal to human transmission but not yet getting the human to human. Chatter is often viral but can be other microbes as well. Viral chatter is a transitional moment in evolution; purely biological for the pathogen but primarily cultural for humans (human practices that help the pathogen make the transition by our behavior).
  • Attenuation hypothesis: evolutionary interests favor microbes not killing their hosts too soon. Works for the first transition when population groups were widely scattered.
  • Virulence hypothesis: Ewald’s concluded that evolution favors virulence for pathogens with multiple hosts. (ex. plague). We can’t take either hypothesis too far as both have contradicting examples.
  • We need to shift from just looking for drugs to combat pathogens and spend more time on factors of human ecology.
  • An interesting chapter on antibiotics and evolution.

Concluding focus: To dispel three myths

  1. Emerging infections are a new phenomenon. They are not. This is why the emerging infections page on this blog begins with emergences in Antiquity / Prehistoric. 
  2. Emerging and re-emerging infections are a natural or spontaneous phenomena. We have a part to play in microbial co-evolution. Epidemiological transitions are intended to balance microbiology in understanding these infections.
  3. Determinants of disease are different today than in the past. They are not.

“The purpose of this Unnatural History is to reveal the macroscopic determinants of human infection just as the germ theorists once revealed their microscopic determinants…. our approach has been one of both seed and soil, acknowledging the importance of pathogens while stressing their evolution in response to human activities: the ways we feed ourselves, the ways we populate and live together, and the ways we relate to each other for better or worse.” (p. 111)


I’m not an anthropologist so I’m not really going to look at this like an anthropologist.  Demographics shifts are what they are, facts. The underlying factors / variables  – subsistence (nutrition), settlement (living conditions/infrastructure), and social inequalities –are the same under all three transitions. As these conditions vary, so do the demographics. This is very useful; a reminder of the importance of human disease ecology. The Unnatural History of the title is reference to human manipulation of the environment creating the conditions for emerging infections. Epidemics are not ‘acts of god’, or simply a natural process that we are helpless to stop. We play our part. Often drugs are the easy way out of the problem, far easier and cheaper than building infrastructure or improving living conditions. 

The paradigm of epidemiological transitions is an anthropological tool. I don’t really have a practical use for labeling ‘transitions’.  As both the second and third transitions are incomplete, they are not of much use to me as concepts. The shortness of these transitions makes me wonder if we are not really looking at just one transition since ca. 1800 that is yet incomplete. It is more important to me to look at these underlying variables and their outcomes at specific times and places. From my point of view, taking generalizations about epidemiological transitions as more than a guide for research or a teaching paradigm can be problematic.

This is a short book and yet I probably highlighted more than any other e-book that I’ve read. The focus here is more theory than details. Some of their plague information is a little out of date but it doesn’t really detract from their main points. It’s a valuable resource for thinking about microbe-human co-evolution.