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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 (monica.green@asu.edu, @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”

Monica:

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).

 

Boris:

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.

last-tree-plague-krause
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.)

 

Monica:

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.

Boris:

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.

References:

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. http://doi.org/10.1098/rstb.2011.0303

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. http://doi.org/10.1038/nature10549

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. http://doi.org/10.1073/pnas.1205750110/-/DCSupplemental/sd01.xls

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. http://doi.org/10.1371/journal.ppat.1001134.t001

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 http://eccmidlive.org/#resources/ancient-pathogen-genomics-what-we-learn-from-historic-pandemics

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. http://doi.org/10.1371/journal.pone.0145194

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. http://doi.org/10.1016/j.chom.2016.05.012

Environment, Society and the Black Death in Sweden

Environment, Society and the Black Death: An Interdisciplinary Approach to the Late Medieval Crisis in Sweden. Edited by Per Lagerås. Oxbow Books, 2016. 


9781785700545_1The Black Death is a bit of a phantom in this book. Like the human body casts of Pompeii, the Black Death is perceptible  by the void it left behind — a void in farm occupation, a void in building,  a void in the population/labor but ironically, also a void in mass burials. Without distinctive plague burials, this is how we should expect a scientific investigation of the plague and its  environment context to be. What these sometimes contradictory seeming voids mean is the challenge taken up in this book.  The studies presented in this book used pollen diagrams, dendrochronology, settlement archaeology and human remains to investigate the entire fourteenth century crisis with the clear signature of the Black Death apparent in each type of investigation.

When the Black Death reached Sweden in 1350, the kingdom was in pretty good shape compared to elsewhere in Northern Europe. Sweden seems to have avoided the Great Famine. The population was spread between small villages and isolated homesteads; there were no large urban areas on par with London or Paris. There was still room to expand settlement toward the uplands in the north-west. The relatively thin settlement and lack of large urban areas explains the lack of mass burials. Based on the population distribution and predicted mortality rate (comparable to the rest of northern Europe), they predict that the thin settlement allowed them to keep up with the burials along with some semblance of usual burial customs, such as coffins. The only indicator of plague deaths (or any epidemic) is the incidence of double and triple graves.  So it’s not a matter of discovering the Black Death burials, they have been in plain sight all along.

Staying with the bodies, their osteological sample included 4876 skeletons from 65 medieval churchyards, three execution sites, and two mass military graves spanning the entire medieval period in the region of Lund. Their primary measure of stress was projected height. The only finding of significance was that women were slightly taller (2.5 cm) in the generation after the Black Death. I think they could have made a little more of this considering that the nutrition of young women has a disproportionate effect on fertility, fetal and maternal health. Enough healthy women of reproductive age is a necessity for a population to recover from a mortality crisis. The overall stature of Swedes was on par with elsewhere in Europe and in the 14th century far shorter than modern Swedes. The average height for a man after the Black Death was only 172.5 cm,  (5′ 8″) and women at 162.7 (5’5″). They reached their low point in the 19th century only to sharply rebound to their tallest point in the 20th century.

The isotope data from selected skeletons from Lund, the largest urban district in Sweden, yielded a few surprises. They did find a diet change to include more animal and marine sources, but unlike elsewhere in Northern Europe, the switch occurred in the 12th century, not the 14th century. Could this explain why there is no evidence of the Great Famine in Sweden? Nearly two-thirds of the specimens from Lund had some marine sources in their diet. Zooarchaeological specimens suggest that cod was the primary marine source and that freshwater fish were not major contributors to the diet.  Regardless, there was no 14th century diet change that the isotopes could detect and no correlation between dietary changes and height. Strontium analysis does not indicate many non-natives after the initial establishment phase of Lund. The Black Death period (1350-1370) had the lowest number of non-locals of the medieval to early modern period. They suggest that this means that contact with the non-Swedish world was reduced during this period.

The bulk of this book addresses settlement and land use changes in the mid-fourteenth century. Beginning with dendrochronology, there is a hundred years gap from 1360 to 1460, reflecting the lack of need of new building or expansion after the Black Death. Amazingly, a few of the farm buildings dating to the pre-Black Death period are still standing. Farm abandonment and landscape change unfortunately can’t be as directly measured as dendrochronology.

The pollen data largely reflects the paradox pointed to in Sing Chew’s The Recurring Dark Ages: Ecological Stress, Climate Change and System Transformation (2006), that periods of human crisis allow ecological rejuvenation.  More simply what is bad for humans, is good for the environment. Periods of decreased human environmental exploitation (or resource extraction, if you prefer) allow the environment to recover.  Chew does not address the fourteenth century, which we might call a Dark Age near miss, a time when the Old World tottered on the brink of another possible Dark Age, but the similarities still make a useful comparison (and open up some interesting questions).

In the decades after 1350, the pollen suggests that arable fields decreased, conversion to pasture and increased woodland expansion. The conversion of unused fields to pasture or hay kept those fields from regenerating their woodlands and making it easier to bring them back into arable production. Yet, there was still considerable woodland regeneration.  They note that seedlings that sprouted in the years after the Black Death formed a mature forest that lasted in some areas for 300+ years. A mature forest with 300+ year old trees will seem like a virgin forest, but it is not; it is still an anthropomorphic landscape.

“In summary the late-medieval crisis and in particular the population drop initiated by the Black Death in 1350 did not only result in profound and long-term social changes, but also in environmental and ecological changes. These changes were not only passive consequences of the crisis – they also affected the course of the crisis through different feedback mechanisms, both positive and negative.”(Lagerås, 2016, loc 3603)

They also note that the only previous rejuvenation of woodlands in Europe occurred in the sixth century around the time of the first plague pandemic. I’m encouraged to see their interest in comparing the 14th century environmental context/consequences to the sixth century. It is refreshing to read a book written with such a clear, scientific tone and approach.

They note that the expansion of woodland allowed a rejuvenation of biodiversity mentioned in  a 1376 royal letter that claimed more wolves and bears were damaging humans and livestock. While the abandonment would have decreased hunting pressure, it is also likely that the expansion of the woodland allowed a flourishing of the entire tropic cascade that was capped by predators like wolves and bears. We are more accustomed to thinking of tropic cascades as being suppressed by top down predation (often caused by humans), but the cascade can also bloom bottom up.  While on the topic of biodiversity,  a discussion of small mammals that could play a role in plague transmission during the 1350 epidemic and later epidemics would have been helpful. This ecological flourishing will radically change the landscape and human relationship to it. What effect, if any, did this have on later plague transmission? In this regard, their comparisons to an 18th century plague would have been just about when the post-Black Death ecological changes were giving way to expansion of arable farmland again and the population had rebounded.

The complexity of the ecological and settlement data is a measure of the long-term contextual changes caused by a single massive epidemic and its aftershocks. Populations would have been moving within the country for many years as heirs took possession of better land, and families depleted of heirs dwindled away over time. They note that the post-Black Death period brings about the end of the self-sufficient manor system. Social order evolves into a more specialized and interdependent system. The ecological changes slowly rolled out as fields turned into pastures or were left fallow; forest encroachment and development occurred over many years. This book is a work in progress on the environmental history of Sweden’s anthropomorphic landscape and its people. It should be considered in the context of other environmental studies of the fourteenth century crisis from Scandinavia, Britain and Ireland, Iceland, and the Northern European continent. I look forward to seeing how their work develops in the future.

 

 

 

Beyond Germs: Native Depopulation in North America

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Beyond Germs: Native Depopulation in North America. Edited by Catherine Cameron, Paul Kelton and Alan Swedlund. University of Arizona Press, 2015.


With the number of emerging infectious diseases climbing and new revelations about plague’s past, this book is a timely caution to the rhetoric surrounding so-called virgin soil epidemics. This book is the publication of an interdisciplinary conference held to discuss the causes of Native American depopulation hosted by the Amerind Foundation. Essays by David Jones, George Milner, Clark Spenser Larsen, Debra Martin, Gerardo Gutiérrez, Alan Swedlund, Catherine Cameron, Paul Kelton, Katheleen Hull, and James Brooks are included. Most of these essays are case studies in depopulation of specific areas.

David Jones opens the book with a discussion of the rhetoric surrounding so-called virgin soil epidemics that are credited with being the primary cause of native depopulation. Admitting the influence of his mentor evolutionary biologist Stephan J Gould, Jones favors social and contingent causes for depopulation over biological determinism. Perhaps the influential role that Gould played in my own formation as a biologist makes me sympathetic to Jones’ argument, but I can certainly live with that. Genetic determinism, in my opinion, is the easy way out to explain what can not be yet understood. His argument against the sweeping rhetoric of ‘virgin soil epidemics’ is, I think, very effective.

Milner’s chapter tackles the tricky problem of the pre-contact population collapse of the Mississippian culture centered at the mid-continent site of Cahokia, near St. Louis. This had been the largest and most (archaeologically) complex native culture in North America but it collapsed so entirely that the mid-continent was still sparsely populated when Europeans arrived a couple of centuries later. Medieval Cahokia had been more populous than  contemporary London. The example of Cahokia must give us pause for assuming that unrecorded demographic collapses that lack signs of massive destruction must be due to epidemics.

Larsen, Martin, Gutiérrez, and Hull cover the effect of the Spanish mission system in Florida, the Pueblo of the Southwest,  Mexico, and California respectively. Structural violence was seen throughout the Spanish mission system from hard, forced labor. Larsen discusses the changed how changed landscapes and lifestyles make natives more susceptible to infection. He sees a dramatic rise in cribra orbitalis/porotic hyperostosis as a sign of iron deficiency when it may actually be malaria. Wet Florida would have been susceptible to endemic malaria and a reservoir for it to spread through the southeast. Martin looks at the bioarchaeological evidence for a ‘creeping genocide’ in the peublos of the south west. Sporatic massacres of pueblo communities was used to enforce compliance by the wider culture. Cultural resilience was also stressed to the breaking point by a prolonged period of drought and environmental deterioration in the southwest that left them with marginal nutritional sufficiency. In this stressed environment, smallpox spread widely among the pueblo communities. Epidemics were part of a set of practices used to destroy or reorient native culture to make it acceptible, and more importantly controllable for the Spanish. Gutiérrez focuses on the methods and effects of identity erasure on demographics. The caste system that developed was very systematic “virtuous cycle”  with the goal of eliminating native identiy and indeed native (and African) ‘blood’ while maximizing Spanish identity and ‘blood’.

Chapters by Swedlund,  Cameron, and Kelton  examine tribes that dealt more closely with the English colonies and early American states. Swedlund looks at the great smallpox epidemic of 1633-34 beyond coastal New England up into the Connecticutt River valley. Cameron reviews the demographic effects of warfare and captive taking had on the Southeast, the northern Pays d’en Haunt (Great Lakes region), and the Southwest tribes. Colonial politics and trade caused more intertribal warfare than warfare directly with European colonists. Kelton writes about the disastrous experiences of the Cherokee with warfare, famine, and disease during the American Revolutionary War.

On of the overarching problems is the difficulty in determining population size before contact and then for the first couple centuries of the colonial period. Problematically, in the past abandoned villages have been assumed to be extinct due to disease rather than simply relocation or the movement of refugees to other tribes. The reality is that many areas that are fertile with Old World methods and domestic livestock were very difficult to make productive with native resources.

Over arching themes that I noticed which point toward other factors than just “germs” causing depopulation:

  1.  Use of starvation as an intentional weapon accomplished by burning fields and disrupting the agricultural cycle.
  2. Selective taking of women of reproductive age as captives/slaves causing a gender imbalance that prevented populations from rebounding.
  3. Selling captives to slavers rather than incorporating them into the tribe as pre-contact tribes often did to bolster their numbers and replace their dead. Sales were often to repay debts for European trade goods, especially weapons and ammunition.
  4.  Use of tribes as proxy militias by European powers to create intertribal warfare and recruitment of tribes by the British during the American revolution and war of 1812. Set up an adversarial relationship with the young American nation.
 In effect, I think the process they are all searching for is a syndemic that combined epidemics, nutritional deficiencies, systemic violence, slavery, and forced assimilation. Unfortunately they didn’t really consult the syndemic literature.

One of the things I took away from this collection is an appreciation for how long it takes to develop a fully agricultural culture. Many Native American groups were still in transition. Lacking domestic animals other than the dog, they were very vulnerable to climate and social disorder disrupting their agricultural cycle and yield. Some tribes adopted domestic animals from Europeans quickly. Colonists were greatly alarmed at how quickly the Cherokee adopted raising hogs and European crops, bringing them nutritional stability. Of course, horses are were adopted so well by natives that its hard for many of us today to even think of Native Americans without them.  The idea that domestic animals were worth the effort may have been what was missing most, rather than a lack of animals capable of being domesticated.

I highly recommend this book for anyone interested the dynamics of depopulation, “dark ages”, and most importantly for comparison to other “virgin soil” epidemic situations. I don’t think it’s a coincidence that other renowned virgin soil epidemics like the first and second plague pandemics occurred in times of ecological and social stress in addition to the epidemic in question. By opening the explanations for Native American depopulation up to other causes than disease,  it also opens up views into colonial life that even contemporaries tried to ignore. Wether their demise to disease was believed by contemporaries to be divine will or by modern historians as biological determinism, it has diverted attention away from the very human causes of depopulation and in some cases genocide.