Category Archives: history of medicine

Evolutionary Clues in 17th-Century Smallpox Genome

By Michelle Ziegler

Smallpox is one of those diseases long believed to have an ancient pedigree, the suspected culprit of legendary epidemics. Yet, so far, smallpox hasn’t made a big impression in ancient DNA surveys. If it was truly endemic throughout the Old World before 1492, so much so that it pops up in the New World almost immediately after contact, it’s odd that it has not been more prominent in ancient DNA surveys. Be ready for a smallpox paradigm shift and reexamination of its reputed history.

In December, Ana Duggan, Maria Perdomo, and the McMaster Ancient DNA Centre team announced the first full ancient smallpox genome isolated from a mummified 17th-century child in Vilnius, Lithuania. Radiocarbon dates of the child place him or her in the mid 17th century (est. c. 1654) in the midst of dated smallpox epidemics from all over Europe.

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Fig 1 (Duggan et al, 2016): Left: Distribution of smallpox records in Europe. Right upper: Dominican Church of the Holy Spirit, Vilnius. Lithuania. Right lower: Crypt containing the child’s remains.

Their finding was unexpected. They were not looking for smallpox at all; the child had no observable lesions. They were hoping to find JC polyomavirus, of particular interest to one of the co-authors, and so they first enriched the specimen for this virus (McKenna 2016). After detecting variola virus (VARV), smallpox, instead they then enriched for VARV to confirm the initial signal.

duggan_cbsmallpox_finalMore than just confirming the signal, they were able to reconstruct the entire genome producing the entire sequence at an average depth of 18X. The surprising child had more revelations in his or her viral sequence. The sequence is ancestral to all existing reference strains. This is consistent with short stretches of aDNA amplified from 300-year-old frozen Siberian remains (Biagini et al, 2012). Unfortunately, the sequences from 2012 were not distinctive enough from the new Lithuanian sequence to give phylogicial resolution between them. Oddly, the frozen Siberian remains also lacked smallpox skin lesions with one showing signs of pulmonary hemorrhages.

Its ancestral position in the phylogeny suggests that a severe bottleneck occurred before c. 1654. As Duggan et al (2016) remark, vaccination would cause a very strong bottleneck, but this occurs after 1654 and there is new diversity among the descendent reference specimens producing two major clades. Yet to be determined is the evolutionary effect of extensive variolation practices in the early modern period. In contrast to vaccination, variolation is a form of intentional smallpox transmission that sometimes went horribly wrong.

Evolution continues unabated. The molecular clock is consistent among the 20th-century specimens and the latest aDNA from the Lithuanian child. The two clades of smallpox collected from 20th-century specimens diverged from each other sometime around the mid-17th century after vaccination began. Interestingly, the less virulent Variola minor strain is not predicted to have emerged from Variola major clade P-II until the mid-19th century.

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Evolutionary history of Variola (Duggan et al, 2016)

It’s not entirely surprising that smallpox, a highly transmissive human-only virus, has a relatively recent last common ancestor; other viruses like measles do as well. Measles last common ancestor is probably in the early 20th century (Furuse, Suzuki & Oshitani, 2010). The dominance of the 1918 influenza strain in recent influenza phylogeny is another example; incomplete because influenza swaps genes with influenza viruses that are circulating primarily in birds, but also in swine and earlier in equines (Taubenberger & Morens, 2005). Improved transmission strains are likely to out-compete strains with a lower transmission rate if they achieve a global spread. For some viruses, though not necessarily all, improved transmissibility and virulence go hand in hand. So, in the end, the relatively recent last common ancestor says more about its global transmissibility than anything else.

The antiquity of the virus needs two components to estimate. The molecular clock must be steady, and it is so far (though this could change with more ancient specimens), and a near relative ‘out group’, related strains outside the Variola clade (a branch of the larger genetic tree). One potential problem here is that as transmissibility improves the clock may speed up. The speed of the clock is determined by the reproduction rate. The relatively steady clock back to this 17th-century specimen suggests that the transmission rate was pretty steady — after the evolutionary/transmission leap that swept aside other Variola strains. The inactivation of several orthopoxvirus genes in smallpox that are functional in vaccinia (used in smallpox vaccines), camelpox, and teterapox  (the ‘out groups’ used) may suggest that one or more of these genes had been protective. When the genes were inactivated, smallpox probably became a much more dangerous virus to humans.

Historical epidemiology suggests that there was once more variation in the virulence of smallpox epidemics.  Securely identifying smallpox epidemics in the historical record is much harder than is generally assumed, and it is harder yet to make a claim for a significant demographic impact prior to the Renaissance (Carmichael & Silverman, 1987). This is the problem with theories that smallpox was the cause of the second century Antonine plague and then failed to cause an epidemic with a major demographic effect for many centuries. I find this very hard to believe. Additionally, the infamous smallpox epidemics in the New World are now also be reevaluated in ways that diminish smallpox’s toll and add in a wide variety of contributing factors to produce a colonization syndemic. This has most recently been summarized in essays collected in Beyond Germs: Native Depopulation in North America (2015).

One other observation from these studies: All ancient smallpox DNA to date has been extracted from mummy tissue, not a tooth or bone. This may point toward one of the limitations of ancient DNA pathogen surveys that currently use primarily teeth. Since neither mummy had visible smallpox lesions, smallpox should be considered a possibility in any mummy.


References

Duggan, A. T., Perdomo, M. F., Piombino-Mascali, D., Marciniak, S., Poinar, D., Emery, M. V., et al. (2016). 17th Century Variola Virus Reveals the Recent History of Smallpox. Current Biology, 1–7. http://doi.org/10.1016/j.cub.2016.10.061

Biagini, P., Thèves, C., Balaresque, P., Géraut, A., Cannet, C., Keyser, C., et al. (2012). Variola virus in a 300-year-old Siberian mummy. The New England Journal of Medicine, 367(21), 2057–2059. http://doi.org/10.1056/NEJMc1208124

McKenna, Maryn (8 Dec 2016) Child Mummy Found with Oldest Known Smallpox Virus. National Geographic. (online)

Carmichael, A. G., & Silverstein, A. M. (1987). Smallpox in Europe before the seventeenth century: virulent killer or benign disease? Journal of the History of Medicine and Allied Sciences, 42(2), 147–168.

Furuse Y, Suzuki A, & Oshitani H (2010). Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries. Virology journal, 7 PMID: 20202190

Taubenberger, J. K., & Morens, D. M. (2005). 1918 Influenza: the mother of all pandemics. Emerging Infectious Diseases, 12(1), 15–22. http://doi.org/10.3201/eid1201.050979

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

Landscapes of Disease Themed Issue

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For the last couple years, I have been writing about a landscape-based approach to the study of infectious disease in general and historic epidemics in particular. When I first wrote about Lambin et al.’s now classic paper “Pathogenic landscapes” nearly three years ago, I did not know then that it would be so influential in my thinking or that the Medieval Congress sessions would be so successful. In the fall of 2014, Graham Fairclough and I began talking about ways that this first congress session could be represented in the journal he edits, Landscapes. This issue is a departure from their usual approach to landscape studies so I would like to thank Graham Fairclough for entrusting me with a whole issue. It has been a challenge for both of us, and I am proud of our product.

This issue represents the wide variety of studies that can be done all contributing to an understanding of past landscapes of disease. One of the reasons why I like the phrase landscape of disease, rather than simply landscape epidemiology, is that it opens up the array of disciplines that can be involved. In the study of diseases of the past, humanistic approaches can be as valuable as scientific methods. Both are required to build a reasonably coherent reconstruction of the past. Science and the humanities need to act as a check and balance on each other, hopefully in a supportive and collegial way.

The issue was published online a couple days ago. Accessing the journal through your library will register interest in the journal with both your library and the publisher, and would be appreciated. By now the authors should (or will soon) have their codes for their free e-copies if you do not have access otherwise.

Table of Contents

Landscapes of Disease by Michelle Ziegler. An introduction to the concept of ‘landscapes of disease’ and the articles in the issue. (Open access)

The Diseased Landscape: Medieval and Early Modern Plaguescapes by Lori Jones

The Influence of Regional Landscapes on Early Medieval Health (c. 400-1200 A.D.): Evidence from Irish Human Skeletal Remains by Mara Tesorieri

Malarial Landscapes in Late Antique Rome and the Tiber Valley by Michelle Ziegler

Epizootic Landscapes: Sheep Scab and Regional Environment in England in 1279-1280 by Philip Slavin

Plague, Demographic Upheaval and Civilisational Decline: Ibn Khaldūn and Muḥammed al-Shaqūrī on the Black Death in North Africa and Islamic Spain by Russell Hopley

plus seven book reviews. Enjoy!

 


Lambin, E. F., Tran, A., Vanwambeke, S. O., Linard, C., & Soti, V. (2010). Pathogenic landscapes: Interactions between land, people, disease vectors, and their animal hosts. International Journal of Health Geographics, 9(1), 54. http://doi.org/10.1186/1476-072X-9-54

The Case for Louse-Transmitted Plague

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Louse illustration by Robert Hooke, Micrographia, 1667. (Public domain)

by Michelle Ziegler

The key to understanding plague — past, present, and future — has always been understanding its vector dynamics. By the latest tally, there are 269 known flea species, plus a small collection of ticks and lice, that can be infected with Yersinia pestis. With this many infected parasites, it’s not a surprise that 344 hosts have been identified (Dubyanskiy & Yeszhanov, 2016), but this list is still incomplete. (It does not include all of the minor hosts in North America.) Regardless, this is not a description of a picky pathogen! Unfortunately, it is far easier to identify infected hosts and potential vectors than to determine which of these insects are effective vectors and their transmission dynamics.

Numerous species of fleas have been identified as plague vectors in specific localities. However, only five infected potential human vectors are possibly involved in a wide distribution of human plague cases — the rat flea Xenopsylla cheopis, the cat flea Ctenocephalides felis, the human flea Pulex irritans,  the human body louse Pediculus humanus humanus, and the human head louse Pediculus humanus capitis. The rat flea and the cat flea are known vectors, but  they are unlikely to account for the full transmission of the massive first and second pandemics.  I recently discussed the possible role of the human flea. Given the worldwide distribution of human lice, they are attractive vectors but there is still work to do before they can be considered likely primary vectors for human to human transmission during the first two pandemics.

Raoult Makes his Case…again

Didier Raoult and his team have been working on plague and their louse transmission hypothesis for a long time.  It has already been ten years since they had enough information to write their first review article putting forth their human ectoparasite theory of plague transmission (Drancourt, Houhamdi, & Raoult, 2006).

At this point, their primary supporting evidence was some experiments with human louse plague transmission in rabbits (Houhamdi et al, 2006) and they thought they could associate louse transmission with an “Orientalis-like” biovar of Yersinia pestis they identified in the first two pandemics (Drancourt et al, 2004).  However, later ancient DNA work showed that the first two pandemics were caused by strains of Yersinia pestis that emerged before the Orientalis biovar. Genetic reclassification of Yersinia pestis has also made the biovars largely obsolete.  Tensions between groups working on ancient plague DNA developed quickly, and have been documented by historians Lester Little (2011) and Jim Bolton (2013).

This summer Didier Raoult (2016) restated his “personal view” on the role of lice in plague transmission. This essay is unusual not only as a first person narrative in science, including individual claims of discovery, but also for being so vindictive in its attack on his rivals. Again, see Little (2011) and Bolton (2013) for less biased accounts.  His team has done very impressive work.

His team has continued to assemble much of the work needed to argue that human lice were instrumental in at least some of the major human outbreaks of plague during the first two pandemics. Combing primarily French medical reports in North Africa, they were able to identify observations that suggest that lice were involved in some mid-twentieth century outbreaks (Raoult, 2016; Malak, Bitam, & Drancourt, 2016).  One of their most interesting findings in 2011 was the discovery of co-infection with Yersinia pestis and Bartonella quintana (trench fever) in late medieval French remains (Tran et al, 2011).  Trench fever is well known to be transmitted by the human louse. Both B. quintana and Y. pestis have been found in contemporary lice taken from plague patients in regions of endemic plague in the Congo (Piarroux et al, 2013; Drali et al, 2015). Unfortunately, neither of these studies mention the presence or absence of fleas.  That blood feeding lice would be infected is not a surprise, but the question of transmission stubbornly remains. There has yet to be a contemporary outbreak where all potential vectors, fleas and lice, were investigated. On a side note, the finding of widespread B. quintana is interesting, and perhaps a proxy for heavy lice infestation.

Modeling Transmission

In the meantime, while Raoult’s latest summary was in press, additional evidence was beginning to be revealed. Graduate student Katharine Dean of the MedPlag project in Oslo was modeling past epidemics for transmission by rat fleas, human lice, and pneumonic transmission. In her master’s thesis, she showed that lice transmission fits the second pandemic epidemics at Givry in 1348, London in 1563-64, and Florence in 1630-31 better than rat fleas or pneumonic transmission (Dean 2015). At the most recent Yersinia meeting in October, Dean presented a poster with expanded data finding outbreaks that fit each of these three modes of transmission (pneumonic in Manchuria, rat fleas in Sydney and Hong Kong, and lice in many locations) (Dean et al, 2016). Their work is still in progress and I’m sure many will be eager to see their results in due course.

Almost there

There are still a few lingering things to nail down. A modern outbreak investigation that looks at all ectoparasites, fleas and lice,  in the region that suggests lice are involved. It would be good to find lice (or fleas for that matter) in a plague burial that yields Y pestis aDNA. Alternatively, detection of more coinfection of Y. pestis with a louse-transmitted infection like B. quintana would lend additional support.  These findings will will require some good fortune. To differentiate between the human flea and lice, a better understanding of the pathology of a Y. pestis infection in the potential vector and its transmission dynamics is really needed. The models can’t differentiate human ectoparasites without more information.

Human ectoparasites are beginning to look much more likely especially for northern epidemics (Hufthammer & Walløe, 2013). More information is still needed to distinguish between human fleas and lice, although they may be both involved in different outbreaks.  We need to be ready for yet another paradigm change in plague history. Looking at the overall plague vector dynamics of the great pandemics, from sylvatic reservoir to distant human populations, is going to get a whole lot more complicated but also more interesting.


Reference:

Bolton, J. L. (2013). Looking for Yersinia pestis: Scientists, Historians, and the Black Death. The Fifteenth Century, XII, 15–38.

Dean, K. R. (2015, June 1). Modeling plague transmission in Medieval European cities. (B. V. Schmid, Supervisor). Oslo. [Master’s Thesis]

Dean, K. R., Stenseth, N. C., Walløe, L., Lingærde, O. C., Bramanti, B., & Schmid, B. V. (2016, October). Human ectoparasites spread plague during the Black Death and Second Pandemic. Yersinia 12th International Symposium. Tbilisi, Georgia.

Drali, R., Shako, J. C., Davoust, B., Diatta, G., & Raoult, D. (2015). A New Clade of African Body and Head Lice Infected by Bartonella quintana and Yersinia pestis–Democratic Republic of the Congo. American Journal of Tropical Medicine and Hygiene, 93(5), 990–993. http://doi.org/10.4269/ajtmh.14-0686

Drancourt, M., Houhamdi, L., & Raoult, D. (2006). Yersinia pestis as a telluric, human ectoparasite-borne organism. The Lancet Infectious Diseases, 6(4), 234–241. http://doi.org/10.1016/S1473-3099(06)70438-8

Drancourt, M., Roux, V., Dang, L. V., Tran-Hung, L., Castex, D., Chenal-Francisque, V., Ogata, H., Fournier, P-E., Crubezy, E, and  Raoult, D. (2004). Genotyping, Orientalis-like Yersinia pestis, and plague pandemics. Emerging Infectious Diseases, 10(9), 1585–1592. http://doi.org/10.3201/eid1009.030933

Dubyanskiy, V. M., & Yeszhanov, A. B. (2016). Ecology of Yersinia pestis and the Epidemiology of Plague. Yersinia Pestis: Retrospective and Perspective, 918(Chapter 5), 101–170. http://doi.org/10.1007/978-94-024-0890-4_5

Houhamdi, L., Lepidi, H., Drancourt, M., & Raoult, D. (2006). Experimental model to evaluate the human body louse as a vector of plague. The Journal of Infectious Diseases, 194(11), 1589–1596. http://doi.org/10.1086/508995

Hufthammer, A. K., & Walløe, L. (2013). Rats cannot have been intermediate hosts for Yersinia pestis during medieval plague epidemics in Northern Europe. Journal of Archaeological Science, 40(4), 1752–1759. http://doi.org/10.1016/j.jas.2012.12.007

Little, L. K. (2011). Plague Historians in Lab Coats. Past & Present, 213(1), 267–290. http://doi.org/10.1093/pastj/gtr014

Malek, M. A., Bitam, I., & Drancourt, M. (2016). Plague in Arab Maghreb, 1940–2015: A Review. Frontiers in Public Health, 4, 18–6. http://doi.org/10.3389/fpubh.2016.00112

Piarroux, R., Abedi, A. A., Shako, J. C., Kebela, B., Karhemere, S., Diatta, G., et al. (2013). Plague epidemics and lice, Democratic Republic of the Congo. Emerging Infectious Diseases, 19(3), 505–506. http://doi.org/10.3201/eid1903.121329

Raoult, D. (2016). A Personal View of How Paleomicrobiology Aids Our Understanding of the Role of Lice in Plague Pandemics. Microbiology Spectrum, 4(4). http://doi.org/10.1128/microbiolspec.PoH-0001-2014

Drali, R., Mumcuoglu, K., & Raoult, D. (2016). Human Lice in Paleoentomology and Paleomicrobiology. Microbiology Spectrum, 4(4). http://doi.org/10.1128/microbiolspec.PoH-0005-2014

Tran, T.-N.-N., Forestier, C. L., Drancourt, M., Raoult, D., & Aboudharam, G. (2011). Brief communication: co-detection of Bartonella quintana and Yersinia pestis in an 11th-15th burial site in Bondy, France. American Journal of Physical Anthropology, 145(3), 489–494. http://doi.org/10.1002/ajpa.21510