Asymptomatic Plague: Qinghai, China, 2005

Now that we know the Tibet-Qinghai plateau region is where Yersinia pestis originated and the region where subsequent pandemics arose, I think its time to look more closely at regional outbreaks and case studies.

In this region, the marmot (Marmota himalayana) is the primary reservoir for Yersinia pestis. This large communal burrowing rodent is hunted by local Tibetan tribesmen for both meat and pelts. Butchering marmots has long been considered a risk factor for contracting plague via their fleas, aerosols or skin abrasions. To investigate the exposure of marmot hunters to plague, Chinese epidemiologists collected serum from 120 Qinghai villagers, 68 male hunters and 52 female family members, along with 120 negative controls from the non-endemic area of Beijing. None of the villagers or controls reported having a fever within the last two years.

The results are eye-opening and illustrates the importance of occupational exposure. Over a third of the male villagers had an antibody response to Yersinia pestis. Only 2% of their female family members produced an antibody response. Wether two fever-free years are enough time to determine if they had symptomatic plague in the past is an open question. Their letter to Emerging Infectious Diseases does not provide much information on the test subject’s histories or oral reports.

Table 1: Plague antibody assays (Li et al, 2005)

The epidemiologists explained this high level of immune protection to the use of prophylactic antibiotics by marmot hunters. They suggest the presence of tetracycline or sulfamethaoxazole, common prophylactic antibiotics in Tibet, in  their system at the time of exposure would be enough to prevent a symptomatic infection while still giving them an immunizing dose of bacteria.

The use of prophylactic antibiotics is, of course, a double-edged sword. It is clearly preventing symptomatic infections and probably outbreaks. The Chinese epidemiologists credit  most outbreaks in Qinghai to marmot hunters who either a lack of prophylactic antibiotics or have ineffective antibiotics.  On the other hand, the use of antibiotics is possibly encouraging them to harvest the easier to catch, sicker marmots. The use of prophylactic antibiotics also promotes antibiotic resistance in Yersinia pestis.

Li, M., Song, Y., Li, B., Wang, Z., Yang, R, Jaing, L., and Yang, R. Asymptomatic Yersinia pestis, China. Emerging Infectious Disease, 2005, 11 (9): 1494-1496.

Fleshing out Yersinia pestis

Up until a few months ago there were a few representative samples of the Yersinia pestis genome. Important windows into its secrets, but windows none the less. In January a Chinese group remedied this situation by expanding the number of fully sequenced genomes from 15 to 133 (Cui et al, 2013).  China supplied 107 genomes selected from over 900 genotyped specimens collected since 1955 to represent bacterial and host diversity. To these, 11 additional isolates from Mongolia, Myanmar (Burma), the former Soviet Union, and Madagascar were fully sequenced. For the analysis, the previously sequenced 15 genomes were added bringing the total up to 133 including the ancient specimens from 14th century London.

The Core-Genome and the Pan-Genome

Even for a bacterium like Yersinia pestis that is considered to have little genetic diversity, its genome is more elastic than any eukaryote (everything but bacteria). The bacterial genome can be divided into its core genome, found in all members of the species, and the accessory genome, sequences found only in some strains. Plasmids are part of the accessory genome but not all of it. Extra genes are also found on the bacterial chromosome. The core genome is 3.53 Mb long with 3450 genes; the accessory genome has 1.92 Mb with 1249 genes (including 451 on the six known plasmids) (Cui et al, 2013, Table S1). So the accessory genome contains 26% of genes found in the species. This may seem like a lot, but more promiscuous species like Escherishia coli (E. coli) have many more accessory genes than core genes. With E. coli the more specimens that are sequenced, the larger the accessory genome gets with no end in sight.

Combining all of the genes found in Yersinia pestis (core and accessory genome), we have the pan-genome. The pan-genome is 5.46 Mb with 4699 genes (Cui et al, 2013).  No one strain has all of these genes. So different strains do have significant differences in their functions but, as far as I know, there are no significant differences in human prognosis. Hopefully, there will be more study in the future that cross-references strain type  or particular genes with human prognosis, transmission routes (% bubonic vs pneumonic), hosts etc.

Branching Out

Using known and new SNPs, the phylogenetic tree has finally been fleshed out into a healthy looking tree . We couldn’t keep the sickly looking Charlie Brown tree of the past forever! Even so, the tree below represents only the main branches.

Click to enlarge, (Cui et al, PNAS, 2013)

To my mind, the most important aspect of the new tree is that nodes of increased diversity are much more apparent. The authors are the most excited by node 7 where there is a four-way branch, adding two new branches  (3.ANT1 and 4.ANT1) to the main stem of the tree. They refer to this diversity point as the ‘big bang’. This node gains the most attention because the 14th century London genomes are just one step off of node 7 down the 1.ANT1 branch. So it stands the reason that node 7 represents a period of diversity that produced the second pandemic. Yet, looking at their diagram, other locations like node 12 have greater diversity. The 1.IN strains are intermediary on the same lineage between the second the third pandemic. Node 14 is the initial diversity that produced the third pandemic.  Calling node 7 a ‘big bang’ seems to me to have more to do with it producing the second pandemic rather than the diversity at the node itself. The new third and fourth branch (3.ANT and 4.ANT) are concentrated in Mongolia, putting emphasis on the importance of doing such deep sequencing in other Central Asian regions. It is impossible to tell which host species these bursts of diversity occurred within, almost certainly not humans. It’s not that diversity can’t be generated in humans especially during a pneumonic plague, but since it is not endemic in humans,  it must make it back to a reservoir to be preserved anywhere other than in ancient DNA.

Biogeography shows clustering of related strains in regions as would be expected, though they are fairly well mixed within the circled zone in the map above. Samples seem to follow ancient roads, although keep in mind all of these strains have been isolated within the last 60 years.   I do wonder why they were not able to identify a route for the eastern branch two isolates. All of the branch two isolates appear to be running along a fairly straight line from southwest to northeast China (extending trade route III to Manchuria). The 107 Chinese specimens were chosen from > 900 strains identified from 5000 isolates for their diversity revealed by genotyping, host diversity and geography (Cui et al, 2013). It would have been interesting to see a map with all 5000 on it as a measure of abundance (with or without typing).

The oldest strain 0.PE7 is found only on the Qinghai-Tibet plateau in China, an area framed by the ancient trade routes along which most of the western strains are found. This has led Cui et al, 2013 to postulate that the  Qinghai-Tibet plateau as the origin of  Yersinia pestis.

Unsteady Molecular Clocks

Estimating ages from genetics can be a very risky business. To estimate years since the last common ancestor, it requires a steady molecular clock , measured in base changes per unit of time. In theory all of the genes from the core genome should have changed to the same degree from the common ancestor, but that is not the case at all. The number of SNPs in the Yersinia pestis core genome varies greatly. Even excluding the most divergent Angola (0.PE3) strain, there is “a nearly 40 fold difference between the slowest and the fastest evolving branches” (Cui et al, 2013). An unsteady molecular clock was also suggested by previous data from Madagascar, though the discussion was buried in the supplementary material (Morelli et al, 2010, p. S10-s18). Mutator phenotypes do occur (Rajanna et al, 2013), though Cui et al, 2013 assure us that none of these strains are mutators.  On the other hand, a Georgian group suggest that the mutator phenotype, a single point mutation, could naturally reverse (back mutate) altering the predictability of the lineage age (Rajanna et al, 2013). The Chinese group concluded that the faster clock rates for some branches are due to a higher reproduction rate, probably due to more or larger epidemics in the lineage (Cui et al, 2013). The types of genetic changes (SNPs) indicate neutral selection, so the increased reproduction rate is not due to the genetic changes.

While I understand that calculating divergence dates an important exercise to people who focus on phylogenetics, for the understanding of historical plague it is not useful. It is not solid or specific enough to base historical events upon alone. Predictions are just that; all of these groups have been proven wrong, sometimes later by themselves, too often.  Most importantly, it appears that it will eventually be trumped by ancient DNA analysis with an archaeological and/or documentary context. As far as I’m concerned, the Angola strain is a genetic and geographic outlier of uncertain provenance. We don’t know important factors like how long it was kept in active culture before it was made into a stock or the conditions of storage. Both of these can effect mutation rates and the molecular clock (Rajanna et al, 2013).  I’m sure the Angola strain’s story is interesting but unlikely to be useful for understanding the whole species unless it turns up in ancient DNA.

Gaining and Loosing Diversity

Returning to these starburst points on the tree, called polytomys, where multiple lineages share the same ancestor, we have some of the most valuable information in the new phylogenetic tree. Epidemics (and presumably epizootics) are believed to have an increased reproduction rate over enzootic plague. Since the mutation rate is directly tied to the reproduction rate, increased reproduction rates predict an increased mutation rate and, therefore, production of genetic diversity.  The team predicts that “higher clock rates are an indicator of epidemic disease, even in the absence of historical evidence” (Cui et al, 2013). It is unclear how an epidemic can be differentiated from an epizootic by genetics alone. We know from modern observations that not all epizootics spill over into the human population. Yet, major polytomys can at least be used to estimate how many bursts of growth the bacterium has gone through in China. We should see other polytomys with increased sequencing of other Central Asian regions.

While these polytomys show a starburst of new lineages, there is also a loss of diversity during every epidemic. Most of the new lineages produced during an epidemic (or epizootic) will die out (become extinct) when the epidemic ends. If the changes are truly neutral, then which lineage survives to endure in the reservoir will be completely random (as will be the number of surviving lineages). We should also remember that clinical isolates  during an epidemic and ancient DNA can preserve lineages that become extinct (and this is normal). In the four individuals they sequenced from 14th century East Smithfield, they found two different clones, with the second being derivative of the first. Both of these clones may only be found in ancient DNA, not in any living specimen. The more time that passes the greater the likelihood that the minor lineages will become extinct. This tends to make the earlier sections of the pylogenetic tree look cleaner by stripping off side branches.

Another recent study by Vogler et al (2013), supports their scenario on a finer scale during the 9 year epidemic in a port town of Mahajana,  Madagascar from 1991 to 1999. Over a decade we can compare the incidence of plague vs. the genetic diversity. Yersinia pestis evolution can be plotted with great precision. In the lower diagram, clones are color coded to the year of isolation. From 1995 to 1999 it is possible to see the next year’s primary clone emerge in the previous year’s epidemic, which supports local cycling within the city. At the same time, most of the diversity generated is not represented in later outbreaks.

Vogler et al, 2013

Vogler et al, 2013

Host Diversity

Host genus vs Y. pestis strain collected (Cui et al, 2013).

The hosts of these 107 strains give us a glimpse into the host diversity for Yersinia pestis within China (Cui et al, 2013). The figure to the right gives an indication of strain diversity within each host but does not tell us abundance or location within China. What jumps out at me, is that humans and marmots have the most strain diversity. The high strain diversity in humans including 0.PE7, the strain closest to the most recent common ancestor, suggests to the Chinese team that Yersinia pestis has been pathogenic to humans since it evolved (Cui et al, 2013). Thus, at no point in its evolution did it gain the ability to infect humans. The few strains that can not infect humans are hypothesized to have lost their ability to infect humans possibly as a function of purifying selection for voles as hosts. It is interesting that the 1.ORI strains of the third pandemic are only found in humans, rats and mice.  We have to be careful about taking this figure to represent abundance or importance of a particular host. The great gerbil, Rhombomys opimus, is a primary host throughout central Asia is is represented by only one strain in this figure.

Studies published this winter have moved us significantly down the road to fleshing out Yersinia pestis. The genetic survey of Y. pestis in China provides a firm foundation to build on as more ancient DNA becomes available and extensive sequencing is done in other regions. Madagascar continues to be the best laboratory for plague ecology and epidemiology, while the Georgian study begins to address unintended intra-laboratory evolution that may shed light on Y. pestis in the wild. I’ll return to these papers again soon as I continue to examine Y. pestis from different perspectives and ruminate on answers to other questions.

References:

Cui, Y., Yu, C., Yan, Y., Li, D., Li, Y., Jombart, T., Weinert, L., Wang, Z., Guo, Z., Xu, L., Zhang, Y., Zheng, H., Qin, N., Xiao, X., Wu, M., Wang, X., Zhou, D., Qi, Z., Du, Z., Wu, H., Yang, X., Cao, H., Wang, H., Wang, J., Yao, S., Rakin, A., Li, Y., Falush, D., Balloux, F., Achtman, M., Song, Y., Wang, J., & Yang, R. (2013). Historical variations in mutation rate in an epidemic pathogen, Yersinia pestis Proceedings of the National Academy of Sciences, 110 (2), 577-582 DOI: 10.1073/pnas.1205750110

Morelli G, Song Y, Mazzoni CJ, Eppinger M, Roumagnac P, Wagner DM, Feldkamp M, Kusecek B, Vogler AJ, Li Y, Cui Y, Thomson NR, Jombart T, Leblois R, Lichtner P, Rahalison L, Petersen JM, Balloux F, Keim P, Wirth T, Ravel J, Yang R, Carniel E, & Achtman M (2010). Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity. Nature genetics, 42 (12), 1140-3 PMID: 21037571

Rajanna C, Ouellette G, Rashid M, Zemla A, Karavis M, Zhou C, Revazishvili T, Redmond B, McNew L, Bakanidze L, Imnadze P, Rivers B, Skowronski EW, O’Connell KP, Sulakvelidze A, & Gibbons HS (2013). A Strain of Yersinia pestis With a Mutator Phenotype from the Republic of Georgia. FEMS microbiology letters PMID: 23521061

Vogler, A., Chan, F., Nottingham, R., Andersen, G., Drees, K., Beckstrom-Sternberg, S., Wagner, D., Chanteau, S., & Keim, P. (2013). A Decade of Plague in Mahajanga, Madagascar: Insights into the Global Maritime Spread of Pandemic Plague mBio, 4 (1) DOI: 10.1128/mBio.00623-12

The Great Pneumonic Plague of 1910-1911

The Great Manchurian Plague of 1910-1911: Geopolitics of an Epidemic Disease

by William C. Summers
Yale U Press, 2012

Manchuria was a political mess at the turn of the 20th century. Although it was the homeland of the Qing dynasty, the Chinese considered it a backwater. Japan and Russia on the other hand saw it as potential colonial territory, a beachhead for Japan’s mainland ambitions or access to a valuable ice-free Pacific port for Russia. By 1910 an uneasy truce held giving Russia and Japan corridors to build railroads with stations and towns to support them while technically still in Chinese sovereign territory. The importance of Manchuria to global politics and trade was underscored by the presence of European and American diplomatic representatives in these upstart towns and ports. Into this delicate situation, the discovery that marmot fur could be dyed to pass as ermine brought a flood of primarily Chinese hunters into the region. The drive for furs (and marmot oil) led many to cast aside traditional hunting practices and safeguards, setting the stage for the plague to come.

The beginning of the plague was sparsely recorded. Starting in October 1910 scattered reports were sent that plague had appeared at sites along the railway, but concern was slow in coming. Summers credits the nearly annual outbreaks of plague, low concern for locals, and the temporary camps of hunters for the lack of information on beginning of the plague. Deaths quickly jumped into the thousands in towns along the rail line but never spread very far from the lines. Summers notes that of the over 43,000 recorded cases during the outbreak only one single person survived (p. 19). Some estimates place the mortality closer to 60,000 when early cases and locals away from the rail line are included. Summers notes that this puts the death toll in the range of the great London plague of 1665. By February 1911, the plague was over; blatant proof the plague outbreaks can flourish in winter (as it sometimes did in medieval European winters).

This plague has some unique features. First, there is no report of bubonic plague at all; it was exclusively pneumonic. Most plagues are primarily bubonic with flair ups of pneumonic transmission. Etiology was confirmed by autopsy and the then new bacteriological techniques including culture. American doctor Richard Strong, working with the Chinese under Wu Lien-Teh, did 25 autopsies before the International Plague Conference called by the Chinese in Mukden. There is no doubt the Yersinia pestis caused this epidemic.

Without antibiotics, quarantine and isolation were the only effective means of control. The means were brutal but effective. In the Russian zone the Chinese were crowded into train cars and not let out until there were several days with no one displaying any symptoms. If a case of pneumonic plague was locked in the car with others, the prognosis for the others was predictably terrible. Within this relatively small region, we can also see three different national approaches (China, Russia, and Japan) to controlling the epidemic each always subordinated to their respective political anxieties.

The chapter on origins of the plague begins to move toward was Edmund Russell envisioned as evolutionary history in his book of the same name (2011). The most useful information here is the history of marmot activity and traditional hunting. Summers hypothesizes that traditional shaman-like practices may have aided hunters in only taking healthy animals. Concern for the health of the animal was one of the early traditions abandoned by hunters eager for furs. Following the reports of the time, Summers believes the plague originated in the marmots, and was distinct from the third pandemic lineage. In accordance with modern strain maps, Summers predicts that the 1910-1911 Manchurian outbreak strain will belong to either the antiqua or medievalis biovars (p. 128-9). If this is true, as is likely, it’s a relatively modern challenge to our notion that plague during pandemics has a single lineage and origin. It should be possible to type this outbreak from graves of the epidemic (which should be relatively easy to locate at barely a century old) or even tissue archived from the autopsies (if it was saved and can be located).

Summers is clearly in his element when he discusses the politics of turn of the 20th century politics. This is a region and time period that most Americans know very little about but is still critically important for Asian politics today with the still uneasy relationship between China, Korea, Japan, and Russia. Summers account lays out the different approaches to healthcare and attitudes toward the epidemic as a national and economic threat. This carried over to the International Plague Conference that nevertheless managed to focus on science and medicine. While the scientific politics was interesting I would have liked to hear more about the contents of the wide-ranging Conference report.

Summers does a good job of being very diplomatic will all parties concerned. In doing so, he does overlook a major legacy of the Manchurian plague. There seems little doubt that this plague, witnessed and closely reported on by Russia, the United States and Japan, played a role in plague being developed as a biological weapon. This plague illustrated the deadly efficiency and sustained transmission of pneumonic plague. This book should be read as a prologue to Japan’s biological ‘experiments’ during World War II beginning in Manchuria (see Sheldon Harris’ Factories of Death) and the continuing programs of the United States and Russia during the Cold War.

This book makes a valuable contribution to plague studies, and early 20th century public health practices. Yet there are still unanswered questions on genetics, epidemiology, and ecology. I hope this book along with Myron Eschenberg’s Plague Ports(2007) and others are ushering in a new period of focus on the plague in the 19th-20th century.

Reactivation of Ancient Plague Foci in Libya, 2009

Landscape around Oran, Algeria (2003), and Tobruk, Lybia (2009) that produced plague cases. (Cabanel et al, 2013)

Plague has been called a re-emerging disease primarily because cases have begun to appear in areas where plague has been absent for decades. Two recent surprising outbreaks occurred in Algeria, where plague had been absent for over 50 years, and in Libya after a 25 year absence. A team led by the Institut Pasteur explored possible relationships between the recent Libyan outbreak and the Algerian outbreaks. All of the information in this post comes from their report to be published in the February issue of Emerging Infectious Diseases (citation and link below).

The outbreaks under consideration were just south of Oran, Algeria in 2003, at Lanhouat, Algeria in 2008 and near Tobruk near the Libyan-Egyptian border in 2009. Another possible outbreak of plague occurred at Tobruk during the Libyan revolution in 2011.  Political unrest prevented a complete disease investigation of the 2011 Libyan epidemic. Past Libyan plague outbreaks have occurred from 1913-1920, 1972, 1976, 1977, and 1984. The largest outbreak in 1917 is credited with 1,449 deaths.

The 2009 Libyan index cases consisted of three children from one nomad family; one child died after two days of intensive care and the other two eventually recovered. Only one child had a tender cervical node. The other two, including the child who died, had signs of a severe infection but no visible buboes. The father reported having axillary lymphadenitis and a couple of sudden deaths in the region in the previous two months. A week after admission Libyan authorities reported 13 possible cases to the World Health Organization and requested assistance. The WHO-Libyan team identified two more women with painful inguinal nodes and “infectious syndrome”, but also concluded the initial estimate overstated the number of cases. There are five confirmed cases. The cases were spread 30-60 km from the index family’s home in Eltarsha, 30 km south of Toburk. Regional response included antibiotic treatment of contact persons, and insect and rodent control measures. No further cases were reported.

Diagnosis was confirmed by standard bacteriological assays and molecular characterization. All five confirmed cases were positive with the F1 antigen dipstick.  Yersinia pestis cultures were isolated from three patients,  all phenotyped to the Medievalis biovar by metabolic assays. Molecular characterization confirmed that all are the same Medievalis strain. Hybridization analysis indicates that it is most closely related to, but distinct from, strains isolated from Iranian Kurdistan in 1947 – 1951.

Using the same methods, the 2003 Algerian isolates were phenotyped to the Orientalis biovar. Molecular characterization confirmed that they are all related but not identical Orientalis strains. Activation of multiple related strains from an ancient foci in the same year suggests an environmental trigger. Comparing the 2003 strains to those isolated in 1944 and 1945 illustrate the complexities of plague foci. The 1944 isolate is a Orientalis strain that belongs to the same cluster of strains as the 2003 isolates and other strains from Morocco and Senegal.  The 1945 strain matched a molecular characterization of  Orientalis isolates from Saigon, Vietnam and is believed to have been transmitted by military transports during World War II.  Cabanel et al conclude that the 2003 Algerian outbreaks were caused by local Yersinia pestis strains. It should be noted that the third pandemic from the turn of the 20th century was a Orientalis biovar (1.Ori1).

Cabanel et al. note this is the only instance they could find of a Medievalis strain in Africa. The spread of cases over a 30-60 km region and isolation of related but different strains support the reactivation of an ancient plague focus. Unfortunately they did not have access to isolates from previous 20th century Libyan outbreaks (if they exist) that could have provided more certainty.

Reactivation of plague foci around the Mediterranean has been associated with climate change. They note that an unusually humid winter and good crops in Libya in 2009 favored rodent and flea abundance. Long dormancies may be part of Yersinia pestis’ natural history particularly in resource limited environments. This possibility will be one of the topics of my next post.

Cabanel et al. note that camel meat and livers have been associated with human plague cases in Libya (1976), Saudi Arabia (1994), Jordan (1997), and Afghanistan (2007). Additional local evidence suggested that the highly susceptible camels contracted the plague from local foci in these instances. Although camels do not survive plague long enough to transmit it very far, camel caravan routes may still have played a role in transmission if only by the other organisms also along the camel caravan route. Camels would have provided an abundant host to amplify the organism along the route. Camel fleas could have been carried among the cargo not unlike rat fleas in ship cargoes. Camel caravans would provide an ancient route for a Medievalis strain to reach Libya from the central Asia.

Reference

Cabanel, N., Leclercq, A., Chenal-Francisque, V., Annajar, B., Rajerison, M., Bekkhoucha, S., Bertherat, E., & Carniel, E. (2013). Plague Outbreak in Libya, 2009, Unrelated to Plague in Algeria Emerging Infectious Diseases, 19 (2), 230-236 DOI: 10.3201/eid1902.121031

On Giants Shoulders #54: A Sleigh Load of History

Welcome to On Giant’s Shoulders #54, the history of science blog carnival! Here, we celebrate the history of science with all its oddities, and modern science delves into the past. I can’t think of a better way to spend my third blogoversary (of regular blogging) here at Contagions. Just a few days away from the winter solstice, I managed to fill my sleigh with a load of science history links. Cuddle up with a warm mug of hot chocolate (or whatever warms you) and settle in for some good reading.

Festive Science and the Holiday Season

Since the culture war between science and religion heated up, there has been friction between science and religious holidays like Christmas. Rupert Cole of Notes & Theories reminds us that this was not always so. In Victorian England, the popularity of science and Christmas festivities peaked with the public at the same time and reveled in each other. Victorian Christmas plays and pageants were followed by science lectures to explain the featured science and technology! Public Christmas trees were decorated with scientific instruments that were given to children. Those were the days. Though some science folks still know how to mix up the traditions. In a throw back to at least the sixteenth century, Diane Mcllmoyle of Esmeralda’s Cumbrian History and Folklore writes about the holiday tradition of mummer’s plays with its requisite quack doctor.

History of Pseudoscience

Let’s kick this carnival off with a stimulating discussion on, of all things, the omnipresence and worth of (what we call today) pseudoscience. Rebekah Higgitt of The H Word addresses claims that pseudoscience is on the rise with a history lesson, and ThonyC of Renaissance Mathematicus goes one step further asserting that pseudoscience has sometimes been helpful to the development of science. Faye Flam of Lightning Rod writes on Michael Gordin’s recent research on pseudoscience. Continuing with the supernatural, Lindsey Fitzharris of The Chirurgeon’s Apprentice discusses Abraham Lincoln’s conversations with the dead.

Darwin and Evolution

As always posts on Charles Darwin must be featured in On Giant’s Shoulders. Suvrat Kher of Rapid Uplift writes about Darwin’s slow, deep-thinking methods. Michael Barton of The Dispersal of Darwin calls out more quote mining of Darwin by anti-Darwinists. James Randerson writes of the private life of Charles Darwin. The Alfred Russel Wallace Correspondence Project also launched this month to coincide with the centenary anniversary of his death in 2013. Tim Jones of Zoonomian celebrated the birthday of the other famous Darwin, the polymath Erasmus Darwin (d. 12.12.1731). He also visits Annie Darwin’s grave and reviews Dr Gully’s water cures.

Joachim D of Mousetrap posted on Herbert Spencer’s synthetic philosophy and the centrality of evolution in his thinking.

Archaeology

Kristina Killgrove of Powered by Osteons summarized Nutrition and Well-Being in the Roman World: The Evidence of Human Bones, a conference this fall in Rome. Katy Myers of Bones Don’t Lie discusses how isotope data from bones informs on the social structure of an Anglo-Saxon settlement. In another post she discusses skeletal weapon trauma in medieval Ireland confirming the violence in Irish medieval records. In her most recent post she discusses the discovery and analysis of the graves of victims of the attempted mutiny of The Batavia off the coast of Australia in 1628.

Epidemiology

Katy Meyers of Bones Don’t Lie discusses a new study examining osteological and molecular evidence of TB at three neolithic sites in Germany at the transition to farming. I have a post on the Black Death Network reviewing the molecular evidence of the Black Death. If you have any interest in the 14th century crises — plague, famine, cattle murrain etc. — check out the Black Death Network. Spirochetes Unwound discusses the latest theory on the mysterious epidemic of 1616-1619 that decimated native Americans along the New England coast. Here on Contagions, I posted on the isolation of smallpox DNA from 17th century Siberia. The History of Vaccines blog posted a sketch of smallpox vaccine production in a cow, along with a discussion of vaccine production in 1872. Bringing us up to the 20th century, Rebecca Kreston of Body Horrors brings us the story of the first case of HIV in a 1961 Norwegian teenager who brought an unusual strain of HIV (group O) to his family and seeded it across in Europe.

Genomics

Genomics can help unravel the history of peoples who have left little documentary record. History of the Ancient World Blog has a post on a new study examining Scythian genetic admixture. Katherine Harmon of Observations covers a new study showing Gypsy or Roma origins in India about 500 CE/AD. This places the movement of the Roma out of India into Central Asia during the Great Migrations period that occurred when the Western Roman Empire fell in the fifth century. Interesting to think of the Roma as the last of the 1500 year old Great Migration peoples. Also covered on Past Horizons.

Mike Drout and his team at Wheaton have been applying DNA analysis and statistics software to Old English texts to determine authorship. They call it Lexomics — check them out.

Medical Practice and Public Health

Early modern medical practice was in the spotlight this month. Mike Rendell, The Georgian Gentleman puts a spotlight on contemporary views of 18th century medical practice. Home remedies were not any more successful, as ThonyC of Renaissance Mathematicus writes about in George Boole’s death from his wife’s homeopathy. Jai Virdi of From the Hands of Quacks explores the motivations of Dr Curtis‘ founding of the Royal Dispensary for Diseases of the Ear. The Secret Histories Project brings us a biography of the unconventional Dr. James Barry, child genius, military surgeon, and annoyance of Florence Nightingale. Venessa Heggie of The H Word, writes on the 70th anniversary of the Beveridge Report, that founds the modern British welfare state, about earlier attempts to build a social safety net in Britain with Elizabethan Poor Laws and the infamous Victorian workhouses. New blogger Jennifer Evans of Early Modern Medicine writes about the rhetoric of men pushing through the pain. Lisa Smith’s of the Sloane Letter project, she looks at the problem of bed wetting in the 18th century. Lindsey Fitzharris of The Chirurgeon’s Apprentice got ready for the holiday season by picking 12 (medical) instruments of Deathmas; most are sure to make you squirm. Caro of The Quack Doctor writes about the fun and games at Illinois Pharmacological Association meetings for traveling salesmen near the turn of the 20th century. Lynsey Shaw of the History of Military Aviation Hospitals writes on The Oxford Military Hospital, 1939-45.

Efforts to figure out the brain were popular this month. Michael Finn of Asylum Science wrote about the use of ophthalmoscope to view the living brain in asylums. The Public Domain Review reprinted “The Brain of Charles Babbage” (1909), the ‘father of the computer’. Darin Hayden wrote about a phrenological examination of Andrew White (who played a role in igniting the friction between science and religion).

On chemicals we are better off without, Marieke Hendriksen of the Medicine Chest writes about how mercury was viewed by early medical practitioners. Deborah Blum of Elemental writes about how early the US FDA knew about radiation dangers in cigarette smoke.

Pharmacy and Diagnostic Texts

Christina Agapakis of the Oscillator writes about the medieval Urine Wheel to diagnose metabolic diseases.

Michelle DiMeo of the Recipe Project writes about Dr Crawford Long’s exploration of the uses of ether for insect bites. Lisa Smith at the Recipe Project writes about a treatise claiming coffee cures the plague. In the area of hard to find reagents, Chelsea Clark of The Recipe Project shines light on the wonders of unicorn horns, bezoars and bones of a stag’s heart for poisoning. Alas, black markets for animal products like Rhino’s horn (a unicorn substitute) and bear gal bladder is still very active and taking its toll on increasingly rare animals. A little easier to resource, Jonathan Cey of the Recipe Project, shows us that feces-containing remedies were common in the early modern pharmacopoeia. So patients were more right than they knew when they said their medicine tasted like crap! Pamela Dangle also of The Recipe Project writes about some really “fishy” remedies for Melancholy (that seem rather unlikely to help, to me). Thinking of odd remedy names, Tim Jones of Zoonomian writes about medical misnomers of the past.

Physics, Astronomy, and Earth Sciences

ThonyC of Renaissance Mathematicus writes about the astronomical and medical roots of the first pocket diary (calendars). I’ll never look at those moon symbols on my calendar the same way again. Sorry Dad, the phases of the moon are not on the calendar to tell you when the fish are biting. Along similar lines of finding practical solutions to scientific dilemmas, Rebekah Higgit of The H Word writes about the catching and keeping of spiders to spin eyepiece filaments for astronomical observations. On the Royal Society blog, Rupert Baker writes about Thomas Hardy’s historical fiction on early astronomers and the royal society.

Let’s get a little textual with our astronomy, starting with Jenny Weston of Medieval Fragments who writes about medieval star-gazing. Astrolabes and Stuff discusses how to construct a medieval equitorium of Mercury and also for the Moon. Katy Barret of the Longitude blog writes about use of Cook’s journals and her longitude book collection. Sarah Werner of The Collation writes about volvelles (movable wheels) on folios of science and pseudoscience books.

Harald Sack at Yovisto writes about the golden-nosed astronomer Tycho Bahre and on Werner Heisenberg and the uncertainty principle. Alberto Vanzo of Early Modern Experimental Philosophy writes about the contributions Geminiano Montanari and the Italian academy. Matt Wisnioski guest posted on American Science about the motto “Change or Die!”

David Bressan of History of Geology writes about how philosophies of the nature of the world effected the study of the history of the Earth, and early efforts to measure its age. BibliOdyssey posts some of the original sketches and paintings of the discovery of Australia and its wildlife and then on Plant atlas from 1878-1783.

Dr SkySkull of Skulls in the Stars sets the record straight on Benjamin Franklin’s kite electricity experiments, outlines Priestly’s 1767 account of Franklin’s experiments and writes of the dangers of experimental ballooning in 19th century. Moving on from riding aloft to the winds on the plains, Carol Clark of Wonders & Marvels writes about the role of wind power in settling the arid American west.

Christian Hansen of Hummus and Magnets writes about the analytical programming of Babbage’s early calculating machines.

Lisa Smith will be hosting the next On Giant’s Shoulders carnival on the Sloane Letter Project in January. So watch for Lisa’s posts on twitter (@historybeagle) for more information.

I hope you found something enlightening and entertaining for a long winter’s night. Watch out for sleighs this holiday season, reindeer get spooked with all the holiday traffic!

The Landscape of Super-Spreading

Super-spreading individuals and disease hot spots have been known for over a century, but rarely have they been considered together. Sara Paull and colleagues [1] have pulled together all of the recent work the ecology of disease hot spots and transmission heterogeneity (super spreading) to explore the continuum between individual transmission heterogeneity and the landscape of disease, otherwise known as disease ecology. Hawley and Altizer [2] have developed the interrelationships further to the cellular level by linking disease ecology directly to ecological immunology, examining the effects of the environment on the immune system of  host populations. Taken together, these fields can be developed into a continuum of macro to micro landscapes  with transmission heterogeneity, better known as  super-spreading, at its center.

Adapted from Hawley and Altizer (2011). (Click to enlarge)

Disease Ecology

Disease ecology is the study of pathogens in the context of their dynamic environment. Unlike most medical experiments conducted in vitro, removing or stabilizing as many variables as possible, disease ecology seeks to understand the place of the pathogen in an an open, responsive environment with an unknown number of variables [3]. In disease ecology, multiple hosts and vectors of zoonotic diseases are considered together as a complex system. It is normal for the system to respond in unpredictable ways and for multiple stable states to be possible; the human gut microbiome consists of up to a thousand bacterial species that can come to at least three stable states (enterotypes) unrelated to easily identified variables (age, gender, ethnicity, etc.) [3].

Some of the basic areas of disease ecology include understanding the multiple hosts of a pathogen including factors effecting the lifecycle of the hosts, ecological drivers, endemic/enzootic and epidemic/epizootic dynamics,  characterization of the rural or urban landscape, and transmission dynamics. The US Environmental Protection Agency (EPA) defines an ecological driver as any biotic or abiotic factor that causes change to the ecological landscape. Ecological drivers can be as diverse as invasive species, climate change or changes to a man-made landscape. Transmission dynamics is also a basic factor in disease ecology.

Transmission Heterogeneity

Transmission between hosts is rarely, if ever, a uniform process. Extreme cases of transmission heterogeneity, where a small number of individuals are responsible for most successful transmissions, are called super-spreaders. These super-spreaders are major factors in epidemic dynamics of an increasing number of human pathogens. Drilling down into why transmission dynamics are heterogeneous yields a variety of causes.

Species level transmission heterogeneity has led to the recognition of ‘amplifying species’ that act as super-spreaders within the landscape.  American Robins as preferential hosts and transmitters of West Nile Virus are a classic example of an amplifying species [1]. Presumably changes in the landscape could alter the degree to which each possible host species contributes to the overall transmission within the environment and which host becomes the amplifying species. It would naturally follow that not all possible vectors are equally responsible for disease transmission. For example, we know that rat fleas, cat fleas, human fleas and possibly human lice can all transmit Yersinia pestis, but they are not equally responsible for transmission.

Landscape contributes to transmission heterogeneity as well. Studies have shown that oak tree vulnerability to sudden oak death syndrome varied with tree genotype but in field tests temperature and rainfall differences  mattered more than the genetics of individual trees [1]. These landscape characteristics go beyond the classical definitions of disease ‘hot spots’. Typical hot spots are defined as areas where there is higher pathogen levels or more amplification hosts [1].  For example, buffalo wallows and sites of buffalo deaths can become anthrax hot spots. Human have created animal disease hot spots; chronic wasting disease is increased among Colorado mule deer near human settlements rather than more remote areas [1]. In Belize, agricultural run-off alters the aquatic plant communities increasing breeding efficiency of the malaria vector Anopheles vestitipennis [1]. Some environmental hot spots can be so strong that they are “analogous to superspreaders” [1].

Which comes first, the hot spot or the super-spreader? Paull et al  note that “logically, superspreaders create hotspots of transmission around them, and hosts in a disease hotspot, by definition, experience an increased infection pressure as compared with others in the population” [1]. Ultimately what really matters is understanding why there is increased transmission. Does the ‘hot spot’ move with the hosts or is it tied to a locality or architectural structure? Some ‘hot spots’, like ships, are capable of moving although the increased transmission is tied to a piece of architecture. Likewise, some types of air conditioning systems can become ‘hot spots’ for Legionellosis, but redesign of the air conditioning system eliminates the ‘hot spot’.

Ecological Immunity

Ecological immunity takes factors of disease ecology and heterogeneous transmission particularly to the cellular and molecular level. For example, high testosterone levels suppress the male immune system (in birds and rodents) while triggering behavior that increases their territory and contact rates making them behavior super-spreaders [1,2]. It has been suggested that testosterone levels could be “a common driver of superspreading phenomena, broadly linking within- and among-host processes across vertebrate host taxa” [2].

The role of the environment and immunologic costs intersect when we look at seasonal effects and nutritional needs of the immune system. Malnutrition depresses the immune system directly and indirectly through hormones like leptin. The cost of immunity comes home when we realize that leptin intentionally cripples the immune system as part of the starvation response. Seasonal effects are easier to understand in animals that have a more defined seasonal pattern of migration, or a defined mating period [2]. Yet human infectious disease fluctuates with the season; influenza being a prime example of a disease with seasonal fluctuations.

Coinfections are also best understood for their impact at the cellular level of the immune system. The cost of the immune response makes immune trade-offs necessary during coinfections.  Focus has zeroed in on a classic immune trade-off between production of T-helper 1  and T-helper 2 cells as at least a partial explanation of poor prognosis for  helminth (worm)  and an intracellular pathogen coinfections [2].  Several studies have now shown that HIV infections progress faster if there is a helminth coinfection [2]. Likewise, in African buffalo helminth infections correlate with tuberculosis vulnerability and rapid progression; “Joelles et al (2008) found evidence for a direct trade-off between circulating levels of IFNγ (Th1 response) and eosinophils counts, their measure for Th2-type response in buffalo” [2]. To decrease vulnerability and improve prognosis for HIV and tuberculosis, treatment for helminths should become a priority.

What constitutes immune fitness must also be reevaluated in light of ecological immunity findings. The high cost of immune defenses are such that unnecessary defenses for the current environment are generally not maintained [2]. Likewise, costs and trade-offs may make it necessary for the immune system to develop tolerance to some pathogens deemed low risk to fight other greater risk challenges. Hawley and Altizer  note that “a ‘competent’ immune system may employ tolerance strategies, making immune ‘competence’ difficult to assess via infection outcome alone” [2].

Today we are only at the very beginning of understanding complex disease ecologies. For zoonotic diseases the impact of ecological drivers and enzootic dynamics all around the world make the identification of the best predictors an imperative. Yet, outbreak prediction will remain an imprecise science, not unlike the prediction of hurricanes or volcanic eruptions.  Increased surveillance will remain key to a rapid response and epidemic mitigation.

References:

[1] Paull, S., Song, S., McClure, K., Sackett, L., Kilpatrick, A., & Johnson, P. (2012). From superspreaders to disease hotspots: linking transmission across hosts and space Frontiers in Ecology and the Environment, 10 (2), 75-82 DOI: 10.1890/110111

[2] Hawley, D., & Altizer, S. (2011). Disease ecology meets ecological immunology: understanding the links between organismal immunity and infection dynamics in natural populations Functional Ecology, 25 (1), 48-60 DOI: 10.1111/j.1365-2435.2010.01753.x

[3] Pepper, J.W. & Rosenfeld, S. (2012). The emerging medical ecology of the human gut microbiome, Trends in Ecology & Evolution, 27 (7) 384. DOI: 10.1016/j.tree.2012.03.002

Poll: Modern Infectious Disease Medicine

I’ve never put a poll up here at Contagions, so let’s try this out with an easy question (but maybe not an easy answer).