john hawks weblog

paleoanthropology, genetics and evolution

pathogens

  • Coprolite microbial ecology

    Thu, 2013-02-28 00:25 -- John Hawks

    The advent of metagenomic analysis of microbial communities has led to some unexpected insights about human biology. These techniques have quietly been leading to new discoveries from old archaeological contexts. One example is Alan Cooper's work demonstrating long-term changes in oral microbiota from ancient dental calculus ("Tracing teeth troubles with fossil bacteria").

    Another is a recent paper from Cecil Lewis' lab, "Insights from characterizing extinct human gut microbiomes." [1]. The paper is open access in PLoS ONE. In it, Raul Tito and colleagues recover DNA data from ancient coprolites, from three archaeological sites in the Americas. As discussed in the paper, they obtain good data from a 1400-year-old site in Mexico. Those people, who lived near present-day Durango, were contemporaries of the classic Maya and Teotihuacanos. As such, their gut microbiomes may provide a really interesting picture of health and diet from a key period in the prehistory of the Americas.

    Coprolites may seem simple, but each represents a unique history of deposition and subsequent preservation. The microbial community may shift during the early stages of this history, and subsequent DNA damage may shift estimates of microbial abundances away from their true values. They found one of their sites appeared to preserve a good signal, while the others were degraded:

    Most striking, both Rio Zape coprolites exhibited a gut microbiome signature with similarities to the children from a rural African village with the exclusion of a sample of U.S. modern adult gut microbiomes (see Figure S4 for a heat map of these data and Figure S5 for the variability in the source proportion estimates). ZA04 also harbored similarities to non-human primate gut. The coprolites from Caserones and Hinds Cave showed little similarity to a gut microbiome environment. A portion of Caserones coprolite microbial community was similar to compost, which may be explained by the post-mortem gut serving as an organic bioreactor filled with carbon and nitrogen from decaying food detritus. The microbial community assignment for Hinds Cave failed to assign well to any source environment.

    From this, we can see that any interpretation of data from a sample of ancient coprolites must be cautious. We're generally interested in how microbial communities may have changed in ancient populations, particularly in response to other factors such as shifts in diet. But as yet it's not very clear what kinds of changes we should predict in association with diet or other changes. That makes it hard to develop a convincing test of a hypothesis.

    This paper is more of a proof of principle. And in its discussion, Tito and colleagues present different ways to explain the kinds of differences that they found in the ancient coprolite microbiota. To me, the most provocative hypothesis is that changes may have more to do with parasite load than diet:

    Information from Rio Zape also supports a current hypothesis about the composition of human microbiomes in traditional communities, potentially revealing an important aspect of the ancestral human microbiome. Spirochaetes are atypical of gut microbiomes in cosmopolitan communities. However, Treponema was reported by Filippo et al. [21] in their comparative study of modern microbiota in children from Europe and rural Africa. In their study, Treponema was observed in the rural African children but was absent in the European children. They hypothesized that the Treponema may enhance the hosts ability to extract nutrients from fibrous foods and may provide anti-inflammatory capability. They raise the hypothesis that microbiota coevolved with ancient diets and that changes in food production greatly impacted the intestinal microbiota. Treponema was also observed in the published rural data for Malawi and Venezuela [22]. The results from Rio Zape provide further support for Treponema as part of the rural human microbiome. Specifically, Treponema now is observed in four rural communities from different continents, three extant communities and one community that has been extinct for over a thousand years.

    As we uncover more comparative data from living people, we will begin to have a better picture of the covariates of microbial community structure. Today's oral bacterial populations in "cosmopolitan" post-industrial peoples are uncharacteristic of past variation. The gut microbiota of cosmopolitan peoples may be just as uncharacteristic. The diversity may have had great importance to ancient health, especially at key times when pathogens were spreading through post-agricultural populations.

    References

    1. Tito RY, Knights D, Metcalf J, Obregon-Tito AJ, Cleeland L, Najar F, Roe B, Reinhard K, Sobolik K, Belknap S, et al. Insights from characterizing extinct human gut microbiomes. PLoS One. 2012;7(12):e51146.
    Tags: 
    microbiome
    gut
    diet
    America
    pathogens
    Holocene
    Synopsis: 
    A look within the gut microbiota of ancient Americans

  • The workings of leprosy

    Fri, 2013-01-18 09:25 -- John Hawks

    Mo Costandi describes a paper with a really fascinating finding about the workings of leprosy: "Leprosy spreads by reprogramming nerve cells into migratory stem cells".

    Anura Rambukkana of the MRC Centre for Regenerative Medicine at the University of Edinburgh and his colleagues isolated Schwann cells from adult mice, grew them in Petri dishes and infected them with M. leprae. They found that the bacterium gradually turns off the genes that give Schwann cells their characteristic properties, and then activates another set of genes that transforms them into something resembling neural crest stem cells, which are only present in the embryo, and which migrate from the developing nervous along various routes to form a wide variety of tissues, including muscle, bone, cartilage, and the Schwann cells and sensory neurons of the peripheral nerves.

    On a scale of how parasites and pathogens manipulate our biological pathways to achieve their own ends, this one runs pretty deep. Exploiting our mechanisms of embryonic development to migrate through the body inside our own cells. Leprosy may be one of the oldest human pathogens, with its long slow course really well suited to spreading in small human communities with infrequent contacts among groups.

    Tags: 
    leprosy
    pathogens
    health
    development

  • Calculus microbially

    Sun, 2012-06-10 22:01 -- John Hawks

    Molecular archaeologist Christina Warinner gave a TED talk and the main ideas are now in a CNN article: "Why your dental plaque is valuable".

    By applying advanced DNA sequencing and protein mass spectrometry technologies to ancient dental calculus, we can begin to reconstruct a detailed picture of the dynamic interplay between diet, infection and immunity that occurred thousands of years ago. This allows us to investigate the long-term evolutionary history of human health and disease, right down to the genetic code of individual pathogens, and it can teach us about how pathogens evolve and why they continue to make us sick.

    This is really neat work, although the article doesn't go into any new results.

    Tags: 
    pathogens
    ancient DNA
    teeth

  • Malaria death toll estimate rises

    Fri, 2012-02-03 07:42 -- John Hawks

    Notable, from the Guardian: "Malaria kills twice as many people as previously thought, research finds".

    The study demolishes conventional thinking on malaria – that almost all the deaths are in babies and small children under the age of five. The study found that 42% were in older children and adults.

    "You learn in medical school that people exposed to malaria as children develop immunity and rarely die from malaria as adults," said Murray, IHME director and the study's lead author. "What we have found in hospital records, death records, surveys and other sources shows that just is not the case."

    It will take some figuring to work out what that means relative to births in areas where malaria is endemic, but we can add to the higher death toll the clear long-term costs of malaria even to its survivors.

    Tags: 
    malaria
    health
    pathogens

  • Malaria book

    Mon, 2010-07-26 16:33 -- John Hawks

    A new book by Sonia Shah covers the history of malaria and the way it affects people today around the world: The Fever: How Malaria Has Ruled Humankind for 500,000 Years.

    I haven't got a copy yet, so I don't know why she picked 500,000 years. I'd have thought that was a fairly unlikely moment to start the story given what we know about the Neu5Gc story.

    The NY Times reviewed the book today. This was scary:

    Meanwhile, in many undeveloped parts of the world, the disease is just one of those things. Despite the urgency of the newest Gates-Clinton-Bono antimalarial cabal, people often consider it a minor malady, like a cold, and shrug at the West’s obsession with taming it. According to one estimate, only 20 percent of those with malaria actually seek curative treatment, and then only a third of those take the drugs as prescribed. Life-saving insecticide-treated mosquito nets, donated by the West with much fanfare, are sometimes repurposed to catch fish.

    UPDATE (2010-07-27): A reader writes:

    It's not clear in your post what you're referring to when you say "This was scary:" - the passage or the irresponsible journalism?

    I've not read the malaria book either but I was annoyed to see the passage you pasted, including the line: donted nets "...are sometimes repurposed to catch fish." They are occasionally used as wedding gowns too (http://news.bbc.co.uk/2/hi/africa/4393375.stm) and probably all kinds of other things but these uses might represent maybe .01% of all nets distributed? I can just hear one of my friends saying, "Oh I'm not going to give money for bednets, those Africans just using them for fishing!"

    Why not discuss the number of countries that had over 50% reduction in malaria cases over the last few years? Seems like a wasted opportunity.

    Good points.

    Tags: 
    health
    disease
    pathogens

  • Fatigued by advocates impeding research

    Sun, 2010-07-04 11:55 -- John Hawks

    Science has a news article that details the conflict over publishing new research on a viral cause of chronic fatigue syndrome (CFS): "Conflicting Papers on Hold as XMRV Frenzy Reaches New Heights".

    It's mainly about the conflicting results of several ongoing studies into whether there is a virus-disease association. Early stages for serious research, and there is as yet little idea of the mechanism that might be involved. But even here, there are big disagreements:

    Science has learned that a paper describing the new findings, already accepted by the Proceedings of the National Academy of Sciences (PNAS), has been put on hold because it directly contradicts another as-yet-unpublished study by a third government agency, the U.S. Centers for Disease Control and Prevention (CDC). That paper, a retrovirus scientist says, has been submitted to Retrovirology and is also on hold; it fails to find a link between the xenotropic murine leukemia virus-related virus (XMRV) and CFS. The contradiction has caused "nervousness" both at PNAS and among senior officials within the Department of Health and Human Services, of which all three agencies are part, says one scientist with inside knowledge.

    I'm pointing to the story because I was interested in the last few paragraphs. CFS sufferers and advocates are eager to see progress toward understanding the disease. This creates pressure on researchers -- especially those who fail to find evidence for this hypothesis:

    Patients have become a loud voice in the scientific debate as well—and it's taking its toll on scientists who don't support the XMRV hypothesis. "It's ghastly, " says retrovirologist Myra McClure of Imperial College London, the lead author on one of the three published studies that came up empty-handed. "I've had people writing me, and I quote, that I don't know my arse from my elbow, and that I should be fired." Four months after her first paper on CFS came out, McClure says it was also her last one. "Nothing on God's Earth could persuade me to do more research on CFS, " she says. "I feel bad for the scientists, because it's true, we are a very angry community, " says Wilhelmina Jenkins, a physicist living in Atlanta who has had CFS since 1983.

    I think in general unrecognized pathogens are likely causes of disorders like CFS, and I agree that researchers for too long failed even to look seriously at them. Yet, there's a lot of diagnostic noise complicating things -- does everyone diagnosed with CFS really have the same condition? -- and for chronic conditions the science is always difficult. A giant epidemiological study may increase the statistical power, but it also vastly increases the political fighting.

    Of course, they write me and tell me I don't know my arse from my elbow, either. I guess you gotta have a thick skin if you're going to deny that ancient aliens directed our evolution!

    Tags: 
    pathogens
    metascience
    disease
    health

  • Dracunculiasis

    Mon, 2009-12-07 19:14 -- John Hawks

    The NYT reports that Nigeria has been free of guinea worm infections for a year.

    Guinea worm — or dracunculiasis — inspires universal horror. People are stricken when they drink pond water infested with microscopic fleas, in which the worm larvae live. The worms grow to resemble translucent three-foot strands of spaghetti and finally emerge by exuding acid that bursts the skin; the pain can be crippling for months.

    Only four countries — Ethiopia, Ghana, Mali and Sudan — still have the worms. About 3,000 of them were found as of last month, down from three million across the globe when Mr. Carter began his effort to wipe them out.

    The WHO page on dracunculiasis eradication doesn't give many more details. A lot more information can be found in a review by Cairncross and colleagues (2002), the complete text of which is free on PubMed. I went looking out of curiosity about animal infections -- it seems too easy to get rid of this thing in humans, considering the presence of dracunculiasis in other mammals. North America in particular has a big problem with the parasite in carnivores -- raccoons get it a lot.

    But the human parasite is part of a larger family of nematode parasites that infect other species and often have different crustacean hosts. There seems to be occasional transfer into humans of various other forms, and transfer of the human parasite into domesticated animals, but access to filtered water is sufficient to break the human cycle. In several countries where human dracunculiasis was eliminated many decades ago, it hasn't returned, so the simple effort to provide clean water seems sufficient to eradicate it.

    References:

    Cairncross S, Muller R, Zagaria N. 2002. Dracunculiasis (Guinea Worm Disease) and the Eradication Initiative. Clin Microbiol Rev 15:223-246. doi:10.1128/CMR.15.2.223-246.2002

    Tags: 
    disease
    pathogens
    health

  • Leprosy evolution in humans

    Fri, 2009-11-27 02:59 -- John Hawks

    Where did leprosy come from as a human pathogen, and how did it spread through the world? Two years ago, this new research would have merited a whole book. Now it's all packed into a single Nature Genetics paper by Marc Monot and coworkers.

    I mean, there's a lot in here:

    1. They used next-gen sequencing platforms to get three additional whole-genome sequences for the pathogen that causes leprosy, Mycotuberculum leprae.

    2. By comparing the different strains together with an already-available one, representing patients in four countries, they measured the genome diversity and found SNPs between strains.

    3. They then genotyped the resulting SNPs in 400 isolates, building a phylogeny of worldwide strains of M. leprae today.

    4. They did a phylogeographic analysis of the strains, testing hypotheses about past transfers of the bacterium among regions.

    5. And then, on top of all that, they recovered skeletal remains from "leprosy graveyards" in six countries, diagnosed the skeletal correlates of leprosy in 13 cases and genotyped the resulting extracts for M. leprae, placing them on the global phylogenetic tree.

    Whew!

    Well, I assume that the skeletal work was done separately, with samples being sent to the lab folks to do their DNA extraction.

    This would be a really good topic for a documentary. There's all the historical information about leprosy to draw upon, including of course its prominent appearance in the Bible and Father Damien. There's the triumph of effective treatments in developed parts of the world -- an aspect that this paper emphasizes, as it attempted to find out whether regions of the world that now lack M. leprae once had the strains expected from their geographic placement. And there's the continuing tragedy of the disease in many less developed parts of the world, with the need to deliver treatment more effectively. Meanwhile, the phylogeographic aspects of this paper provide another historical angle, about the spread of leprosy around the world on human trade routes.

    Plus there's the whole mystery of how it got into humans in the first place:

    Finally, it is worth discussing the enormous discrepancy between the period at which pseudogene formation is thought to have arisen and the origin of early humans. It has been estimated recently that the bulk of the pseudogenes in M. leprae arose no earlier than 9 million years ago. Pseudogene formation is an indicator of radical change in the lifestyle of the host bacterium, such as from the free-living to pathogenic state or of adaptation to life within a particular tissue or cell type. In the case of M. leprae, obligate parasitism of humans or another primate species would represent such a change. Although modern humans represented by H. sapiens have existed only since approximately 250,000 years ago and left Africa within the last 100,000 years to settle other regions, earlier hominids are thought to have diverged from chimpanzees over 5 million years ago. Reconciliation of the estimated time of pseudogene formation with human evolution could be achieved if an ancestor of M. leprae infected an early primate and then underwent genome decay and was subsequently transmitted vertically—although this seems unlikely, given that more genetic diversity among M. leprae isolates would be expected if this were true. Alternatively, the genome decay could well be ancient, but M. leprae may only recently have become a human pathogen. For instance, it is conceivable that an ancestral form of M. leprae infected an invertebrate host such as an insect, which later acted as a vector for transmitting the bacillus to humans. Support for the latter scenario is provided by studies of the related pathogen Mycobacterium ulcerans, which is at an early stage of reductive evolution and appears to be transmitted to humans by water bugs and/or mosquitoes. Further insight into the timing of pseudogene formation in M. leprae will be provided by microbiology and paleomicrobiology and by deeper genome sequence analysis.

    In rough outline, you "date" a pseudogene by counting the number of nonsynonymous substitutions in comparison to some other species where the gene is functional. When the gene was functional, most substitutions of nonsynonymous mutations would have been prevented by purifying selection. You generally apply more detailed assumptions, but that's the basic process. I raise the point because dating a 9-million-year-old event in a bacterial species on the basis of nonsynonymous mutations is probably not going to give a very tight confidence interval, to put it charitably. Maybe 9 million is 4 million?

    In any event, leprosy is one more addition to a growing story about the coevolution of pathogens with Homo. It may have a long history with us, like its congener, tuberculosis. It apparently doesn't have a long history of coevolution within different regionally variable human populations -- tuberculosis does. Possibly it is a relatively recent invasion from another species, which would make it maybe more like the evolutionary dynamics of vivax malaria.

    We don't lack for examples, and tabulating the histories of all of these pathogens may give us a better picture of the population ecology of Homo in Pleistocene times.

    References:

    Monot M and many others. 2009. Comparative genomic and phylogeographic analysis of Mycobacterium leprae. Nat Genet 41:1282-1289. doi:10.1038/ng.477

    Tags: 
    genomics
    disease
    paleogenomics
    health
    pathogens
    phylogeography
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