1B. New Agendas for Researching Global Diseases PDF

    From the Prehistoric to the Medieval to the Modern: New Agendas for Researching Global Diseases Monica H. Green [email protected] Panel: “A Prospectus for Global Health Hi...

    From the Prehistoric to the Medieval to the Modern: New Agendas for Researching Global Diseases Monica H. Green [email protected] Panel: “A Prospectus for Global Health History” American Historical Association, Annual Meeting, 3-6 January 2013 abstract: In a little over a decade, microbiologists have sequenced the genomes for all the major pathogens that cause human disease. They have also, together with bioarcheologists, developed techniques for identifying the presence of fragments of these pathogens in ancient remains. In other words, the investigative biomedical laboratory of the 19th century can now literally reach back into the past to tell us where specific pathogens were found. At the same time, genomics research has allowed the construction of phylogenies of various microorganisms, allowing us to reconstruct the “family trees” of pathogens. Just as global economics are creating a “flat earth” of interconnected markets, the “historicist sciences” are “flattening” our ability to study the history of human health and disease. From Paleolithic tuberculosis and malaria to medieval leprosy and plague to modern HIV and other emerging diseases, there is now some common basis for looking at disease processes and health-seeking behaviors across time and space. This presentation will provide an overview of how these investigative methods, coupled with and expanded by traditional historicist ones, can create a framework for a global history of health. *** In 1998, Nancy Tomes told us of the Gospel of Germs, the efforts in the United States in the late 19th and early 20th centuries to persuade the general public that germs, invisible microorganisms, were real and needed to be fought in sustained battle for control of human life. The “Gospel of Germs” I will be preaching today is a new call to take seriously microorganisms not merely because we are finding that they have histories amenable to reconstruction, but because those histories can in fact aid in the reconstruction of our own species’ history. This is a kind of materialist history, but the “material” in this case is not a commodity (cotton or rice) nor climate or environment broadly. Unlike those “materials,” the microorganisms of which I’ll be speaking are living chains tied to the bodies of human beings. New work over the last decade and a half in two of our sister historicist fields— microbiology and physical anthropology (specifically, its subdiscipline known as bioarcheology)—has transformed what can be known about the history of many of the major infectious diseases that have afflicted humankind. But if we are to travel with these sister disciplines, we as historians must develop a sense for the different standards of measure and evidence they bring to their work. We must be willing, at least on occasion, to move on different scales of both mass and time. The payoff for engaging Green  –  AHA  Roundtable  on  Global  Health   2   simultaneously with, on the one hand, the sheer hours that make up the lifespan of some microbes and, on the other, the many millennia of hominin evolution is that the history of these pathogens can become for us tracer elements, proxies for the human voices and footprints we historians normally search for in drawing connections from human to human, epoch to epoch. In my own work, I have been examining simultaneously the reconstructed histories of eight infectious diseases, which collectively can be taken as paradigmatic both of the scientific methods now being deployed in a historicist mode, and of the kinds of questions the historian of global health would like to ask about how diseases develop and are sustained in human populations.1 Of these eight diseases—tuberculosis, malaria, leprosy, smallpox, plague, syphilis, cholera, and HIV/AIDS—I will focus today just on two, TB and leprosy. But first, some background. In a little over a decade, microbiologists have sequenced the genomes for all the major pathogens that cause human disease. The move to study pathogens at the molecular level has had two radical effects on history. First, together with bioarcheologists, microbiologists have developed techniques for identifying the presence of fragments of these pathogens in ancient remains. In other words, the investigative biomedical laboratory of the 19th century—the one that formalized the germ theory of disease with its reliance on microscopes and chemical dyes to confirm the presence of specific microorganisms in diseased bodies—can now literally reach back into the more distant past to tell us where specific pathogens were found. I initially became aware of this growing body of microbiological work because, as a medievalist, I was on the lookout for new research on the two paradigmatic diseases that most defined life in “my” world, plague and leprosy. As the previous session today will have made clear,2 plague has become the poster child of the hunt for methods to prove the presence of microorganisms within historical human remains. This work has not been without controversy, but consensus has now been reached that aDNA (“ancient DNA”) of Yersinia pestis can be reliably retrieved and identified. 2011 was a banner year for plague, when it became the first bacterial pathogen to have a historical copy of its complete DNA sequenced. (This figure [slide 2] shows the present state of play.) Second (and again, plague is at the head of these developments), genetics research has                                                                                                                      1  Study  of  the  historical  development  of  major  human  infectious  diseases,  besides  being  of  intrinsic   interest  for  biologists  interested  in  evolution,  has  also  attracted  the  attention  of  epidemiologists   because  of  the  implications  for  current  public  health,  including  the  question  of  how  new  diseases   emerge.    See,  for  example,  Barrett,  R.,  C.  W.  Kuzawa,  T.  W.  McDade,  and  George  J.  Armelagos,   “Emerging  and  Re-­‐emerging  Infectious  Diseases:  The  Third  Epidemologic  Transition,”  Annual  Review   of  Anthropology  27  (1998),  247–271;  Nathan  D.  Wolfe,  C.  P.  Dunavan,  and  Jared  Diamond,  “Origins  of   major  human  infectious  diseases,”  Nature  17:  279–283;  Gabriel  Trueba  and  Micah  Dunthorn,  “Many   Neglected  Tropical  Diseases  May  Have  Originated  in  the  Paleolithic  or  Before:  New  Insights  from   Genetics,”  PLoS  Pathogens  6,  no.  3  (March  2012),  e1393;  and  Monica  H.  Green,  “The  Value  of   Historical  Perspective,”  in  The  Ashgate  Research  Companion  to  the  Globalization  of  Health,  ed.  Ted   Schrecker  (Aldershot:  Ashgate,  2012),  pp.  17-­‐37.    In  the  present  essay,  I  have  given  preference  to  the   most  recent  and  authoritative  assessments  of  pathogen  evolution.        2  The  Power  of  Cartography:  Remapping  the  Black  Death  in  the  Age  of  Genomics  and  GIS.   Green  –  AHA  Roundtable  on  Global  Health   3   also allowed the construction of phylogenies of microorganisms, allowing us to reconstruct the “family trees” of pathogens. So what do these family trees tell us? Like all family trees, they tell us who is related to whom, what the lines of descent are. The “biological clocks” that are often affixed to these trees are, at the moment, of rather questionable accuracy: there is not a lot that they can tell us about the timing of events in the species life-stories of pathogens that we, as calendar-oriented historians, will find very satisfying or persuasive. But as rough estimates they have their utility, because they are tied to concrete geographical information bound up in the collection of the microorganism samples themselves. To wit, the phylogenies show not simply relations of time and genealogical distance, but also relations of space: we can begin to infer not simply when but also where species-defining characteristics of the organisms first developed, and to where they spread. And this is why certain kinds of pathogens are of distinct historical interest for us. These are the obligate pathogens. As opposed to organisms like Vibrio cholerae, which causes cholera, or Bacillus anthracis, which causes anthrax, both of which can persist happily in the open environment with nary a human (or other animal) actor around for years or millennia at a time, obligate pathogens are those microorganisms that have become so adapted to their host that they cannot survive (or at least not replicate) outside the microenvironment of their host species. Indeed, they are “inherited” as host species develop, being called “heirloom diseases” when they pass from one species to its successors. [slide 3] Tuberculosis (TB) is a consummate obligate pathogen. Currently estimated to infect one- third of the world’s population (and this after more than a century of germ-theory based interventions have radically reduced the presence of the disease in westernized countries), TB is one of the principle organisms whose history has recently been turned upside down because of work on its genome. Up until recently, it had been assumed that, aside from cases of infection with bovine tuberculosis, most human cases of TB throughout the world were caused by a single organism of surprisingly minimal intraspecific diversity, Mycobacterium tuberculosis. Indeed, an important study in 1997 suggested that M. tuberculosis had only speciated from its common ancestor with other mycobacteria as recently as 15-20,000 years ago.3 Since then, however, studies of the full M. tuberculosis genome and related species have proven the great antiquity of TB as a human disease. [slides 4-6] Estimated now to be at least 2.6 to 3 million years old,4 the M. tuberculosis complex has been shown to be divisible into six distinct groups, which map almost perfectly onto major human population groups as they would have existed before the great period of intercontinental migrations began in the early modern period. Most                                                                                                                      3  Sreevatsan,  S.,  Pan,  X.,  Stokbauer,  K.E.,  Connell,  N.D.,  Kreiswirth,  B.N.,  Wittam,  T.S.,  Musser,  J.M.,   1997.  Restricted  structural  gene  polymorphism  in  the  Mycobacterium  tuberculosis  complex  indicates   evolutionarily  recent  global  dissemination.  Proc.  Natl.  Acad.  Sci.  USA  94,  9869–9874.        4  Summaries  of  changing  perspectives  on  the  dating  question  can  be  found  in  Anne  C.  Stone,  Alicia   K.  Wilbur,  Jane  E.  Buikstra,  and  Charlotte  A.  Roberts,  “Tuberculosis  and  Leprosy  in  Perspective,”   Yearbook  of  Physical  Anthropology  52  (2009),  66-­‐94;  and  Sebastien  Gagneux,  “Host-­‐pathogen   Coevolution  in  Human  Tuberculosis,”  Philosophical  Transactions  of  the  Royal  Society.  B:    Biological   Sciences  367  (2012),  850-­‐59.    The  date  range  I  have  cited  here  comes  from  Anne  C.  Stone,  Arizona   State  University,  personal  communication  (2011).   Green  –  AHA  Roundtable  on  Global  Health   4   importantly, recent work has shown a pronounced dominance in virulence by strains coming out of Europe, which seem to have overtaken most others they encountered, including those present in the pre-Columbian Americans and in Southern Africa.5 TB’s apparent lack of genetic diversity—the kind of accumulated change we would expect in a regular Darwinian model of constant environmental pressure to adapt—may be reflective of how comfortably it has adapted to its human host which, in turn, has developed various immune responses to keep the organism (usually) in a quiescent state.6 The last 200 years, in fact, may have seen more evolutionary change in the organism, expanding as it has throughout a burgeoning human population, than it saw in several millennia.7 But what does this new science have to offer History, the discipline that has brought us here together today? Yes, we can marvel at the ingenuity and brilliance of our scientist colleagues, but this story of TB research seems only to confirm the patterns of intercontinental migration, transatlantic slavery, and colonialism with which we are already familiar. The answer to the “So what?” question is that the “redundancy” in itself is significant. The fact that the stories we tell as historians and the stories microbiologists and bioarcheologists tell concur says a lot. It tells us we’ve got it right, that different kinds of evidence are reinforcing our interpretations. Michael McCormick, who has been issuing a call for engagement with the historicist sciences for over a decade, has recently called on pursuit of consilience as a goal for researchers engaging with “the sciences of the human past.” If, he argues, consilience in fact shows that the written historical record about climatic events and the geologic and biological records agree, then shouldn’t that be an encouragement to press our collaborations even further? As he says, “from new science comes new questions.”8                                                                                                                      5  Ruth  Hershberg,  et  al.,  “High  functional  diversity  in  Mycobacterium  tuberculosis  driven  by  genetic   drift  and  human  demography,”  PLoS  Biology  6  (2008),  e311  [Coscolla  and  Gagneux  2010  call  this  “the   most  complete  MTBC  phylogeny  to  date”;  but  note  the  reservations  raised  by  Wang  and  Chen  2012   preprint,  who  suggest  that  there  may  be  even  more  diversity  and  active  evolution  in  MBTC  than   Hershberg  supposed]    On  the  issue  of  MTBC  heterogeneity,  see  also  Comas,  I.,  Chakravartti,  J.,  Small,   P.  M.,  Galagan,  J.,  Niemann,  S.,  Kremer,  K.,  Ernst,  J.  D.  &  Gagneux,  S.,  “Human  T  cell  epitopes  of   Mycobacterium  tuberculosis  are  evolutionarily  hyperconserved,”  Nature  Genetics  42  (2010),498–503   (summarized  by  Christopher  M  Sassetti  and  Eric  J  Rubin,  “Relics  of  selection  in  the  mycobacterial   genome,”  Nature  Genetics  42  (2010),  476–478);  Ford  C,  Yusim  K,  Ioerger  T,  Feng  S,  Chase  M,  Greene   M,  Korber  B,  Fortune  S.  Mycobacterium  tuberculosis-­‐-­‐heterogeneity  revealed  through  whole   genome  sequencing    Tuberculosis  (Edinb).  2012  May;92(3):194-­‐201.  doi:   10.1016/j.tube.2011.11.003.  Epub  2012  Jan  3;  Gutierrez  MC,  Brisse  S,  Brosch  R,  Fabre  M,  et  al.,   “Ancient  Origin  and  Gene  Mosaicism  of  the  Progenitor  of  Mycobacterium  tuberculosis,”  PLoS   Pathogens  1(1)  (2005):  e5;  Namouchi  A,  Didelot  X,  Schöck  U,  Gicquel  B,  Rocha  EP.  After  the   bottleneck:  Genome-­‐wide  diversification  of  the  Mycobacterium  tuberculosis  complex  by  mutation,   recombination,  and  natural  selection.    Genome  Research  2012  Apr;22(4):721-­‐34.  doi:   10.1101/gr.129544.111.      6  Only  about  10%  of  latently  infected  individuals  will  develop  active  TB  during  their  lifetime.    [the   work  of  Comas  et  al.  2010,  etc.,  are  exploring  why  MBTC  doesn’t  seem  to  mount  a  strong  genetic   response  to  evade  detection  by  its  human  host]        7  Mireilla  Coscolla  and  Sebastien  Gagneux,  “Does  M.  tuberculosis  Genomic  Diversity  Explain  Disease   Diversity?,”  Drug  Discovery  Today:  Disease  Mechanisms  7,  no.  1  (Spring  2010),  e43-­‐e59.        8  Michael  McCormick,  “History’s  Changing  Climate:  Climate  Science,  Genomics,  and  the  Emerging   Consilient  Approach  to  Interdisciplinary  History,”  Journal  of  Interdisciplinary  History  42,  Number  2   (Autumn  2011),  251-­‐73,  at  p.  252.   Green  –  AHA  Roundtable  on  Global  Health   5   So, can an alliance between Biology and History take us someplace that one discipline or another could not by itself? Here I turn to the example of leprosy. For various reasons, this is not a “sexy” disease for either historians or biologists. But it is one that offers us a useful example today. For the past 150 years, it has been assumed that worldwide leprosy, a disease with a range of different manifestations in the human body, was caused by a single organism, Mycobacterium leprae. Genome-based studies in the past decade have fully confirmed that M. leprae is indeed distributed globally. M. leprae is the ultimate “clonal” organism: samples taken from persons suffering from leprosy throughout the world show an astounding level of genetic similarity. Studies by Monot and colleagues have usefully extrapolated the historical ramifications of these genetic findings, suggesting that leprosy throughout the world can be classed into just four main subtypes which, in turn, can be broadly mapped onto global patterns of major human migrations in the last few millennia. [slide 7] The widespread uniformity of M. leprae in the present-day world suggests that its transmission has been quite regular. If that is the case, however, there are several large questions in the global history of leprosy that our standard narrative has not yet addressed. Why, for example, did leprosy suddenly become an urgent social concern in 11th and 12th-century western Christian Europe when, as the bioarcheological record is increasingly showing, this extremely slowly-progressing disease had been present in European populations for the previous several centuries. And why, again suddenly, was there a worldwide panic about leprosy in the 19th century? Had leprosy recently been spread to new-contact peoples, such as those in the Pacific Islands, by Europeans or other Old World migrants, or had it been endemic there for centuries?9 Add on to these questions a massive new one: how do we account for the fact that a “new” species of leprosy has now been identified? [slide 8] The fact that this new species, called Mycobacterium lepromatosis, was discovered in the genomics era (indeed, it was identified as a new species because of its distinct molecular signature) has allowed its history to be conceived from the beginning in genetic terms.10 To cut to the chase: M. lepromatosis (the “new” leprosy) and M. leprae (the “old” leprosy, Hansen’s leprosy) are most closely related to each other among the mycobacteria species. It is currently                                                                                                                      9  To  my  knowledge,  aDNA  work  has  not  yet  been  done  to  isolate  which  subgroup  of  M.  leprae  was   most  responsible  for  leprosy  cases  globally  in  the  19th  century.    On  the  sense  that  there  was  in  fact  a   later  19th-­‐century  “epidemic,”  even  in  Europe,  see,  for  example,  Josep  Bernabeu-­‐Mestre  and  Teresa   Ballester-­‐Artigues,  “Le  retour  d’un  péril:    la  lèpre  dans  l’Espagne  contemporaine,  1872-­‐1932.    Aspects   démographiques  et  sanitaires,”  Annales  de  démographie  historique  (1997),  115-­‐34.        10  The  story  of  M.  lepromatosis  has  interesting  parallels  with  another  recently  discovered   mycobacterium,  M.  canettii,  which  like  M.  tuberculosis  causes  tuberculosis  in  humans  and  is  clearly   very  ancient  as  a  species;  M.  canettii,  however,  does  not  appear  to  be  an  obligate  human  pathogen.     See  Koeck,  J.-­‐L.;  Fabre,  M.;  Simon,  F.;  Daffé,  M.;  Garnotel,  É.;  Matan,  A.  B.;  Gérôme,  P.;  Bernatas,  J.-­‐J.  et   al.,  “Clinical  Characteristics  of  the  Smooth  Tubercle  Bacilli  ‘Mycobacterium  canettii’  Infection  Suggest   the  Existence  of  an  Environmental  Reservoir,”  Clinical  Microbiology  and  Infection  17,  no.  7  (2011),   1013–19.       Green  –  AHA  Roundtable  on  Global  Health   6   estimated that the common ancestor of M. leprae branched away from the other mycobacteria around 66 million years ago. At some point between about 100,000 years and 10 million years ago, M. lepromatosis then branched away from M. leprae. The fact that both organisms seem to have acquired their common pseudogenes before divergence suggests that their most recent common ancestor was also an obligate pathogen that had already become so well adapted to its host that it lost much of its genetic material. A historical window so wide open that it can allow variance of between 105 and 107 years makes us historians decidedly uncomfortable. But let the discomfort pass, because the really critical question is this: was that host in which M. lepromatosis developed hominin or some other kind of primate?11 For if it was hominin, we have a very interesting problem on our hands. As I said, the biological data comes with built-in geographic data as well. And M. lepromatosis has been found in current-day populations to cluster extraordinarily heavily in Mexico and the Caribbean. Our out-of-Africa narrative tells us that humans have inhabited the New World only in the last 17,000 years or so—well outside the lower limit of 100,000 years for the speciation of M. lepromatosis, which must have occurred in Africa if we are talking of hominin hosts.12 Yet no paleopathological evidence has ever been found to suggest the presence of M. leprae in the New World prior to the arrival of Europeans. So how did M. lepromatosis get to Central America when M. leprae (apparently) did not? And when?13 It may be that the answers to those questions, when they come, will fall predictably within the grand narratives of New World migrations from Asia in prehistoric times or from Europe or Africa in the period of transatlantic colonization and slavery. But it is astounding that at the moment, we cannot say which narrative will prevail. And, at the moment, one of the most intriguing nuggets of information we have is this, coming from a classically historical source: the Portuguese used the term “lepra” to describe not only a disease they saw in West Africa in the 1480s and in Goa, India, in the 1550s, but also a                                                                                                                    11  The  likelihood  of  disease  transfer  between  closely  related  species  (in  our  case,  between  hominins   and  non-­‐human  primates)  is  extremely  high  precisely  because  of  genetic  similarities.    Malaria  and   HIV  are  two  examples,  and  the  discovery  of  leprosy  in  monkeys  and  chimpanzees  raises  the  question   with  respect  to  leprosy,  too.    See  Green,  “Value,”  pp.  29-­‐30;  and  T.  Jonathan  Davies  and  Amy  B.   Pedersen,  “Phylogeny  and  Geography  Predict  Pathogen  Community  Similarity  in  Wild  Primates  and   Humans,”  Proceedings  of  the  Royal  Society.    B:  Biological  Sciences  275,  no.  1643  (Jul.  22,  2008),  1695-­‐ 1701.      12  Data  on  the  possibility  that  there  may  be  other  natural  hosts  for  M.  leprae,  specifically  other   primate  species,  is  not  yet  extensive  but  it  is  intriguing.      This,  of  course,  raises  the  possibility  that  M.   lepromatosis,  too,  has  some  connection  with  other  primates.    However,  the  current  view  that  New   World  monkeys  separated  from  their  Old  World  kin  well  over  20  million  years  ago  seems  to  put  them   out  of  the  running  as  being  possible  transmission  hosts  to  explain  M.  lepromatosis’s  presence  in   Central  America.   13  M.  leprae  is  found  in  modern-­‐day  Mexico  and  the  Caribbean,  but  it  has  been  established  that  it   and  M.  lepromatosis,  though  being  found  co-­‐infecting  some  individuals,  seem  overall  to  have  different   geographic  spreads,  suggesting  that  they  have  been  disseminated  through  the  populations  via   different  routes  and  at  different  times.    See  Xiang  Y.  Han,  Kurt  Clement  Sizer,  Jesús  S.  Velarde-­‐Félix,   Luis  O.  Frias-­‐Castro,  and  Francisco  Vargas-­‐Ocampo,  “The  Leprosy  Agents  Mycobacterium   lepromatosis  and  Mycobacterium  leprae  in  Mexico,”  International  Journal  of  Dermatology  51  (2012),   952–59.   Green  –  AHA  Roundtable  on  Global  Health   7   disease they saw in Bahia, Brazil.14 However the history of M. lepromatosis works out, therefore, historians—regular old text-based historians, “linguistically turned” or not— will need to be centrally involved. The histories of infectious disease have been invoked before in the context of global history: all here will know the names of the historians Alfred Crosby and William McNeill and the non-historian Jared Diamond. Their arguments that disease is “a force in history” will get no contest from me; having just completed a seminar on the history of the Black Death, I am more chastened than ever that, if anything, we have vastly underestimated how powerful a role infectious diseases have played in human history. But I do wish to conclude on a cautionary note. As much as I acknowledge the pioneering work of a previous generation of global disease historians, I think we must also recognize that much of the science of disease on which they based their histories has changed profoundly in the past 40 years. To take but one example, I think almost all their claims about the “immunity” of populations need to be thoroughly questioned. To speak of whole populations or even civilizations as “immune” to certain diseases is often erroneous, since “immunity” is established at different levels for different diseases. Moreover, with greater ability to distinguish different microbial lineages, it becomes obvious that disease susceptibility may also be a function of differences in the pathogen as well as the host or environment. The example of tuberculosis is one case where it will no longer be adequate to speak without distinction of a single “disease” since the different strains have different virulences.15 The “historicist sciences” are “flattening” our world, creating the possibility to study the history of human health and disease on a truly global scale. I am not advocating multi- disciplinarity for the sake of fashion or trendiness. I’m advocating it because radically new kinds and amounts of data and interpretation are now available to us and I believe we must seize on them. As a medievalist who for the last thirty years has lived a data- starved life, I relish the opportunity that our sister disciplines have opened up to interrogate more broadly, more deeply, and more creatively the history of diseases that tied the fate of “my” medieval people to many millions of other human beings throughout the world. As my fellow panelists will show, it may be more than historians who benefit from that endeavor.                                                                                                                      14  My  thanks  to  Hugh  Cagle,  who  will  be  presenting  this  evidence  in  a  paper  at  the  AAHM  later  this   year.        15  An  excellent  meditation  on  the  importance  of  carefully  defining  “virulence”  can  be  found  in   Daniela  Brites  and  Sebastien  Gagneux,  “Old  and  New  Selective  Pressures  on  Mycobacterium   tuberculosis,”  Infection,  Genetics  and  Evolution  12  (2012),  678-­‐85.    See  also  Janis  Antonovics,  et  al.,   “The  Origin  of  Specificity  by  Means  of  Natural  Selection:    Evolved  and  Nonhost  Resistance  in  Host-­‐ Pathogen  Interactions,”  Evolution,  Article  first  published  online:  24  SEP  2012.