Egger, Matthias

Fenner, Lukas

Gagneux, Sebastien

RERO DOC Digital Library

EDITORIALAnnie Darwin’s death, the evolution oftuberculosis and the need for systemsepidemiologyLukas Fenner,1,* Matthias Egger1 and Sebastien Gagneux2Accepted 17 November 2009Keywords HIV, AIDS, tuberculosis, co-evolution, evolution, Charles Darwin,Annie Darwin, genomics, multi-disciplinary, host, pathogen,interactionsWhen Charles Darwin’s daughter Anne Elizabeth(‘Annie’, Photograph 1) died at the age of 10 yearson April 23, 1851 her parents were devastated.Charles Darwin was a devoted father and constantlyconcerned about the health of his 10 children. Hisconcerns were also motivated by fear of the conse-quences of marriage between relatives: EmmaWedgewood, his wife, was also his first cousin.1 Thepossible adverse effects of consanguineous marriage,which was not uncommon in England at that time,were a matter of debate. Annie’s death, andself-fertilization experiments in plants, made himsuspect that ‘marriage between near relations is like-wise injurious’.2 In 1870, Darwin motivated hismathematician son George to study the prevalenceof close-kin marriages in patients in asylums in com-parison with the prevalence of the general population.The study, which is reprinted in this issue of thejournal,3 with several commentaries,1,2,4,5 was firstpublished in 1875 and concluded that ‘the evil [ofmarriages between cousins] has been often muchexaggerated’ and that ‘under favourable conditionsof life, the apparent ill-effects were frequentlyalmost nil’.3Indeed, Annie died after a lingering illness, mostlikely of tuberculosis (TB) caused by Mycobacteriumtuberculosis,6 and not of the consequences of a highcoefficient of inbreeding (the F coefficient thatfeatures in one commentary2). Of note, althoughDarwin may have been aware of the studies by hiscontemporaries, Pasteur and Koch, he did not con-sider the role of microbes and infectious diseases inhis work.7 M. tuberculosis would, however, surely have1 Institute of Social and Preventive Medicine, Finkenhubelweg11, University of Bern, CH-3012 Bern, Switzerland.2 Division of Mycobacterial Research, MRC National Institutefor Medical Research, London, UK.* Corresponding author. lfenner@ispm.unibe.chPhotograph 1 Daguerreotype photograph of AnneElizabeth (’Annie’) Darwin 1849. Annie Darwin died in1851, probably of tuberculosis.  English Heritage PhotoLibrary. Reproduced with permissionPublished by Oxford University Press on behalf of the International Epidemiological Association The Author 2009; all rights reserved.International Journal of Epidemiology 2009;38:1425–1428doi:10.1093/ije/dyp3671425been of interest. This obligate human pathogen hasco-evolved with humans for millennia8 and hasbeen extremely successful: today one-third of theworld’s population is estimated to be infected and1.7 million people die from TB each year, morethan anytime during previous human history.9,10Co-infection with HIV is an important risk factor forTB, increasing the lifetime risk of progression frominfection to active disease from 5% per lifetime to5% per year,11 which is a particular problem insub-Saharan Africa. Moreover, the emergence of bac-terial strains resistant to most current antimicrobialdrugs threatens to make TB untreatable.9 Edmondsand colleagues,12 in this issue, document the stagger-ingly high incidence of TB in HIV-infected children inKinshasa, Democratic Republic of Congo: 20.4 per100 person-years. Anti-retroviral therapy halved theincidence of TB, but as Boulle and Eley emphasizein their commentary,13 additional interventions areneeded to control TB in this population, includingefforts to improve the diagnosis of TB in childrenco-infected with HIV.Darwin would of course understand: the theory ofevolution which he outlined in his seminal workOn the Origin of Species by Means of Natural Selection, orthe Preservation of Favoured Races in the Struggle for Life isalso ‘the modern story of TB’.14 The recent emergenceof HIV and the introduction of effective drugsrepresent selection pressures that M. tuberculosis hasnot experienced for most of its evolutionary history.As one consequence of the widespread (and notalways well supervised) use of drugs, resistant strainshave developed. Many drug resistance-conferringmutations in M. tuberculosis lead to a reduction inbacterial fitness, although compensatory evolutionmay mitigate fitness defects.15 In HIV-infected,immune-compromised hosts even strains withhigh-cost resistance mutations could be propagatingefficiently, which might explain why drug-resistantTB has been associated with HIV co-infection.16,17TB patients could thus serve as a ‘breeding ground’for highly compensated drug-resistant strains, with anincreased capacity to spread in the general population.To date, no study has addressed this disturbingpossibility. The strain genetic background has alsobeen shown to influence the fitness of drug-resistantM. tuberculosis. For example, the Beijing lineage hasbeen associated with drug resistance,18 suggestingthat this lineage might be ‘pre-adapted’ to resistance.Importantly, Beijing has also been associated withHIV19,20 and is now emerging in South Africa,probably as a consequence of the HIV epidemic.21,22Genomics, the study of the genomes of organisms, isbecoming increasingly important for communicableMycobacteriumtuberculosisHIV epidemicUrbanisationGlobalisationEvolutionStrain variationDrug resistanceHuman geneticsImmunologySocio-economic conditionsHousingTB control measuresEvolutionCo-evolutionFigure 1 A ‘systems epidemiology’ approach to tuberculosis, which integrates demography, ecology and systems biology.Picture credits: Drawing from Koch R. Die Aetiologie der Tuberkulose. Berliner Klinische Wochenschrift, 1882; Dens ofDeath. Photograph from Riis JA. The Battle with the Slum. New York: MacMillan Company, 1902; Drawing of man withtuberculosis (source unknown).1426 INTERNATIONAL JOURNAL OF EPIDEMIOLOGYdisease epidemiology and control. Infectious diseasesresult from complex interactions between microbes,host and the environment, which are subject to evo-lutionary pressures and ecological changes (Figure 1).Genetic and immunological studies can answer fun-damental questions about host–pathogen interaction,pathogenesis, host genetic susceptibility and thefactors influencing response to treatment and progno-sis.23 Humans show remarkable variation in theirresponse to infectious agents. For example, particularhuman gene polymorphisms explain some of the vari-ation among individuals who differ in their ability tocontrol HIV infection.24,25 In addition to host geneticdiversity, genetic variation within particular microbialspecies can influence the outcome of infectionand disease. In M. tuberculosis, for example, a recentstudy demonstrated that the rate of progression toactive TB depended on the bacterial lineage.26 Otherstudies showed M. tuberculosis lineages to be associatedwith different clinical manifestations of TB.27,28Both the recent changes in the human host (i.e. theemergence of HIV) and in the bacterium (i.e. theemergence of drug resistance) will influence theevolutionary trajectory of M. tuberculosis. We urgentlyneed a better understanding of the genetic diversityand evolution of M. tuberculosis and the epidemio-logical and clinical consequences. How doesco-infection affect the genetic population structureand evolution of M. tuberculosis in sub-SaharanAfrica? What are the clinical and epidemiologicalimplications of these effects? Does HIV co-infectioninfluence the frequency and distribution of antimicro-bial resistance-conferring mutations in M. tuberculosis?Do the clinical correlates of M. tuberculosis geneticdiversity and the transmission dynamics of M. tuber-culosis differ depending on HIV status and degree ofHIV-induced immunodeficiency?Improved understanding of the complex interactionsbetween genetically diverse hosts and pathogens inchanging environments will require new multidisci-plinary approaches. In particular, the integration ofsystems biology with population sciences and ecology,in what might be described as ‘systems epidemiology’is promising (Figure 1).29 This involves combininggenomic and evolutionary analyses of the host andthe pathogen, with immunology, molecular andclinical epidemiology, and mathematical modelling.‘Darwinian Medicine’, where evolutionary biologyand biomedicine interact to enhance our understand-ing of both biological and evolutionary processes, ispart of this concept.30 If successful, such anintegrated approach will inform the development ofnew diagnostics, drugs and vaccines, and guidefuture public health interventions. Thus, eventhough Charles Darwin might not have fully appre-ciated the significance of infectious microbes at thetime, his legacy will play a crucial role in addressingchallenges such as the dual epidemics of HIV and TB.Conflict of interest: None declared.References1 Kuper A. Commentary: A Darwin family concern. Int JEpidemiol 2009;38:1439–42.2 Brittle AH. Commentary: the background and outcomesof the first cousin marriage controversy in Great Britain.Int J Epidemiol 2009;38:1453–58.3 Darwin GH. Reprints and reflections: marriages betweenfirst cousins in England and their effects. Int J Epidemiol2009;38:1429–39.4 Stoltenberg C. Commentary: of the same blood. Int JEpidemiol 2009;38:1442–47.5 Evans A. Commentary: Darwin’s origin: the Irish connec-tion. Int J Epidemiol 2009;38:1448–52.6 Keynes R. Annie’s Box: Charles Darwin, His Daughter, andHuman Evolution. London: Fourth Estate Publishers, 2001.7 Lederberg J. J. B. S. Haldane (1949) on infectious diseaseand evolution. Genetics 1999;153:1–3.8 Hershberg R, Lipatov M, Small PM et al. High functionaldiversity in Mycobacterium tuberculosis driven by geneticdrift and human demography. PLoS Biol 2008;6:e311.9 World Health Organization. WHO report 2008. Globaltuberculosis control. Geneva: WHO, 2008.10 Corbett EL, Watt CJ, Walker N et al. The growing burdenof tuberculosis: global trends and interactions with theHIV epidemic. Arch Intern Med 2003;163:1009–21.11 Selwyn PA, Alcabes P, Hartel D et al. Clinical manifesta-tions and predictors of disease progression in drug userswith human immunodeficiency virus infection. N Engl JMed 1992;327:1697–703.12 Edmonds A, Lusiama J, Napravnik S, Kitetele F, VanRie A, Behets F. Anti-retroviral therapy reduces incidenttuberculosis in HIV-infected children. Int J Epidemiol2009;38:1612–21.13 Boulle A, Eley B. Commentary: reducing HIV-associatedtuberculosis in children. Int J Epidemiol 2009;38:1621–23.14 Iseman MD. Extensively drug-resistant Mycobacteriumtuberculosis: Charles Darwin would understand. Clin InfectDis 2007;45:1415–16.15 Gagneux S, Long CD, Small PM, Van T, Schoolnik GK,Bohannan BJ. The competitive cost of antibioticresistance in Mycobacterium tuberculosis. Science 2006;312:1944–46.16 Gandhi NR, Moll A, Sturm AW et al. Extensivelydrug-resistant tuberculosis as a cause of death in patientsco-infected with tuberculosis and HIV in a rural area ofSouth Africa. Lancet 2006;368:1575–80.17 Raviglione MC, Smith IM. XDR tuberculosis–implications for global public health. N Engl J Med 2007;356:656–59.18 Borrell S, Gagneux S. Infectiousness of drug-resistantMycobacterium tuberculosis. Int J Tuberc Lung Dis 2009;13:1456–66.19 Middelkoop K, Bekker LG, Mathema B et al. Molecularepidemiology of Mycobacterium tuberculosis in a SouthAfrican community with high HIV prevalence. J InfectDis 2009;200:1207–11.20 Caws M, Thwaites G, Stepniewska K et al. Beijing geno-type of Mycobacterium tuberculosis is significantly associatedwith human immunodeficiency virus infection andmultidrug resistance in cases of tuberculous meningitis.J Clin Microbiol 2006;44:3934–39.THE EVOLUTION OF TUBERCULOSIS 142721 Emergence of Mycobacterium tuberculosis with extensiveresistance to second-line drugs–worldwide, 2000–2004MMWR Morb Mortal Wkly Rep 2006;55:301–5.22 Cowley D, Govender D, February B et al. Recent and rapidemergence of W-Beijing strains of Mycobacterium tubercu-losis in Cape Town, South Africa. Clin Infect Dis 2008;47:1252–59.23 Cooke GS, Hill AV. Genetics of susceptibility to humaninfectious disease. Nat Rev Genet 2001;2:967–77.24 Fellay J, Shianna KV, Ge D et al. A whole-genomeassociation study of major determinants for host controlof HIV-1. Science 2007;317:944–47.25 Telenti A. Adaptation, co-evolution, and human suscept-ibility to HIV-1 infection. Infect Genet Evol 2005;5:327–34.26 de Jong BC, Hill PC, Aiken A et al. Progression toactive tuberculosis, but not transmission, varies byMycobacterium tuberculosis lineage in the Gambia. J InfectDis 2008.27 Caws M, Thwaites G, Dunstan S et al. The influence ofhost and bacterial genotype on the development ofdisseminated disease with Mycobacterium tuberculosis.PLoS Pathog 2008;4:e1000034.28 Thwaites G, Caws M, Chau TT et al. Relationship betweenMycobacterium tuberculosis genotype and the clinical pheno-type of pulmonary and meningeal tuberculosis. J ClinMicrobiol 2008;46:1363–68.29 Comas I, Gagneux S. The past and future of tuberculosisresearch. PLoS Pathog 2009;5:e1000600.30 Shanks N, Pyles RA. Evolution and medicine: the longreach of ‘‘Dr. Darwin’’. Philos Ethics Humanit Med 2007;2:4.1428 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

Annie Darwin's death, the evolution of tuberculosis and the need for systems epidemiology

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library