Reading 1.2.1 Mackenbach 2006 PDF - The Origins of Human Disease

81 REVIEW The origins of human disease: a short story on ‘‘where diseases come from’’ Johan P Mackenbach............................................................................................................................... J...

81 REVIEW The origins of human disease: a short story on ‘‘where diseases come from’’ Johan P Mackenbach............................................................................................................................... J Epidemiol Community Health 2006;60:81–86. doi: 10.1136/jech.2005.038661 Most of public health is based on the working hypothesis study, and by Doll and Peto’s famous study on the causes of cancer. This used the 10-fold to that disease is caused by exposure to noxious factors in the 100-fold worldwide variation in incidence for external environment. While this approach has produced most cancers, and the changes in incidence upon great successes in primary prevention, a general theory of migration from one environment to the other, to point to the potential avoidability of this disease.7 the origins of human disease cannot be found in the This ecological view has become a central part of textbooks of public health or epidemiology. This paper the paradigm of public health as it has developed suggests that, in all its manifestations, disease is a reaction since the 19th century, and has laid the founda- tion for many successful primary prevention of the human organism to, and/or a failure to cope with, measures.8 one or more unbalancing changes in its internal And even further reductions in disease rates environment. These are caused by one or more may be feasible: many public health reports have trodden in the steps of Doll and Peto, and argued unfavourable exchanges with the external environment that enormous reductions of disease rates are and/or failures in the structural and functional design of possible if we would reduce exposure to a the organism. In the final analysis, human disease is number of current disease determinants. Every four years, the Dutch National Institute for attributable to the dependence of organisms on a Public Health and the Environment publishes fundamentally hostile external environment and to the population attributable risks for a range of unfortunate evolutionary legacies. While this sketch of a risk factors in the Netherlands. The most recent estimates are that 15% of all deaths are theory suggests that there will ultimately be some hard attributable to smoking alone,9 10% to diet, and limits to primary prevention, it also helps in identifying another 5% to obesity.10 Recently it has been possible new approaches to prevention, including suggested that regular consumption of a ‘‘poly- meal’’, an admittedly improbable combination of interfering with disease mechanisms, and remedying healthy ingredients, will reduce cardiovascular human organisms’ design failures. morbidity and mortality by more than 75%.11........................................................................... As these examples show, public health is an exciting enterprise, but one wonders where the limits to primary prevention lie. These estimates I n early spring 2004, I had the opportunity of suggest that after the successes of the first visiting Crete for a project meeting funded by epidemiological transition, in which incidence the European Union. We had lunch in a and mortality from infectious diseases were village, and were served a Cretan meal that reduced by more than 90%,12 we may one day included one of its more mysterious ingredients: succeed in nearly or totally eliminating their green purslane leaves salad. The fame of the successors, cardiovascular disease and cancer, Cretan diet was established in the seven coun- leading to a second major transition. Is this tries study, which showed that men in Crete had plausible, and if so, what will happen then? Can incredibly low rates of cardiovascular disease: we push back disease rates indefinitely by less than 10% of the rate in Finland and the primary prevention? Do all diseases originate in USA.1 This has been ascribed to their consump- the environment? Is there a real possibility of a tion of olive oil, fruits, vegetables, and red wine,2 counterfactual ‘‘paradise’’, in which human and perhaps wild greens such as purslane that beings would not be exposed to noxious envir-....................... are rich in cardioprotective compounds such as a onmental circumstances, and remain totally free linolenic acid and flavonoids.3 of disease? Correspondence to: Stories of how our diet influences our health Professor J P Mackenbach, These rather naive questions all boil down to Department of Public are part of a wider ‘‘ecological’’ view of what an even more simple but equally unanswered Health, Erasmus MC, causes disease in living organisms. As many question: where do diseases actually come from? University Medical Centre textbooks of epidemiology and public health Unlike physicists, who spend much of their Rotterdam, PO Box 1738, routinely explain, this tradition goes back to 3000 DR Rotterdam, research budgets in trying to find a ‘‘unified Netherlands; Hippocrates’ treatise ’’Airs, waters, places’’,4 and field theory’’, which should be capable of j.mackenbach@ has inspired empirical studies of variations in describing nature’s forces within a single and erasmusmc.nl disease rates between different localities until coherent framework,13 epidemiologists and pub- late in the 19th century.5 6 Such studies are still lic health researchers do not show much interest Accepted for publication 10 September 2005 important sources of knowledge on determinants in finding a unified theory of disease causation........................ of disease, as shown by the seven countries One will look in vain for such a theory, or even a www.jech.com 82 Mackenbach brief general introduction on the nature and origins of disease, in the textbooks of public health and epidemiology Box 1 Examples of pathological onsets, disease (and, for that matter, in textbooks of pathology or general mechanisms, and related disease entities medicine). Nevertheless, a few possible ingredients can be sketched—and will be offered here for further discussion and Congenital elaboration. In this exercise, we will search our way back from manifestations to onsets of disease, from onsets to N Hereditary DNA abnormalities—impairments in growth and development and in homoeostatic adjust- direct causes of disease, and from direct causes to origins of ment mechanisms—Down’s syndrome, Huntington’s disease (see fig 1). disease, cystic fibrosis MECHANISMS OF DISEASE: REACTIONS TO N Various pathological onsets during pregnancy and childbirth—interference with normal fetal development UNBALANCING CHANGES IN THE INTERNAL or with perinatal health—congenital rubella, cerebral ENVIRONMENT palsy attributable to hypoxia at birth Medicine has long been dominated by ontological theories of disease—that is, theories in which diseases had an existence Acquired independent or separate from the suffering organism. The N Invasion with micro-organisms—injury to cells and naive question ‘‘where do diseases come from?’’ actually organs by micro-organisms, toxins, and inflammatory reflects this popular error. It was only in the 19th century that processes—measles, tuberculosis, malaria Rudolf Virchow declared that ‘‘diseases have no independent or isolated existence; they are not autonomous organisms, N Induction of autoimmune reaction—inflammatory damage to cells and organs—Graves’ disease, perni- not beings invading a body, nor parasites growing on it; they cious anaemia, rheumatoid arthritis are only the manifestations of life processes under altered conditions’’.14 Since then, disease is seen as an attribute of an N Induction of allergic reactions—inflammatory damage organism—a set of pathological manifestations that we can to cells and organs—asthma, atopic eczema, hay fever classify in different categories (disease entities), but that N Nutrient deficiencies—insufficient growth and loss of should be viewed as reactions of the organism to certain cells and organs—iron deficiency anaemia, kwashior- pathological onsets. The link between pathological onsets and kor, iodine deficiency hypothyroidism clinical manifestations is provided by so called disease N Derangements of metabolic processes—chemical dis- mechanisms.15 turbance of milieu intérieur and its effects on organs— Box 1 gives important examples of pathological onsets, diabetes mellitus, hypercholesterolaemia disease mechanisms, and resulting diseases. Despite the enormous variety in mechanisms, most can be understood as N Formation, rupture, and thrombotic complication of atherosclerotic plaques—ischaemic damage to reactions of the organism to, and/or a failure to cope with, organs—ischaemic heart disease, cerebrovascular some unbalancing change in their ‘‘internal environment’’ disease, peripheral vascular disease (Claude Bernard’s milieu intérieur). This fits within a systems theory of life: living organisms can be seen as N Cytogenetic abnormalities—uncontrolled cell growth— systems that are in a state of dynamic equilibrium, not with lung cancer, leukaemia, Kaposi’s sarcoma their external environment but internally. To survive, they N Mechanical wear and tear to supportive structures— must continuously exchange energy and matter with their direct and indirect (inflammatory) damage to locomo- external environment, while keeping the composition of their tor organs—lumbar hernia, osteoarthritis milieu intérieur stable within narrowly defined limits.16 17 N Ingestion of noxious chemical substances—damage to They adjust to changes in their internal environment through cells and organs—acute intoxication, alcoholic liver a variety of homoeostatic mechanisms, such as behavioural cirrhosis, adverse drug reactions responses, immune reactions, and detoxification procedures. According to this view, disease results when changes in the N Encounter with large kinetic forces—damage to organs—haemorrhage, hip fracture, shoulder disloca- internal environment temporarily or permanently exceed the tion Signs and symptoms capacity for adjustment of the organism, or when a defect in Pathogenesis: mechanisms of disease the adjustment mechanism leads to an inadequate response.18 It is beyond the scope of this paper to review even a tiny Pathological onset fraction of the explanatory insights that research into disease mechanisms has generated. In the case of infectious diseases, the ‘‘unbalancing change’’ in the internal environment is Aetiology: direct causes of disease invasion by micro-organisms. When the immune system does not succeed in timely elimination of invaders, injury to cells, and organs will occur, both directly (as a result of the Unfavourable exchanges and design failures invasion) and indirectly (as a result of the actions of the immune system).15 18 The uncontrolled cell growth that defines cancer, results from cytogenetic abnormalities caused Ecology and evolutionary biology: origins of disease by mutations in somatic DNA (attributable to random replication errors or mutagenic factors that inactivate a tumour suppressor gene or activate an oncogene), co- Environmental hostilities and evolutionary legacies occurring with a failure of the organism’s defence mechan- isms (for example, DNA repair, apoptosis of aberrant cells, Figure 1 Three levels of disease explanation. immune reactions against aberrant cells).15 18 Multistage www.jech.com The origins of human disease 83 theories of carcinogenesis are based on the hypothesis that, abnormalities are a clear example of diseases where most because of the elaborate mechanisms controlling cell growth, cases are probably attributable to such a design failure only. several mutations in a single cell are necessary to produce a Huntington’s disease is thought to be attributable to a cancer.19 number of CAG repeats on chromosome 4, the expression of which does not seem to be influenced by any external factors DIRECT CAUSES OF DISEASE: UNFAVOURABLE (although the mutation itself could theoretically be because EXCHANGES AND DESIGN FAILURES of environmental exposure of an ancestor).15 24 The impor- Because changes in the internal environment are induced tance of design failures in the causation of disease goes much either by exchanges with the external environment, or by an further than their role in rare inherited disorders, however. autonomous derailment of internal mechanisms, all diseases At least three types of commonly occurring design failures must be attributable to either unfavourable exchanges with can be distinguished. the external environment, or to failures of the design of The first is that human organisms cannot always cope organisms, or to a combination of the two. effectively with unfavourable exchanges with the external Exchanges of energy and matter with the external environment. We dispose of a large variety of adjustment environment are usually advantageous, because they provide mechanisms, ranging from behavioural responses and the organism with basic necessities (food, oxygen, warmth, protective structures to detoxification mechanisms and and water).20 Problems arise, however, when the intake of immune responses. Some failure of these adjustment these basic necessities is insufficient or excessive, or when mechanisms therefore can usually be identified when disease the organism encounters or ingests harmful forms of energy occurs—and is probably involved in, and to provide the and matter (physical, chemical, biological, psychological theoretical rationale for, many gene-environment interac- noxae).21 It is important to note that these exchanges with tions.25 26 the external environment are usually active processes, and But design failures are not limited to those that interfere are therefore determined as much by the behaviour of the with our responses to the external environment. Another is organism as by events or circumstances in the environment. that human organisms cannot deal perfectly with entropy.27 The interaction between organism and environment blurs the Survival requires constant reproduction—of germ cells (for distinction between the two: the environment of an organism creating progeny) and of somatic cells (for repair and should perhaps even be defined as the set of external maintenance). During cell reproduction, small random errors conditions with which it interacts.22 It is worth noting that occur from time to time, and although we have exquisite the active term exchanges with the environment removes the repair and search and destroy mechanisms, some errors are need to separately distinguish behaviour as a cause of not detected in time, and may lead to congenital disease in disease. progeny or to cancer in ourselves.28 Despite the incompleteness of our knowledge about the And then we have a third design failure: we have limited aetiology of diseases, it seems reasonable to suspect that most supplies of vital stocks. It is probable that aging is at least in diseases can, and often do, arise as a result of unfavourable part determined by cumulative effects of various noxae and exchanges with the external environment. This is immedi- our failure to deal effectively with them,29 but not all of aging ately obvious for pathological onsets and disease mechanisms can be explained in this way. For example, women are born that have been defined in terms of the consequences of a with a limited number of eggs, and when their supplies are specific exchange with the external environment (for exhausted reach menopause. A similar example is that our example, infectious disease, nutrient deficiencies, mechanical immune system has only a limited stock of immune cells that wear and tear, intoxication, injury). But unfavourable can be directed at specific antigens: after we have exhausted exchanges with the external environment probably also play these supplies, we cannot cope with new micro-organisms some part in the aetiology of most other disease mechanisms: any more.28 autoimmune reactions, allergic reactions, metabolic disorders There is no need to claim that unfavourable exchanges and such as diabetes mellitus, atherosclerosis, cancer, …15 23 design failures entirely determine the occurrence of disease. While this comes close to public health’s ecological Random events within cells at the level of molecular paradigm, it is important to note that there is no scientific interactions, or within organisms at the level of interactions basis for the claim that all cases of all diseases can be between organ systems or metabolic processes, will partly attributed to unfavourable exchanges with the external determine the outcome of the process.22 30 It is therefore an environment. Some cases of all, and many cases of some illusion to think that all inter-individual variation in disease diseases may be entirely attributable to an autonomous occurrence can ever be explained.31 derailment of internal mechanisms, caused by an apparent failure in the (genetically determined) structural or func- ORIGINS OF DISEASE: HOSTILE ENVIRONMENTS tional design of the human organism. Hereditary DNA AND EVOLUTIONARY LEGACIES Why do human organisms have unfavourable exchanges with the external environment? The historical successes of What this paper adds public health show that not all these exchanges are inevitable, but it is unlikely that they can ever be totally This paper is an attempt to sketch a coherent but short story eliminated. This is because we are dependent on the external on where diseases come from. It suggests that, in all its environment, and because the external environment is manifestations, disease is a reaction of the human organism fundamentally hostile. Living organisms can be characterised to, and/or a failure to cope with, one or more unbalancing as open, non-equilibrium thermodynamic systems that changes in its internal environment. These are caused by one continuously exchange energy and matter to decrease or more unfavourable exchanges with the external environ- internal entropy.16 17 But energy and matter have to be ment and/or failures in the structural and functional design of extracted from an environment that is often hostile, as the organism. In the final analysis, human disease is due to shown by the fact that the same elements in the abiotic, the dependence of organisms on a fundamentally hostile biotic, and human environments that we are dependent on, external environment and to unfortunate evolutionary lega- can make us sick as well. cies. Dependence on a hostile abiotic environment takes many forms. The simplest illustration is oxygen: all higher life on www.jech.com 84 Mackenbach Policy implications Box 2 Possible implications for primary prevention While this sketch of a theory suggests that there will ultimately be some hard limits to primary prevention, it also helps in identifying some new approaches to prevention, including N Human organisms actively produce disease: by gen- erating signs and symptoms as a reaction to patholo- interfering with disease mechanisms before detectable gical onsets; by engaging in unfavourable exchanges disease has occurred, and remedying human organisms’ with the external environment; and by creating a structural and functional design failures. hostile abiotic, biotic, and human environment. Whether or not we succeed in primary prevention is, to a large extent, in our own hands. earth is dependent on oxygen, but oxygen is a dangerous compound, as one can see from the fact that it destroys iron. N There is an enormous theoretical potential for primary prevention of human disease, not all of which has been During the processing of nutrients in our bodies, oxygen is clearly recognised: (1) interfering with disease released, and this has been shown to contribute to mechanisms before detectable disease has occurred; cardiovascular disease and cancer.32 Fortunately, antioxidants (2) reducing unfavourable exchanges with the external like flavonoids from purslane give a little bit of protection, environment, either directly (by limiting these but this is only partial. All life on earth is dependent on exchanges) or indirectly (by improving the environ- sunlight, but exposure to ultraviolet and other radiation may lead to mutations and cancer.33 There is also a fundamental ment); (3) remedying the organism’s structural and hostility, in the form of competition, between different functional design failures, either directly (by modifying lifeforms. Human beings need plants and animals for structure or function) or indirectly (by genetic modifica- survival, but the latter do not always cooperate, and some- tion). times behave like enemies. For example, plants protect N Conventional approaches to primary prevention, which themselves against predation by containing toxins that may focus on exchanges with the external environment, make us ill.34 Bacteria feed on us, and although we have have not yet been used to the full. Existing knowledge developed sophisticated mechanisms of defence, they are on entry points for reducing unfavourable exchanges smarter, and continuously succeed in circumventing our with the external environment can be used better. New countermeasures. And we need other human beings: the knowledge will probably emerge from further research prosperity of the Western world that has helped to almost into disease mechanisms, and from further research eliminate infectious disease and double life expectancy at into associations between disease occurrence and birth, is the result of an intricate division of labour, at all environmental and design factors. levels of human organisation (families, cities, countries, globally).35 But at all these levels we also compete with other N It is probable that we will in the future reach a limit to conventional approaches to primary prevention, human beings for reproduction and survival, causing diseases in those who are less successful, as the everlasting socio- because of our dependence on a fundamentally hostile economic inequalities in health show.36 environment. Progress in primary prevention will then Exposure to a hostile environment sometimes results from become more dependent upon our capacity to interfere actively seeking novel environments with dangers to which with disease mechanisms or to remedy the organism’s we have not yet developed adequate adjustment mechan- many structural and functional design failures. isms, or from human interventions that have made the environment more hostile.37 Novelty seeking may even be an element in our design that has stimulated the spread of the human species around the world—sometimes at the expense called design failures contributing to disease have benefits of health risks to individual organisms.38 Human activity has too, for example in other environments or in the same destroyed local environments in the past, and currently environment at younger ages. Sickle cell anaemia is the threatens to erode the life supporting aspects of the global classic example: persons heterozygous for the sickle cell gene environment.39 get substantial protection from malaria.43 Familial hyperch- Why do human organisms have design failures? This olesterolaemia and other genetically determined cardiovas- question can probably best be answered with reference to cular risk factors may have provided protection against evolutionary biology. The structural and functional charac- famine in the not too distant past.44 Similar trade offs are teristics of the human organism have been shaped over invoked by the theory of antagonistic pleiotropy, which states millions of years, and have been carefully selected for their that senescence (and disease associated with senescence) is fitness (ability for survival and reproduction) in a hostile the inevitable by product of adaptations that increase fitness environment.40 Despite its incredible sophistication, however, earlier in life.45 For example, mechanisms that limit cellular our design is far from perfect. This lack of perfection is proliferation protect against cancer in early life, but promote because we have not been created from scratch, but evolved degradation of organ function in later life.46 gradually through survival of the fittest in different environ- A second explanation of imperfect evolutionary legacies is ments, and that achieving perfection during this process was constraints: some design problems are caused by the fact that useless. The only thing that was necessary for us to be alive, evolution is an incremental process. Major changes are was that the genes of our ancestors were transmitted to their difficult, and some elements of our design still reflect their children, before their bodies fell apart due to the effects of a usefulness in previous environments. One simple example, hostile environment.41 Many aspects of aging can neatly be already noticed by Charles Darwin, is that our food passes explained from this disposable soma theory,29 which predicts, through a tube in front of the windpipe, and must cross it to among other things, that there must be a limit to further get to the stomach, thus exposing us to the danger of increases in human life expectancy. choking. If we had been designed from scratch, our nostrils Pioneers of Darwinian medicine have suggested that this would have been below our chin—but we have gradually imperfect evolutionary legacy has a number of specific developed from creatures living in water for which this explanations.25 42 One is trade offs or compromises: many so design was appropriate.25 42 www.jech.com The origins of human disease 85 DISCUSSION AND CONCLUSIONS related to lack of the essentials for life), and diseases of My short story of where diseases come from thus reads as affluence (diseases manifested after birth that are attribu- follows: In all its manifestations, human disease is a reaction of table to maladaptation or hazards related to industrialisa- organisms to, and/or a failure to cope with, one or more unbalancing tion).20 This distinction is firmly rooted in an understanding changes in their internal environments. These are caused by one or of the links between disease and the material world we live more unfavourable exchanges with their external environments and/ in, particularly the food sources we are dependent on. It or failures in the structural and functional design of organisms. In seems to over-emphasise the role of too little or too much the final analysis, human disease is attributable to the dependence of prosperity in disease causation, however, perhaps as a result organisms on a fundamentally hostile external environment and to of McKeown’s historical analyses of mortality decline in unfortunate evolutionary legacies. England and Wales that had shown the important role of Although such a concise and broadly applicable formula- living standards.55 While economic circumstances are cer- tion can, to the best of my knowledge, not be found in any of tainly important determinants of unfavourable exchanges the existing textbooks of epidemiology, public health, with the external environment, environmental hostilities pathology, or general medicine, most of its elements are of cannot be reduced to economics. Again, there is little course far from new. attention to the possible role of design imperfections in It can, for example, be usefully compared with the host disease causation. agent environment model that has been popular in textbooks Concise generalisations usually come at the expense of of epidemiology and public health. After the near elimination being too abstract or too a-specific, and my short story is no of infectious diseases, whose occurrence had been under- exception. Upon arrival at these slightly trivial rock bottoms stood on the basis of a simple host-agent-environment of disease explanation, some disappointment is perhaps model, many textbooks adopted a similar conceptual model inevitable. It is not more than a sketch asking for further for the understanding of chronic diseases, such as cardio- elaboration and refinement, but suggests a few new thoughts vascular disease and cancer. In addition to infectious agents, about opportunities and limits for primary prevention (listed the model now included new agents such as nutritive in box 2). There seems to be a much wider range of excesses, allergens, and ionising radiation.47 48 The latter can opportunities for primary prevention than usually thought, only be seen as (active) agents in a metaphorical sense, and epidemiology and public health would do well to pay however, and such a model does not help to clarify the role of more attention to the opportunities offered by insights in behaviour that was relegated to the category of host factors. disease mechanisms and the role of design failures. More complex models have been proposed, such as the web It is unlikely that we can ever prevent all disease, because of causation49 and more dimensional models taking into our capacity to change the external environment is limited, account different levels of organisation and different time and so is our capacity to improve the design of the human scales (an eco-social model visualised as a fractal structure,50 organism. We are far from having reached these limits, an eco-epidemiological model visualised as a set of Chinese however, as shown by the seven countries study and other boxes,51 and a social-ecological perspective visualised as a exciting results of public health research. Although paradise cube moving through time52). The latter are useful frame- is not a realistic option, further improvements in our works that help to bring more (social) theory into epidemiol- environment seem feasible, and we may in the future also ogy and public health.53 Although these models do not specify have more opportunities for interfering with disease mechan- where diseases come from, they can be used to structure isms or improving our design. These may contribute to various strands of explanation, including the type of short further substantial improvements in healthy life expectancy. story given above, into a larger coherent novel that also tries to explain in some depth how noxae come together in time ACKNOWLEDGEMENTS and space with susceptible organisms. This paper is based on an essay written on the occasion of New Year’s It may also be usefully compared with the teachings of two dinner 2005 of the Department of Public Health of Erasmus Medical giants of public health in the 20th century who have written Centre, Rotterdam, Netherlands. Useful comments on a previous extensively on this topic, René Dubos and Thomas McKeown. version of this paper were received from Gabriël ten Velde, Ewout The great microbiologist René Dubos published his influential Steyerberg and Jan Vandenbroucke. Mirage of health in 1959,38 followed by Man adapting in 1965.54 Funding: none. In these books he argued that ‘‘states of health or disease are Conflicts of interest: none declared. the expression of the success or failure experienced by the organism in its efforts to respond adaptively to environ- mental challenges’’. But ‘‘complete freedom from disease and REFERENCES from struggle is almost incompatible with the process of 1 Menotti A. Prevalence and incidence of cardiovascular diseases in the seven living’’, because the accomplishments of science and tech- countries study. In:Kromhout D, Menotti A, Blackburn H. Prevention of nology ‘‘ignore the dynamic process of adaptation to a coronary heart disease. Diet, lifestyle and risk factors in the seven countries constantly changing environment that every living organism study. Norwell/Dordrecht: Kluwer Academic, 2002. 2 Kromhout D, Bloemberg B. Diet and coronary heart disease in the seven must face’’. In the case of human organisms, some adaptive countries study. In: Kromhout D, Menotti A, Blackburn H. Prevention of challenges are due to the fact that mankind follows ‘‘urges coronary heart disease. Diet, lifestyle and risk factors in the seven countries and strivings that have nothing to do with species survival’’, study. Norwell/Dordrecht: Kluwer Academic, 2002. but are entirely the result of novelty seeking. These elements 3 Trichopoulou A, Vasilopoulou E, Hollman P, et al. Nutritional composition and flavonoid content of edible wild greens and green pies: a potential rich source can also be found in the short story developed in this paper, of antioxidant nutrients in the Mediterranean diet. Food Chem but there are important differences too, particularly because 2000;70:319–23. of Dubos’ lack of attention to the role of design failures in 4 Lloyd GER, ed. Hippocratic writings. Harmondsworth: Penguin Books, 1978. disease causation, perhaps because of the less prominent role 5 Dictionary of the history of ideas. Environment. http://etext.lib.virginia.edu (accessed 9 Dec 2004). of aging in population health at the time he worked. 6 Rosen G. A history of public health. Baltimore: Johns Hopkins University Press, McKeown’s The origins of human disease was published in 1993. 1988, and was a bold attempt at classifying all diseases in 7 Doll R, Peto R. The causes of cancer. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer only three categories: prenatal diseases (all diseases mani- Inst 1981;66:1192–308. fested before birth), diseases of poverty (diseases manifested 8 CDC. Ten great public health achievements—United States, 1900–1999. after birth that are attributable to deficiencies or hazards MMWR 1999;48:241–3. www.jech.com 86 Mackenbach 9 Van Oers JAM, ed. Gezondheid op koers? Volksgezondheid Toekomst 31 Doll R. The age distribution of cancer and a multistage theory of Verkenning 2002. Bilthoven: Rijksinstituut voor Volksgezondheid en Milieu, carcinogenesis. Int J Epidemiol 2004;33:1183–4. 2002. 32 Rodriguez H, Cutler RG, eds. Critical reviews of oxidative stress and aging. 10 Van Kreijl CF, Knaap AGAC, eds. Ons eten gemeten; gezonde voeding en New York: World Scientific Publishing, 2003. veilig voedsel in Nederland. Bilthoven: Rijksinstituut voor Volksgezondheid en 33 Lee JA. The relationship between malignant melanoma of skin and exposure Milieu, 2004. to sunlight. Photochem Photobiol 1989;50:493–6. 11 Franco O, Bonneux L, de Laet C, et al. The polymeal: a more natural, safer, 34 Diamond J. Guns, germs and steel. A short history of everybody for the last and probably tastier (than the Polypill) strategy to reduce cardiovascular 1000 years. London: Vintage, 1998. disease by more than 75%. BMJ 2004;329:1447–50. 35 Landes DS. The wealth and poverty of nations. New York: Norton, 1998. 12 Wolleswinkel-van den Bosch JH, Poppel FWA van, Tabeau EWA, et al. 36 Marmot M. Status syndrome. How your social standing directly affects your Mortality decline in the Netherlands in the period 1850–1992: a turning point health and life expectancy. London: Bloomsbury, 2004. analysis. Soc Sci Med 1998;47:429–43. 37 McMichael AJ. Human frontiers, environments and disease. Cambridge: 13 Greene B. The elegant universe. Superstrings, hidden dimensions, and the Cambridge University Press, 2001. quest for the ultimate theory. London: Jonathan Cape, 1999. 38 Dubos R. Mirage of health. Utopias, progress and biological change. (reprint 14 Kräupl Taylor F. The concepts of disease, illness and morbus. Cambridge: of original 1959 edition). New Brunswick: Rutgers University Press, 1987. Cambridge University Press, 1979. 39 McMichael AJ. Planetary overload. Global environmental change and the 15 Tomlinson S, Heagerty AM, Weetman AP, eds. Mechanisms of disease. An health of the human species. Cambridge: Cambridge University Press, 1993. introduction to clinical science. Cambridge: Cambridge University Press, 40 Dawkins R, Jones S, Martin RD, et al. The Cambridge encyclopedia of human 1997. evolution. Cambridge: Cambridge University Press, 1992. 16 Odum EP, Barrett GW. Fundamentals of ecology. 5th ed. Belmont: Thomson 41 Dawkins R. The selfish gene. 2nd ed. Oxford: Oxford University Press, 1989. Brooks/Cole, 2005. 42 Nesse RM, Williams GC. Why we get sick. The new science of Darwinian 17 Capra F. The web of life. A new scientific understanding of living systems. medicine. New York: Vintage Books, 1996. New York: Anchor Books, 1996. 43 Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004;364:1343–60. 18 Underwood JCE, ed. General and systematic pathology. Edinburgh: Churchill 44 Sijbrands EJ, Westendorp RG, Defesche JC, et al. Mortality over two centuries Livingstone, 2004. in large pedigree with familial hypercholesterolaemia: family tree mortality 19 Armitage P, Doll R. The age distribution of cancer and a multi-stage theory of study. BMJ 2001;322:1019–23. carcinogenesis. Br J Cancer 1954;8:1–12. 45 Williams GC. Pleiotropy, natural selection, and the evolution of senescence. 20 McKeown ThF. The origins of human disease. Oxford: Basil Blackwell, 1988. Evolution 1957;11:398–411. 21 Last JM. Public health and human ecology. 2nd ed. Stamford: Appleton and 46 Weinstein BS, Ciszek D. The reserve-capacity hypothesis: evolutionary origins Lange, 1997. and modern implications of the trade-off between tumor-suppression and 22 Lewontin R. The triple helix. Gene, organism, environment. Cambridge: tissue-repair. Exp Gerontol 2002;37:615–27. Harvard University Press, 2000. 47 Lilienfeld AM, Lilienfeld DE. Foundations of epidemiology. 2nd ed. New York: 23 Wallace RB, Doebbeling BN, eds. Maxcy-Rosenau-Last public health and Oxford University Press, 1980. preventive pedicine. 14th ed. Stamford: Appleton and Lange, 1998. 48 Donaldson RJ, Donaldson LJ. Essential public health medicine. Dordrecht: 24 Leavitt BR, Wellington CL, Hayden MR. Recent insights into the molecular Kluwer, 1993. pathogenesis of Huntington disease. Semin Neurol 1999;19:385–95. 49 MacMahon B, Pugh ThF. Epidemiology—principles and methods. Boston: 25 Stearns SC, ed. Evolution in health and disease. Oxford: Oxford University Little, Brown, 1970. Press, 1999. 50 Krieger N. Epidemiology and the web of causation: has anyone seen the 26 Khoury M, Davis R, Gwinn M, et al. Do we need genomic research for the spider? Soc Sci Med 1994;39:887–903. prevention of common diseases with environmental causes? Am J Epidemiol 51 Susser M, Susser E. Choosing a future for epidemiology: II. From black-box to 2005;161:799–805. Chinese boxes and eco-epidemiology. Am J Public Health 1996;86:674–7. 27 Kirkwood T. Time of our lives. The science of human aging. Oxford: Oxford 52 McMichael AJ. Prisoners of the proximate: loosening the constraints on University Press, 1999. epidemiology in an age of change. Am J Epidemiol 1999;149:887–97. 28 Rickleffs RE, Finch CE. Aging. A natural history. New York: Scientific 53 Krieger N. Theories for social epidemiology in the twenty-first century. An American Library, 1995. ecosocial perspective. Int J Epidemiol 2001;30:668–77. 29 Kirkwood TBL, Austad SN. Why do we age? Nature 2000;408:233–8. 54 Dubos R. Man adapting. New Haven: Yale University Press, 1965. 30 Coggon DIW, Martyn CN. Time and chance: the stochastic nature of disease 55 McKeown ThF. The modern rise of population. London: Edward Arnold, causation. Lancet 2005;365:1434–7. 1977. www.jech.com