Metchnikoff and the Phagocytosis Theory

PERSPECTIVES

TIMELINE Metchnikoff and the phagocytosis theory

Alfred I. Tauber

Metchnikoff’s phagocytosis theory was less century. Indeed, the clonal selection theory and an explanation of host defence than a the elucidation of the molecular biology of the proposal that might account for establishing immune response count among the great and maintaining organismal ‘harmony’. By advances in biology during our own era5. tracing the phagocyte’s various functions Metchnikoff has been assigned to the wine cel- Figure 1 | Ilya Metchnikoff, at ~45 years of through phylogeny, he recognized that eating lar of history, to be pulled out on occasion and age. This figure is reproduced from REF. 14. the tadpole’s tail and killing bacteria was the celebrated as an old hero. same fundamental process: preserving the However, to cite Metchnikoff only as a con- integrity, and, in some cases, defining the tributor to early immunology distorts his sem- launched him into the turbulent waters of evo- identity of the organism. inal contributions to a much wider domain. lutionary biology. He wrote his dissertation on He recognized that the development and func- the development of invertebrate germ layers, I first encountered the work of Ilya tion of the individual organism required an for which he shared the prestigious van Baer Metchnikoff (1845–1916; FIG. 1) in Paul de understanding of physiology in an evolution- Prize with Alexander Kovalevski. By the age of Kruif’s classic, The Microbe Hunters 1.Who ary context. The crucial precept: the organism 22 years, he was appointed to the position of would not be struck by the description of this was composed of various elements, each vying docent at the new University of Odessa, where, fiery Russian championing his theory of for dominance. In such a world of competi- apart from four years at St. Petersburg, he phagocytes? His description of mobile cells tion, Darwin’s ‘struggle of species’ was enacted remained until 1882, pursuing comparative battling invading pathogens was visually within the organism. But instead of a sim- embryological investigations as a means of immediate and dramatic. Written in the style plisitic ‘survival of the fittest’, Metchnikoff understanding evolutionary relationships. He of an adventure story, his findings made for sought a theory to account for the harmoniz- joined the Pasteur Institute in Paris in 1888 and great reading. But the drama extended beyond ing of the elements required for the satisfactory remained there until his death in 1916. the microscope. De Kruif vividly portrayed function of the organism. How does such inte- Metchnikoff’s developmental biology Metchnikoff as a controversialist; the mad sci- gration and coordination of cells, structures research was eventually joined to another entist, flailing away at the German scientific and physiological processes occur? What is its branch of evolutionary biology, one that community led by Robert Koch, the imperial mechanism? How, indeed, were new challenges directly impacted on human welfare. In the scientific Bismarck of the period. Metchnikoff met by physiological structures and how were mid-1870s, pathogenic bacteria were identified was cast as the ‘country bumpkin who made the functions of these structures adapted to, as the aetiological agents of infectious diseases. good’ thanks to his extraordinary scientific and used for, different purposes and under dif- This momentous discovery (see TIMELINE) gave imagination. He shared the Nobel Prize with ferent demands? These were new questions, birth to several modern disciplines: microbiol- Paul Ehrlich in 1908, largely to call a truce in a and by asking them and offering a solution, ogy, inflammatory pathology, infectious dis- divisive war 2.Francophile immunologists had Metchnikoff must be counted as one of the ease as a medical discipline, and — most championed Metchnikoff’s cellular theory great theorists of nineteenth century biology. importantly for Metchnikoff’s story — against those of their German competitors, immunology. Although these various fields who advocated the humoral theory of comple- Metchnikoff, the evolutionist diverged and commanded their own histories, ment and antibodies (see TIMELINE). The two Metchnikoff stands apart from other immu- the last decades of the nineteenth century were contending schools called a tentative truce nologists of the late nineteenth century dominated by research physicians such as Emil once phagocytes and opsonins (serum sub- because of his unique scientific background6. von Behring, who studied infectious diseases, stances, such as antibodies and complement, Born into a middle-class Russian family in and those, such as Paul Ehrlich, who laid the that increase the susceptibility of microbes for 1845, he soon distinguished himself as being foundations of the biochemistry of host phagocytosis) were conclusively shown to have intellectually gifted at Kharkov Lycee and pub- defence4,7.Metchnikoff, alone, was an embryol- a synergistic effect in killing bacteria. lished a book review of a geology text in the ogist. He was intrigued by the potential of Conventional histories see serology and the Journal de Moscow at the age of 16 years. Even defining phylogenetic relationships through biochemistry of immune specificity as the as an adolescent he had a keen interest in the study of the embryology of invertebrate dominant themes of the next four decades of Rudolf Virchow’s cellular theory, and the wun- species, and believed that a deeper understand- immunological research3,4.Metchnikoff derkind soon envisioned himself creating a ing of embryonic anatomical structures and receded as a founder of the subject, and grand theory of medicine. Metchnikoff accel- functions of these more primitive animals although phagocyte pathophysiology became erated his studies at Kharkov University, and might lead to insights about adult anatomy an active area of investigation in its own right, published his first research — on the possible and physiology. How these interests eventually the lymphocyte and its products dominated analogy between the stalk of Vorticella with centered on his ‘phagocytosis theory’ is a com- immunology in the latter half of the twentieth muscle — in Muellers Archives in 1863, which plex, but intriguing, story.

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Timeline | Metchnikoff and the origins of immunology and infectious diseases

Metchnikoff begins Bacterial aetiology of infectious Phagocytosis theory elaborated as a comparative embryological diseases established by Robert Koch: case of ‘physiological inflammation’; Discovery of antibacterial research. He shows a Staphylococcus (1873); Bacillis begins studies of phagocyte substance in the blood (George critical attitude towards anthracis (1876); Mycobacterium bactericidal capacity against certain Nuttal4); Metchnikoff contests Ilya Metchnikoff born. Darwinism. tuberculosis (1882); REF.29. microorganisms. the humoral theory of immunity.

1845 1859 1865 1872 1873 1873–78 1883 1881–92 1888 1890

Darwin publishes On Ernst Haeckel’s Metchnikoff publishes a series of papers on sponges; Metchnikoff extends Efficacy of immune serum the Origin of Species ‘gastrea’ theory attacks Haeckel’s gastrea hypothesis and argues for comparative embryological against diptheria and by Means of Natural proposed. ‘parenchymella’ as the primordial metazoan; focuses on the studies and embraces tetanus infections shown Selection. origin and function of mesodermal cells; turns to the Darwinism. (Emil von Behring4). problem of intracellular digestion; formulates a physiological approach to the task of genealogical reconstruction.

Evolution and argument embryonic-layer formation. Using embryos Metchnikoff began his descriptive embryologi- from sponges, hydroids and lower medusae, cal studies shortly after the publication of On they saw cellular ‘introgression’ (unipolar or The Origin of Species by Means of Natural multi-polar) as the primordial process, and Selection in 1859. In late autobiographical argued that embryonic layers were formed accounts of his scientific career8, it is clear that from an initially undifferentiated cellular mass Gastraea Parenchymella/ Metchnikoff saw the development of his (parenchyma) that arose from cells migrating Phagocytella phagocytosis theory as a response to Darwin’s from the periphery in a less ordered fashion to thesis, and indeed it was. But in Metchnikoff’s fill the inner space of the gastrula sphere (FIG. 2, retrospective accounts of his research career, he right). Metchnikoff called his hypothetical ur- chose to ignore his initial ambivalence about metazoan parenchymella and, because he mod- The Origin of Species by Means of Natural elled it on more primitive animals than Selection in order to straighten the curves and Haeckel’s gastrea, the Russian could claim the switchbacks marking his investigative path and phylogenetic priority of introgression as a the various theoretical orientations he later more ancient mechanism of gastrulation. adopted6,9.In short, Metchnikoff re-wrote his Simply, in the competition to describe the ear- scientific biography with keen hindsight to liest metazoan, Metchnikoff upstaged Haeckel appear consistently close to Darwinism. on claims that the older ancestry showed a Putting aside how Metchnikoff finally arrived more basic developmental process. at his mature understanding of evolution, the phagocytosis theory arose from a theoretical Creating harmony from chaos dispute with the German evolutionist Ernst The gastrea/parenchymella controversy might Haeckel over the genesis of the hypothetical have been fought over the mechanism of gas- first complex multicellular organism6. trulation, but for Metchnikoff, the issue intro- Figure 2 | Hypothetical stages in the evolution Both Haeckel and Metchnikoff used onto- duced the beguiling problems not only of how of early metazoans. Haeckel’s gastrea (left genetic recapitulation to understand phyloge- competing cell lines were formed, but how they column) was postulated as arising from netic development10,but arguments arose over were integrated into a harmonious whole. He recapitulated embryonic stages of early which data were considered pertinent. Haeckel, discovered that specialization of function vertebrates. Possessing a distinct extrapolating from Amphioxus (lancelet) devel- resulted in a set of problems that was unique to anterior–posterior axis and differentiation of opment, suggested that multicellularity arose metazoan organization — namely, he saw cell somatic and reproductive cells, gastrea from an organism that was formed by an types in competition with each other11.He rec- purportedly formed by invagination from a blastea stage to create a double-walled, sac-like invagination (emboly) of a primordial gastrula ognized, with increasing clarity, that evolution organism. Metchnikoff, citing that cnidarians to form a dual-layered embryo (FIG. 2,left). must be understood by selective processes that gastrulate by introgression (where cells proliferate This so-called ‘gastrea’was therefore analogous operate on the interactions of cell lineages with from the blastula wall into the interior blastocoel to to the invaginated gastrulas that were observed each other to limit self-replication by any one produce a solid gastrula) suggested that in primitive chordates, in which the outer layer component in favour of the interests of the invagination arose as a secondary mechanism of of cells moved into the spherical inner space as organism as a whole. Rather than marvel at gastrulation. The planuloid ancestor (that is, planula larva of cnidarians) was first named a second primary layer, and subsequently their cooperative development, he regarded parenchymella, and then phagocytella (right side). developed into digestive (endodermal) struc- the organism as intrinsically ‘disharmonious’. This figure is modified with permission from REF. 30 tures (FIG. 2,left). But Metchnikoff and And, given the animal’s unstable state, he © (1987) Thomson Publishing. Koveleski had discovered a second pattern of sought the mechanisms by which they

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The phagocytosis theory At the interface of physiology (the present) and evolution (the past), Metchnikoff created a Metchnikoff delivers Nobel Prize awarded to conceptual integration. If metazoan evolution Lectures on the Behring; Metchnikoff publishes designates specialized cells to fulfill specific Comparative Pathology his opus magnum, Immunity in Nobel Prize jointly awarded of Inflammation12. Infectious Diseases17. to Metchnikoff and Ehrlich2. functions, what coordinates and integrates these competing cell types? This question underlies the most fundamental problem that links evolutionary and developmental biology. 1891 1897–1900 1901 1905 1908 1916 Metchnikoff’s starting point, unlike Claude Bernard’s notion of homeostasis as an idealized equilibrium, was disharmony6.In this view, a

Paul Ehrlich standardizes Nobel prize Ilya Metchnikoff dies. Darwinian struggle was occurring within the antitoxins and proposes the awarded to organism as cell types competed for their self- ‘side-chain’ theory of Robert Koch29. antibody formation7. aggrandizement. Harmony became an ideal to be synthesized from the potential disharmonious assembly of evolved constituents. Metchnikoff dubbed the harmonizing process ‘physiological inflammation’,an integrative, restorative and curative undertaking (FIG. 4). achieved a harmonious synthesis. This task he of this cell was so dominant in Metchnikoff’s assigned to the phagocyte (FIG. 3). thinking that he changed the name of his Physiological inflammation hypothetical primordial metazoan from Metchnikoff identified phagocytes as possess- From parenchymella to phagocytella parenchymella to phagocytella in 1886. The pre- ing a primitive volatility, essentially free of any Parenchymella’s cells (parenchyma) in their occupation with phagocytes originated in his commitments to anatomical location or func- primordial state were called ‘wandering cells’, attempt to define the fundamental principles of tion. In short, they possessed an ancient a generic term for the early undifferentiated comparative embryology. The centrality of pluripotential autonomy that conferred on cells that filled the gastrula space. Specialized digestive function convinced Metchnikoff that them the ability to ‘eat’ and then ‘feed’ other cells differentiated from parenchyma, and in following the phylogenetic fate of phago- cells by their dual capacity to ingest particulate those wandering cells that retained their cytes, he had a tool for discerning genealogical nutrients and move, apparently at will, mobile and phagocytic capacities served as relationships that previously was unavailable. throughout the organism. Phagocytes thereby nutritive cells in animals without a gut. In Metchnikoff, during the 1880s, pursued a became the agents of the organism as a whole higher animals, Metchnikoff observed how dual research programme, each arm of which through their ancient digestive role. And in this parenchymatic mass further differenti- was linked by the phagocyte. This cell became a animals with a gut, phagocytes continued to ated into two layers: endoderm and meso- ‘marker’ of the mesoderm, and he tracked its ‘eat’,but now with a new regulative function of derm. Endoderm assumed the specialized appearance and various functions from the maintaining the integrity of the organism by digestive function, whereas the mesoderm simplest aquatic animals to mammals12.In so protecting the animal from foreign invaders or gave rise to the circulatory, respiratory and doing, he discovered that the phagocyte clearing the body of unwanted cellular debris. locomotive functions; the mesodermal ingested not only to feed itself and other cells, So, these ‘eating cells’ became the brokers of phagocyte retained its original mobility and but also to protect the organism from invaders. pathological inflammation. They continued to scavenging abilities. In 1882, in a celebrated experiment in Messina devour, but now in the service of host defence By 1882, Metchnikoff’s attention became — where Metchnikoff had taken refuge from by engulfing and killing bacteria, congregating firmly fixed on these latter amoeboid digestive the political turmoil in Odessa — he observed around foreign bodies, and appearing at cells, which were dubbed phagocytes from ‘pha- phagocytes surrounding and attempting to wounds (FIG. 5). gos’(to eat) and ‘cyte’(cell). Indeed, the centrality devour a splinter he had introduced into the The phagocyte became Metchnikoff’s transparent body of a starfish larva. In this research focus, and some would say his obses- ‘eureka’ experiment, Metchnikoff thought he sion. By the 1890s, the debates between had understood the function of phagocytes to Metchnikoff and those who advocated include host defence and so expanded their humoral immunity as key to host defence aboriginal function from ‘eating to feed’,to ‘eat- stimulated him to expand his claims for the ing to defend’.Merging his interests in this pro- phagocytic theory. His mature and most tean cell with the newly discovered pathology explicit statement describing the protean roles of infectious diseases, Metchnikoff quickly of the phagocyte can be found in a short paper developed a grand theory to account for the ‘The struggle for existence between parts of the diverse functions of the phagocyte in develop- animal organism’ which was published in 1892 ment and in adult physiology. The so-called (REF.13), shortly after he delivered his famous Figure 3 | Scanning electron micrograph of a ‘phagocytosis theory’ was presented to Rudolf Paris lectures on comparative inflammation12. phagocyte. The image shows a macrophage, a type of phagocyte that is specialized in the Virchow in 1883, who apparently was Whereas the latter work emphasizes the role of ingestion and destruction of bacteria. Image favourably impressed, and Metchnikoff spent the phagocyte in combating pathogens and reproduced with permission from REF. 32 © (2003) the rest of his career championing his grand repair of injury in adult animals, the short Macmillan Magazines Ltd. synthetic theory. paper gives a broad overview of phagocyte

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regarded inflammation not only as restorative, formed the foundation of Metchnikoff’s think- but also constructive. ing, and, more particularly, the German failed to grasp that Metchnikoff arrived at his theory Immunity Phagocytes as police by seeing digestion (the universal function) Metchnikoff’s critics soon pounced on the the- leading to defensive phagocytosis, not vice Pathological inflammation ory as lacking strict scientific evidence and suf- versa. So Metchnikoff rejected the charge of fering from both teleological and vitalistic telological thinking by citing the evolutionary Physiological inflammation notions6.For instance, Paul Baumgarten, a evidence,“[A]moeboid cells by no means are leading microbiologist and pathologist, destined for healing activity, but the latter is a Harmony/disharmony rejected the phagocytosis theory, citing two result of their capacity to engulf and digest dif- general objections. The first, which simply ferent foreign bodies. The activity, which has a Figure 4 | Metchnikoff’s theory of inflammation. Metchnikoff regarded the highlighted the inconsistent role of phagocytes long history, is based upon the digestive func- organism as intrinsically ‘disharmonious’ and in host defence, related to whether intracellular tions of sponges and other animals possessing stated that ‘physiological inflammation’ comprised digestion could be correlated with bacterial intracellular digestion. From this point of view, all those activities that strove to establish killing — 20% of Daphne could not resist the danger to the animal does not seem to be ‘harmony’ in developing embryos and adult infection; anthrax spores were resistant, predestined, but appears as a result of the animals. In mature animals that are subjected to whereas bacilli were sensitive to phagocyte phagocytes’ inactivity, conditioned by one or injury, cell death and infection, the sentinel phagocyte was directed to regaining disrupted killing; certain bacterial strains were sensitive, another cause.” (REFS 6,16).In other words, harmony and so became the effective restorative whereas others were not; and diverse exoge- Metchnikoff regarded the phagocyte to have agent of ‘pathological inflammation’. ‘Immunity’ nous factors (such as temperature) seemed assumed a new evolutionary role as a result of was the subset of these functions that was important. Baumgarten concluded that it was new demands. The function was the same; the directed most specifically against invasive more likely that phagocytes had a passive role context was different. pathogens. Modified with permission from REF. 31 in the natural demise of the pathogens, which Where Baumgarten saw only a metaphor of © (1991) Johns Hopkins University Press. died by other means. phagocyte protective behaviour, Metchnikoff Baumgarten’s objections were eventually recognized a long phylogenetic and ontoge- function in normal development and body quelled by the elucidation of the particular con- netic history of these freely mobile cells. economy. By drawing explicit parallels between ditions that were required for phagocyte effec- Whereas the Baumgartenian school of reduc- phagocytes devouring the tadpole’s tail — tiveness, but a deeper problem faced tionist thinking prevailed in the developments which is ‘eaten’ at the appropriate time of Metchnikoff in deflecting the charge that he of immunochemistry, Metchnikoff provided a metamorphosis — and wound repair or bacte- assigned phagocytes an unwarrented autonomy crucial biological component to the chemical rial killing, it is clear that Metchnikoff regarded to police the organism — that is, assigning programme: host defence involved an active the role of the phagocyte in the evolutionary them a self-generated vitality and purpose. The response by the organism to pathogenic inva- drama as essentially unchanged in these vari- new positivist science of the late nineteenth ous settings or by the species in which they century rejected teleology outright as being were observed13.In using the tadpole, he explanatory of biological function — seeking extrapolated back into phylogenetic history to instead to ground phenomena in a materialistic illustrate the most basic ‘identity’ function of schema, reducing organic functions to physics the phagocyte — namely, that under certain and chemistry.And Baumgarten, an advocate developmental conditions, this cell was of this new science, pointedly accused ‘responsible’ for defining organismal struc- Metchnikoff of retrogressive thinking (REF.15 tures. Later, he speculated that the ageing and discussed in REF.6). Part of Metchnikoff’s process incurred changes in normal cells that problem was that he was trained as a descriptive phagocytes recognized and then targeted for biologist, and he lacked both the expertise, and, elimination14.In each case, Metchnikoff more importantly, the mindset to seek such believed that phagocytes were engaged in mechanistic explanations. He was satisfied essentially the same process — clearing the instead to understand phagocytic function in its body of dysfunctional elements (endogenous full phylogenetic context, seeing its role in host ‘other’) and unwanted external intruders. The defence as a specialized expression of more phagocytosis theory therefore accounted for a universal functions. Metchnikoff wrote, “I wide functional spectrum, of which host cannot share Baumgarten’s opinion in accor- defence against pathogens was only one aspect. dance to which any physico-chemical explana- The analogical monitoring of both develop- tion has to be of greater significance than a mental and senile processes, under the heading biological one. If the possibility to reduce all Figure 5 | Metchnikoff’s drawing of phagocytes of ‘physiological inflammation’,made phago- phenomena of life to mechanical and chemi- reacting to injury caused by cauterization. cytes the purveyors of organismal identity. And cal laws was the final goal of studies of nature, Metchnikoff’s drawing of phagocytes at a site of here we discern the key significance of it would not follow from this that a prelimi- inflammation (caused by the application of silver Metchnikoff’s theory: before modern genetics nary physico-chemical formulation of a ques- nitrate ) in the caudal fin of a Triton embryo. The injury was observed over time, allowing Metchnikoff had been formulated, he attempted to define a tion has to signify a success in solution of the to monitor the progressive appearance of new mechanism by which organismal identity given question.” (REFS 6,16). phagocytes reacting to the injury. This drawing was is established and maintained. His theory, Baumgarten, on the other hand, had no made 5 hours after cauterization.This figure is understood within a developmental context, appreciation of the evolutionary dynamics that reproduced from REF.12.

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© 2003 Nature Publishing Group PERSPECTIVES sion. This was an essential conceptual leap defence. Inflammation in his formulation was 5. Podolsky S. H. & Tauber, A. I. The Generation of Diversity: Clonal Selection Theory and the Rise of Molecular from passive theories, which accounted for an ongoing process of self-definition. Killing Immunology (Harvard Univ. Press, Cambridge, USA, bacterial demise by extrapolating from the test- invaders was dramatic and the focus of intense 1997). 6. Tauber A. I. & Chernyak L. Metchnikoff and the Origins of tube model that showed microbes dying when scientific and popular interest, but, more fun- Immunology: From Metaphor to Theory (Oxford Univ. Press, Oxford, 1991). they exhausted important nutrients. So, damentally, Metchnikoff conceived that host 7. Silverstein, A. M. Paul Ehrlich’s Receptor Immunology. whereas the German microbiologists focused defence was only a more specialized case of The Magnificent Obsession (Academic Press, San Diego, 2002). on the bacteria that caused disease, and the determining self and non-self. Indeed, what is 8. Metchnikoff, O. The Life of Elie Metchnikoff 1845–1916 immunochemists defined the antibodies that ‘the self’? The phagocyte addressed both arms (Constable, London; 1924). (Translated by E. R. Lankester.) 9. Metchnikoff, E. The Evolutionary Biology Papers of Elie conferred specificity, it was Metchnikoff who of this fundamental question — namely, an Metchnikoff (eds Gourko, H., Williamson, D. I. & Tauber, A. I.) provided immunology with a key insight ability to recognize ‘self’ and ‘other’,and then a (Kluwer Academic Publishers, Dordrecht, 2000). 10. Gould, S. J. Ontogeny and Phylogeny (Harvard Univ. about inflammation: the body uses phagocytes capacity to rid the organism of the unwanted Press, Cambridge, USA, 1977). to mount an active response to infection, and foreign matter. These capabilities evolved from 11. Buss, L. The Evolution of Individuality (Princeton Univ. Press, Princeton, 1987). this response must be understood as a specific its earliest function as a nutritive cell, by which 12. Metchnikoff, E. Lectures on the Comparative Pathology of aspect of a more general physiology. it discerned host and foreign substances, eating Inflammation. (Reprinted by Dover, New York, 1968). (Translated by F. A. Starling and E. H. Starling.) Metchnikoff’s Immunity in Infective Diseases the latter and ignoring the former. So, in simple 13. Metchnikoff, E. in The Evolutionary Biology Papers of Elie (1901) is a seminal synthesis of experimental animals,‘eating’ is the most primitive expres- Metchnikoff (eds Gourko, H., Williamson, D. I. & Tauber, A. I.) 207–216 (Kluwer Academic Publishers, Dordrecht, 2000). observation undergirded by theory, and should sion of the more general capability of a selec- 14. Metchnikoff, E. The Nature of Man. Studies in Optimistic be counted as one of the nineteenth century’s tive ‘attack’ apparatus. The basic characteristics Philosophy (G. P. Putnam and Sons, London, 1903). 15. Baumgarten, P. Referte. Berl. Klin. Woch. 21, 802–804 17 great works in evolutionary biology . of the phagocyte were adapted in animals with (1884). a gut into a different form of ‘eating’.In these 16. Metchnikoff, E. Ueber den Kampf der Zellen gegen Erysipelkokken, ein Beitrag zur Phagocytenlehre. Arch. Conclusion higher animals, the nutritive function is dis- Pathol. Anat. [Virchow’s Archiv.] 107, 209–249 (1887). 17. Metchnikoff, E. Immunity in Infective Diseases (Cambridge Metchnikoff was fundamentally correct in rec- placed, and the rudimentary capacities of Univ. Press, Cambridge, Reprinted 1905). (Translated by ognizing the unity of the role of the phagocyte recognition and destruction are directed both F. G. Binnie.) 18. Abramson, J. S. & Wheeler, J. G. (eds.) The Neutrophil in cellular turnover and in host defence. to foreign invaders (pathogens) and to host (Oxford Univ. Press, New York, 1997). Phagocytes have clearly been shown to have a elements that have become ‘foreign’ — that is, 19. Burke, B. & Lewis, C. E. (eds.) The Macrophage (Oxford Univ. Press, New York, 2002). role in immunity against bacteria, fungi and they are damaged or dying. The earlier phylo- 20. Brown, S. et al. Apoptosis disables CD31-mediated viruses18,19,but, more recently, the mechanisms genetic functions are expressed as the phago- detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203 (2002). by which they continuously monitor cell via- cyte is used to rid the body of senescent red 21. Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis bility have been elucidated. In addition, much cells, bacteria, malignant cells, cell debris, and promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001). has been learnt about engulfment and apopto- so on. Traces of such ‘identity functions’ were 22. Hoeppner, D. J., Hentgartyner, M. O., & Schnabel, R. sis20–22, and phagocytes have extended their even observed in development (for example, in Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202–206 function beyond simply ‘eating’.For example, the tadpole), but pathological inflammation, a (2001). they have an important role in regulating phenomenon characteristic of adult animals, 23. Sunderkotter, C., Steinbrink, K., Goebeler, M., Bhasdwaj, R. & Sorg, C. Macrophages and angiogenesis. J. Leuk. angiogenesis, both by secreting growth fac- offers the clearest insight into the basic func- Biol. 55, 410–422 (1994). tors23 and by actively re-structuring vascular tion of the phagocyte. 24. Diez-Roux, G. & Lang, R. A. Macrophage induced apoptosis in normal cells in vivo. Development 124, tissue through macrophage-induced apoptosis Metchnikoff would not have been sur- 3633–3638 (1997). of normal vascular endothelial cells24,25.This prised at the widening horizons of inflamma- 25. Diez-Roux, G., Argilla, M., Makarenkova, H., Ko, K. & Lang, R. Macrophages kill capillary cells in G1 phase of the newly described role in angiogenesis would, in tion and, in particular, the newly discovered cell cycle during programmed vascular regression. Development 126, 2141–2147 (1999). all likelihood, be interpreted by Metchnikoff as protean roles of the phagocyte. For him, the 26. Tauber, A. I. The elusive immune self: a case of category completely consistent with its assignment as a embryologist, the individual was not given, but errors. Perspect. Biol. Med. 42, 459–474 (1999). 27. Tauber, A. I. Moving beyond the immune self? Semin. mediator of physiological inflammation. In underwent constant change as it developed Immunol. 12, 241–248 (2000). this view, angiogenesis is just another example and adapted to ever-changing inner and outer 28. Gilbert, S. F. & Sarkar, S. Embracing complexity: organicism for the 21st century. Dev. Dyn. 219, 1–9 of a developmental process in which the environments. From this perspective, we can (2000). phagocyte partakes in ‘defining’ the individual, now appreciate his theory as an early articula- 29. Brock, R. D. Robert Koch: A Life in Medicine and Bacteriology (American Society for Microbiology Press, not by destroying an unwanted ‘other’,but by tion of a scientific enigma about organismal Washington DC, 2000). contributing to the creation of new structures. identity that is still unresolved and the pro- 30. Barnes R. D. in Invertebrate Zoology 5th edn. p. 65 (Saunders College Publishing, Philadelphia, 1987) This is only one class of newly discovered found implications of which are again being 31. Tauber A. I. The immunological Self: A centenary diverse physiological role carried out by phago- assessed, both in immunology26,27 and in devel- perspective. Perspect. Biol. Med. 35, 74–86, 1991. 28 32. Rosenberger, C. M. & Finlay, B. B. Phagocyte sabotage: cytes. It amply illustrates how inflammatory opmental biology . disruption of macrophage signalling by bacterial pathogens. Nature Rev. Mol. Cell Biol. 4, 385–396 (2003). mechanisms, when broadly construed, extend Center for Philosophy and History of Science, well beyond host defence to include diverse Boston University, 745 Commonwealth Avenue, roles that contribute not only to the general Boston, Massachusetts 02215, USA. Online links e-mail: [email protected] maintenance of organismal integrity, but, FURTHER INFORMATION more fundamentally, serve in defining organis- doi:10.1038/nrm1244 Boston University, Alfred I Tauber: http://www.bu.edu/philo/faculty/tauber.html mal identity. 1. de Kruif, P. The Microbe Hunters 2nd edn Ilya Mechnikov — Nobel Lecture: If we understand that Metchnikoff con- (Harcourt, Brace and Jovanovich, San Diego, http://www.nobel.se/medicine/laureates/1908/mechnikov- 1954). lecture.html ceived inflammation within a developmental 2. Tauber A. I. The Immune Self: Theory or Metaphor? Doc Kaiser's Microbiology Website, The Innate Immune context and framed by the context of evolu- (Cambridge Univ. Press, Cambridge, 1994). system: http://www.cat.cc.md.us/courses/bio141/ 3. Silverstein, A. M. A History of Immunology (Academic lecguide/unit2/innate/phagoprocess.html tionary dynamics, then we might better appre- Press, San Diego, 1989). University of Leicester, Phagocytosis: ciate how the phagocytosis theory was applied 4. Mazumdar, P. M. H. Species and Specificity: http://www-micro.msb.le.ac.uk/MBChB/bloodmap/ An Interpretation of the History of Immunology Phagocytosis.html well beyond explaining mechanisms of host (Cambridge Univ. Press, Cambridge, 1995). Access to this interactive links box is free online.

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