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. NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 4 | NOVEMBER 2003 | 897 © 2003 Nature Publishing Group PERSPECTIVES 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