Metchnikoff Advances the Cellular Theory of Immunity

Date 1882-1901

Elie Metchnikoff demonstrated that amoeboid white blood cells combat disease by engulfing and killing bacteria. He was the first modern pathologist to view inflammation as part of the healing process.

Locale Italy; Russia; France

Key Figures

• Élie Metchnikoff (1845-1916), Russian zoologist
• Alexander Kovalevsky (1840-1901), Russian zoologist, founder of vertebrate embryology
• Louis Pasteur (1822-1895), French bacteriologist, founder of modern microbiology
• Paul Ehrlich (1854-1915), German chemist
• Rudolf Virchow (1821-1902), German cellular pathologist

Summary of Event

The genius of science frequently manifests itself under unexpected circumstances. A line of research that to the layperson would probably be seen as obscure and peripheral to bettering the human condition can produce a result that, when viewed in a certain light, proves to hold the key to some fundamental physical or biological process. Such is the phenomenon of cellular immunity, whose significance the Russian zoologist Élie Metchnikoff stumbled upon in 1882 while studying the development of invertebrate embryos.

Thanks to the work of Louis Pasteur, Robert Koch , and others, the pathology of infectious disease and the microbial nature of many of the agents was already well known, but the crucial role of white blood cells in fighting infection was not. Immunity to diseases following infection was thought to arise primarily out of a host’s production of specific antitoxins. Pasteur favored the depletion theory for recovery from primary infection, postulating that bacteria used up some vital growth factor and were no longer able to reproduce, thus limiting disease.

As professor of zoology at the university in Odessa, Russia, Metchnikoff labored far from the European centers of biomedical research. A passionate Darwinist, professed atheist, and political radical, he followed the lead of his fellow Russian Alexander Kovalevsky in choosing comparative embryology as the discipline most likely to elucidate evolutionary relationships in the animal kingdom.

Believing that “ontogeny recapitulates phylogeny,” Metchnikoff reasoned that studying developmental stages of the simplest multicellular invertebrates would yield fundamental insights into the evolutionary process. At the same time, following the lead of Rudolf Virchow , who maintained that pathology ultimately derived from disturbances of cells and could be understood only at the cellular level, Metchnikoff directed his microscope at inflammation. At a congress of naturalists and physicians in Odessa in 1882, he first set forth his hypothesis that phagocytosis was the basis of the healing process. Following the assassination of Czar Alexander II , academic freedom at Russian universities took a sharp downturn. Metchnikoff chose to emigrate, settling first in Messina, Italy, where he had done his doctoral research. His wife’s inheritance freed him from the necessity of paid employment, both in Italy and later at the Pasteur Institute in Paris.

While observing the development of starfish embryos, Metchnikoff noticed that amoeboid cells that migrated to form the digestive surface bore a strong resemblance to vertebrate leukocytes, and wondered if the amoeboid cells would behave in a similar manner. He verified that pricking the embryos with a fine thorn caused the cells to migrate to the site of the injury, and that the cells enveloped dye particles, thus providing further evidence that the ability of such cells to engulf foreign particles, including bacteria, played a role in protection against disease.

Metchnikoff next turned to Daphnia (water fleas), small, nearly transparent arthropods with a defined gut and body cavity. He noted that amoeboid cells in the cavity fluid engulfed and destroyed spores of a parasitic fungus to which the organism had some immunity. His first paper reporting these discoveries on the intracellular digestion of invertebrates (1883) attracted little attention from the medical community, but Metchnikoff persisted, extrapolating his findings to inflammation following trauma and maintaining that the migration of white blood cells to infection sites, pus formation, and changes in other cells associated with inflammation were part of an active process by which the body combated disease organisms. This ran contrary to prevailing medical opinion, and plunged Metchnikoff into the thick of a raging conflict between rival schools of pathology.

Metchnikoff’s work attracted the attention of Louis Pasteur, who, in 1888, offered him a position with the newly opened Pasteur Institute. Metchnikoff became the institute’s director following Pasteur’s death in 1895, continuing an active research program until the outbreak of World War I all but closed the institute. While at the institute, he delivered a series of lectures and then published two major books summarizing his findings: Leçons sur la pathologie comparée de l’inflammation (1892; Lectures on the Comparative Pathology of Inflammation, 1893) and L’immunité dans les maladies infectieuse (1901; Immunity in Infective Diseases, 1905). In these books, he maintained that the phagocyte was the chief means of defense against disease and that circulating antibodies, the so-called humoral factors, were secondary in importance.

Significance

By 1901, the two schools of immunology—cellular and humoral—had become sharply drawn along national lines, with the French, led by the Russian expatriate Metchnikoff, championing the role of the cell, and the Germans, headed by Koch’s successor Paul Ehrlich , maintaining that circulating chemicals, rather than cells, constituted the key to defense against disease.

The German school was supported by the development of specific therapies. Ehrlich had demonstrated that guinea pigs fed increasing doses of lethal vegetable toxins developed immunity to them, and that the immunity derived from a chemical present in blood serum. Working with diphtheria and cholera, diseases whose causative agents produce potent toxins, Ehrlich’s laboratory in Berlin was able to produce animal sera effective against these scourges. Cellular immunity, in contrast, appeared to be rather nonspecific.

By the time the Nobel Prize committee decided to award the Nobel Prize in Physiology or Medicine jointly to Metchnikoff and Ehrlich in 1908, the humoral theory of immunity appeared to have triumphed over cellular theory. Metchnikoff had become convinced that a well-balanced intestinal flora held the key to prolonging human life, and he devoted much of his energies in the last decade of his life to promoting the consumption of yogurt to achieve a condition he called orthobiosis.

In choosing to make a joint award to two rivals whose theories, in 1908, appeared to some extent to be in opposition, the Nobel committee anticipated the eventual integration of the two theories into a comprehensive model of immune system function. In his History of Immunology (1989), Arthur Silverstein noted that the controversy between humoral and cellular theories of immunity provided a striking example of the ways in which nonscientific events (notably the Franco-Prussian War) shape research. He considers it a case in which the triumph of one concept (the humoral theory) stifled developments dependent on the other, to the detriment of science. Metchnikoff’s death in 1916 left no distinguished proponent of his theory to take up the mantle, and cellular immunology remained on the back burner for decades.

The discovery of antibiotics revived interest. Antibiotics function by depressing growth rates rather than killing bacteria outright, thereby giving white blood cells an advantage. Serum factors have little effect on antibiotic effectiveness, but a robust cellular immune system is essential.

Bibliography

Lagerkvist, Ulf. Pioneers of Microbiology and the Nobel Prize. River Edge, N.J.: World Scientific, 2003. Describes Metchnikoff’s research and provides an insider’s view of the workings of the Nobel committee that awarded him the prize in 1908.

Metchnikoff, Elie. Lectures on the Comparative Pathology of Inflammation. Translated by F. A. Starling and E. H. Starling. New York: Dover, 1968. Metchnikoff’s book on the subject of inflammation, with a new introduction by scholar Arthur M. Silverstein.

Silverstein, Arthur M. A History of Immunology. New York: Academic Press, 1989. The long chapter on cellular versus humoral immunity integrates many threads, including philosophy and nationalism.

‗‗‗‗‗‗‗. Paul Ehrlich’s Receptor Immunology: The Magnificent Obsession. San Diego, Calif.: Academic Press, 2002. Emphasis is on Ehrlich and the Berlin school, but contains considerable information on Metchnikoff, especially on his conflicts with Ehrlich.

Tauber, Alfred I. Metchnikoff and the Origins of Immunology: From Metaphor to Theory. New York: Oxford University Press, 1991. A thorough account of the scientific aspects of Metchnikoff’s work.