Development of the concepts of phagocytosis as a defense mechanism of the body and the mechanism of action of antitoxins and cell receptors provided a springboard for future advances in knowledge concerning immunity.
In 1796, Edward Jenner introduced the first vaccination against smallpox—so named to distinguish it from syphilis, the “Great Pox”—by employing exuded matter from cowpox pustules as the inoculant. In so doing, he used a principle of animal biology with which he and others were not familiar. Jenner’s success rested on the principle of immunity to prevent disease.
Immunity can be defined simply as the state of protection against disease, particularly infectious disease. It is the response of the animal body and its tissues to an assault by a variety of antigens. In the context of present-day knowledge, understanding, and research in the field of immunity, this definition is as uninformative as a definition of life. The weakness of the definition is not in what it covers, but rather in what it leaves out for the sake of brevity.
In the context of late nineteenth century science, the field of immunity, aside from being young, was fraught with seemingly incongruous results. Élie Metchnikoff and Paul Ehrlich, who shared the 1908 Nobel Prize in Physiology or Medicine
Metchnikoff correctly interpreted and advanced the concept of phagocytosis as a major mechanism by which the animal organism combats foreign particles and disease organisms invading the body. He first used the term “phagocyte,” derived from the Greek, in Carl Claus’s Arbeiten (1893; work); Claus, a zoologist, was keenly interested in the phagocytosis theory. Metchnikoff was educated as a zoologist, but his studies led him increasingly into the field of pathology. In 1865, he made the first observation that would lead to his concept of phagocytosis as a disease-fighting mechanism. He examined the intracellular digestion in the roundworm Fabricia, which compared with that of protozoans. Although this phagocytic-type process was originally discovered and noted in 1862 by Ernst Haeckel, it was Metchnikoff who correctly interpreted the relationship between phagocytic digestion and phagocytic defense mechanisms.
In 1882, while studying transparent starfish larvae, Metchnikoff observed mobile cells engulfing foreign bodies introduced into the larvae. He noted that these cells arose from the mesoderm layer (middle layer) of the embryo rather than the endoderm layer, which is associated with the digestive system. Metchnikoff examined the degeneration of the tadpole tail and observed that it occurred by the phagocytic process also. These observations led him to spend the next twenty-five years in developing and advancing his theory of phagocytosis. The need for phagocytosis in an actively diseased animal led him to study a fungus infection of the water flea, daphnia.
Metchnikoff demonstrated that human white blood cells
It was in the study of the higher animal systems that Metchnikoff faced his most significant challenge in understanding phagocytosis and disease. His choice of infection was the anthrax bacillus. His observations appeared to conflict because phagocytosis seemed to be limited depending on virulence—very virulent bacilli were not attacked, whereas weaker bacilli were. Complicating Metchnikoff’s study was the observation that resistant animals exhibited active phagocytosis and susceptible stock displayed no phagocytosis. Metchnikoff was up against the multifaceted complexity of immunity—the humoral versus cellular dichotomy—and the basis of his day’s confusion and controversy in immunity studies.
Beginning in 1883, Metchnikoff’s ideas were published in Rudolf Virchow’s Archiv für pathologische Anatomie und Physiologie, und für klinische Medizin (archives for pathological anatomy and physiology and clinical medicine). By 1892, phagocytosis in combating disease was established, and the knowledge was published in The Comparative Pathology of Inflammation. Metchnikoff wrote a comprehensive book in French in 1901, L’Immunité dans les maladies infectieuses, that reviewed both comparative and human immunology and proved a defense of his phagocytosis theory. The book was translated into English in 1905 under the title Immunity in Infective Diseases.
While Metchnikoff wrestled with establishing phagocytosis as a mechanism of defense in disease, Ehrlich studiously examined antitoxins. His first major accomplishment was the improvement of the effectiveness of the diphtheria antitoxin
Whereas Metchnikoff studied the factors associated with phagocytosis and thus the cellular aspect of immunity, Ehrlich studied the factors associated with the humoral aspects of immunity—immunity embodied in the bodily fluids. Ehrlich’s research on toxins and antitoxins aided later studies and the development of an understanding of antigens and antibodies (immunoglobulins). Ehrlich’s accomplishments included the introduction of quantification and graphical representations of the relationships existing between toxins and antitoxins.
Ehrlich’s work with ricin established that animals can build an immunity to such toxic substances when they are administered initially minute doses of the substances, with the size of the doses gradually increasing over time. Furthermore, he demonstrated in mice the transference of this immunity to the offspring through maternal milk. From his work on diphtheria toxin, he developed a quantitative standardization method for antitoxin dosage characterization.
Ehrlich’s work in immunity arose from his study of blood, particularly staining with various dyes. His findings convinced him that the cell does bind certain dyes by distinct chemical affinities. The variously discovered blood components and the differential staining methods Ehrlich developed not only prepared him for his immunity researches but also marked him as the founder of modern hematology. Additionally, the Wassermann test for syphilis, developed by August von Wassermann in 1906, was a direct outgrowth of Ehrlich’s immunological research and views.
Prior to the phagocytosis doctrine advanced by Metchnikoff, the commonly held view was that resistance to bacterial infection resided in chemical properties of the blood. This view enjoyed reinforcement because antibodies in blood had been demonstrated. In 1903, the English scientists Sir Almroth Edward Wright
Phagocytosis is most pronounced in acute (extracellular) infection, although bacteria protected by a capsular coat are not readily attacked. Phagocytosis is of limited importance in the case of intracellular infections, such as viruses. In the early stages of infection antibody production has not yet begun, thus phagocytosis is the first defensive action initiated against foreign microorganisms. The administration of antibiotics slows bacterial growth and multiplication, permitting phagocytic blood cells to kill these small populations.
Today it is understood that several types of cells are involved in defense against infection.
Ehrlich’s work in immunity had far-reaching consequences for general medicine. His studies provided the earliest methods of standardization of bacterial toxins and antitoxins, which are still employed, essentially unaltered from his original methods. Ehrlich demonstrated further that the lethal action of toxin and its antitoxin-binding potential are actually two separate and distinct properties of the toxin. Additionally, with ricin, he showed that a lag time exists between exposure to a toxin and the manufacture of antibodies against it. Furthermore, Ehrlich distinguished clearly between the concepts of active immunity and passive immunity during his studies of immunity transmission through milk and placenta.
Through these studies—all of which rested on his fundamental belief in chemical affinities between a cell and chemical substances—Ehrlich went on to study ways of curing disease by chemical means. His early work and successes with trypanosome infection utilizing trypan red and atoxyl derivatives led to his most celebrated application of Salvarsan, an arsenical, as a cure for syphilis.
Armed with the knowledge and insight into the mechanics of immunity and chemotherapy to which Ehrlich’s and Metchnikoff’s work contributed, along with ongoing advances in biotechnology, modern medicine can fight microorganisms on their own ground—the molecular level—and win.
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Glasser, Ronald J. The Body Is the Hero. New York: Random House, 1976. Several chapters provide in simple language the historical and scientific basis of knowledge concerning the major cellular components of the human immune system. -
Marks, Marguerite. “Paul Ehrlich: The Man and His Work.” McClure’s, December, 1910, 186-200. Avoids scientific jargon and relates in simple terms the work done by Ehrlich and its historical importance. An excellent source to review before examining more scientifically based commentaries on Ehrlich. -
Marquardt, Martha. Paul Ehrlich. London: William Heinemann Medical Books, 1949. Marquardt, Ehrlich’s secretary, provides glimpses into the man and his work. Presents a picture of his thinking, his mannerisms, and his temperament. Uses a minimum of technical jargon. -
Metchnikoff, Élie. Immunity in Infective Diseases. Translated by Francis G. Binni. Cambridge, England: Cambridge University Press, 1905. Written by Metchnikoff himself in French and translated to English. A treatise of Metchnikoff’s views and findings in his research on immunity. The seventeen chapters contain few illustrations. For readers who are relatively well versed in science and seek insight into the thinking of the researcher himself. -
Metchnikoff, Olga. Life of Élie Metchnikoff. New York: Houghton Mifflin, 1921. The second wife of Élie Metchnikoff provides a record of his life from childhood to his death at the Pasteur Institute. Discusses his family and his own development; depicts Metchnikoff’s loves, dislikes, and weaknesses. An excellent book for those more interested in the man than in his studies. -
Silverstein, Arthur M. A History of Immunology. New York: Academic Press, 1989. Covers the study of immunology from its beginnings in the first decades of the eighteenth century. Discusses the work of Ehrlich and Metchnikoff as well as other early immunologists and examines the controversies over competing theories as the field developed. Includes appendixes, glossary, and indexes. -
_______. Paul Ehrlich’s Receptor Immunology: The Magnificent Obsession. New York: Academic Press, 2001. Focuses on Ehrlich’s many contributions to the field of immunology, placing them in the context of their times. Includes appendixes and indexes. -
Tauber, Alfred I., and Leon Chernyak. Metchnikoff and the Origins of Immunology: From Metaphor to Theory. New York: Oxford University Press, 1991. Biography of Metchnikoff explores his influences, including how his development as an embryologist prepared him to study immunity and the impact of Darwin’s theory of evolution on his research progress. Places Metchnikoff’s work within the context of late nineteenth and early twentieth century debates on vitalism, teleology, and mechanism. -
Vernon-Roberts, B. “Phagocytosis, Pinocytosis, and Vital Staining.” In The Macrophage. Cambridge, England: Cambridge University Press, 1972. Provides a fine overview of phagocytosis, covering chemotaxis, mechanical factors, recognition of foreign substances, ingestion, the cytochemical changes of significance to ingestion, and the fate of ingested or engulfed materials. -
Woglom, William H. “Phagocytosis.” In Discoverers for Medicine. New Haven, Conn.: Yale University Press, 1949. Describes the theory of phagocytosis and how Metchnikoff strove to establish it. Begins with a brief description of Metchnikoff’s life and education. -
Wood, Barry W., Jr. “White Blood Cells v. Bacteria.” Scientific American 184 (February, 1951): 48-52. Written for readers with some general background in biological science. Examines the role of white blood cells in acute infection. Places particular emphasis on Metchnikoff’s theory of phagocytosis in disease states.
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