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Dr. Elie Metchnikov - Discoverer of Macrophages and the Immune System

April 6, 2020

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History of Medicine
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Photograph of Nobel Prize winner, Ilya Ilyich Mechnikov, who discovered phagocytes.Photo credit: by Agence Rol - This image comes from Gallica Digital Library and is available under the digital ID btv1b6926750k/f1, Public Domain, https://commons.wikimedia.org

Ilya Ilyich Mechnikov (Elie Metchnikoff; 1845 - 1916) was a Russian zoologist best known for his pioneering research in immunology. In particular, he is credited with the discovery of phagocytes (macrophages) in 1882. This discovery turned out to be the major defense mechanism in innate immunity. Mechnikov and Paul Ehrlich were jointly awarded the 1908 Nobel Prize in Physiology or Medicine "in recognition of their work on immunity". He is also credited by some sources with coining the term gerontology in 1903, for the emerging study of aging and longevity. Mechnikov also established the concept of cell-mediated immunity, while Ehrlich established the concept of humoral immunity. Their works are regarded as the foundation of the science of immunology. In immunology, he is given an epithet the "father of natural immunity".

Mechnikov was born in the village Ivanovka, Kharkov Governorate, now Dvorichna Raion, Ukraine. He was the youngest of five children of Ilya Ivanovich Mechnikov, a Russian officer of the Imperial Guard. His mother, Emilia Lvovna (Nevakhovich), the daughter of the Jewish writer Leo Nevakhovich, largely influenced him on his education, especially in science. His elder brother Lev became a prominent geographer and sociologist.

Mechnikov entered Kharkiv Lycee in 1856 where he developed his interest in biology. Convinced by his mother to study natural sciences instead of medicine, in 1862 he tried to study biology at the University of Wurzburg, but the German academic session would not start by the end of the year. So he enrolled at Kharkiv University for natural sciences, completing his four-year degree in two years. In 1864 he went to Germany to study marine fauna on the small North Sea island of Heligoland. He was advised by the botanist Ferdinand Cohn to work with Rudolf Leuckart at the University of Giessen. It was in Leuckart's laboratory that he made his first scientific discovery of alternation of generations (sexual and asexual) in nematodes and then at Munich Academy. In 1865, while at Giessen, he discovered intracellular digestion in flatworm, and this study influenced his later works. Moving to Naples the next year he worked on a doctoral thesis on the embryonic development of the cuttle-fish Sepiola and the crustacean Nebalia.

A cholera epidemic in the autumn of 1865 made him move to the University of Gottingen, where he worked briefly with W. M. Keferstein and Jakob Henle. In 1867 he returned to Russia to get his doctorate with Alexander Kovalevsky from the University of St. Petersburg. Together they won the Karl Ernst von Baer prize for their theses on the development of germ layers in invertebrate embryos. Mechnikov was appointed docent at the newly established Imperial Novorossiya University (now Odessa University). Only twenty-two years of age, he was younger than his students. In 1868 he transferred to the University of St. Petersburg. In 1870 he returned to Odessa to take up the appointment of Titular Professor of Zoology and Comparative Anatomy.

In 1882, Mechnikov resigned from Odessa University due to political turmoil after the assassination of Alexander II. He went to Sicily to set up his private laboratory in Messina. He returned to Odessa as director of an institute set up to carry out Louis Pasteur's vaccine against rabies; due to some difficulties, he left in 1888 and went to Paris to seek Pasteur's advice. Pasteur gave him an appointment at the Pasteur Institute, where he remained for the rest of his life.

Research

Mechnikov became interested in the study of microbes, and especially the immune system. At Messina he discovered phagocytosis after experimenting on the larvae of starfish. In 1882 he first demonstrated the process when he inserted small citrus thorns into starfish larvae, then found unusual cells surrounding the thorns. He realized that in animals which have blood, the white blood cells gather at the site of inflammation, and he hypothesized that this could be the process by which bacteria were attacked and killed by the white blood cells. He discussed his hypothesis with Carl Friedrich Wilhelm Claus, Professor of Zoology at the University of Vienna, who suggested to him the term “phagocyte“ for a cell which can surround and kill pathogens. He delivered his findings at Odessa University in 1883.

Mechnikov's theory, that certain white blood cells could engulf and destroy harmful bodies such as bacteria, met with skepticism from leading specialists including Louis Pasteur, Behring and others. At the time, most bacteriologists believed that white blood cells ingested pathogens and then spread them further through the body. His major supporter was Rudolf Virchow, who published his research in his Archiv fur pathologische Anatomie und Physiologie und fur klinische Medizin (now called the Virchows Archiv). The discovery of these phagocytes ultimately won him the Nobel Prize in 1908. Mechnikov also worked with ?mile Roux on calomel (mercurous chloride) in ointment form in an attempt to prevent people from contracting the sexually transmitted disease syphilis.

In 1887, Mechnikov observed that leukocytes isolated from the blood of various animals were attracted towards certain bacteria. The first studies of leukocyte killing in the presence of specific antiserum were performed by Joseph Denys and Joseph Leclef, followed by Leon Marchand and Mennes between 1895 and 1898. Almoth E. Wright was the first to quantify this phenomenon and strongly advocated its potential therapeutic importance. The so-called resolution of the humoralist and cellularist positions by showing their respective roles in the setting of enhanced killing in the presence of opsonins was popularized by Wright after 1903, although Metchnikoff acknowledged the stimulatory capacity of immunosentisitized serum on phagotic function in the case of acquired immunity.

This attraction was soon proposed to be due to soluble elements released by the bacteria. Some 85 years after this seminal observation, laboratory studies showed that these elements were low molecular weight (between 150 and 1500 Dalton (unit)s) N-formylated oligopeptides, including the most prominent member of this group, N-Formylmethionine-leucyl-phenylalanine, that are made by a variety of replicating gram positive bacteria and gram negative bacteria. Mechnikov's early observation, then, was the foundation for studies that defined a critical mechanism by which bacteria attract leukocytes to initiate and direct the innate immune response of acute inflammation to sites of host invasion by pathogens.

Mechnikov also developed a theory that aging is caused by toxic bacteria in the gut and that lactic acid could prolong life. Based on this theory, he drank sour milk every day. He wrote The Prolongation of Life: Optimistic Studies, in which he espoused the potential life-lengthening properties of lactic acid bacteria (Lactobacillus delbrueckii subsp. bulgaricus). He attributed the longevity of Bulgarian peasants to their yogurt consumption.

Mechnikov died in 1916 in Paris from heart failure. According to his will, his body was used for medical research and afterwards cremated in Pere Lachaise Cemetery crematorium. His cinerary urn has been placed in the Pasteur Institute library.

Mechnikov was greatly influenced by Charles Darwin's theory of evolution. He first read Fritz Muller's Fur Darwin in Giessen. From this he became a supporter of natural selection and Ernst Haeckel's biogenetic law. His scientific works and theories were inspired by Darwinism.

Awards and Recognitions

Mechnikov with Alexander Kovalevsky won the Karl Ernst von Baer prize in 1867 based on their doctoral research. He shared the Nobel Prize in Physiology or Medicine in 1908 with Paul Ehrlich. He was awarded honorary degree from the University of Cambridge in Cambridge, UK, and the Copley Medal of the Royal Society in 1906. He was given honorary memberships in the Academy of Medicine in Paris and the Academy of Sciences and Medicine in St. Petersburg. The Leningrad Medical Institute of Hygiene and Sanitation, founded in 1911 was merged with Saint Petersburg State Medical Academy of Postgraduate Studies in 2011. This became the North-Western State Medical University named after Mechnikov.

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