Tag Archives: leukocyte

Elie Metchnikoff: The “Father of Innate Immunity”

The legend of Isaac Newton being struck on the head by a falling apple has long been enshrined in scientific lore. Likewise, there is the tale of Mendeleev suddenly grasping the relationship between the elements (i.e., discovering the Periodic Table) while struggling over how to organize them for a chemistry textbook he was writing. And, there is the myth of Kekule envisioning the benzene ring structure while dreaming of a snake grasping its own tail. Also, there are the fables of Ben Franklin and his Kite, Darwin and his finches, and Galileo dropping objects from the Leaning Tower of Pisa, among others.

Here we have the tale of Russian zoologist Elie Metchnikoff (1845-1916) who, in 1882, discovered leukocyte recruitment and phagocytosis as key elements in the body’s natural defenses. The mythical aspect of Metchnikoff’s discovery is that it allegedly happened while he was experimenting on starfish larvae. Metchnikoff was awarded a share the 2008 Nobel Prize in Physiology or Medicine for his discovery. German microbiologist Paul Ehrlich shared the 2008 award for his pioneering discoveries in humoral immunity.

Elie Metchnikoff
Elie Metchnikoff

We are fortunate to have Metchnikoff’s account of his 1882 epiphany, written in his own words shortly after he was awarded the Nobel Prize in 2008 (1).

“One day, as the whole family had gone to the circus to see some exceptional trained monkeys, while I had remained alone at my microscope and was following the life of motile cells in a transparent starfish larva, I was struck by a novel idea. I began to imagine that similar cells could serve the defense of an organism against dangerous intruders. Sensing that I was on to something highly interesting, I got so excited that I started pacing around, and even walked to the shore to gather my thoughts.

I hypothesized that if my presumption was correct, a thorn introduced into the body of a starfish larva, devoid of blood vessels and nervous system, would have to be rapidly encircled by the motile cells, similarly to what happens to a human finger with a splinter. No sooner said than done. In the shrubbery of our home, the same shrubbery where we had just a few days before assembled a ‘Christmas tree’ for the children on a mandarin bush, I picked up some rose thorns to introduce them right away under the skin of the superb starfish larva, as transparent as water. I was so excited I couldn’t fall asleep all night in trepidation of the result of my experiment, and the next morning, at a very early hour, I observed with immense joy that the experiment was a perfect success! This experiment formed the basis for the theory of phagocytosis, to whose elaboration I devoted the next 25 years of my life.

So, at a time when virtually nothing was known about the body’s natural defenses, Metchnikoff proposed that the mobile cells (later dubbed “phagocytes” or cell-eaters), which gathered around the thorns in the starfish larvae, were agents of healing. Moreover, he proposed that those cells are the first line of an organism’s defense against invading pathogens. Metchnikoff’s use of starfish larvae in his breakthrough experiment owed to his interest in marine invertebrates which, in turn, reflected his broad interest in natural history.

Metchnikoff’s passionate interest in science, natural history, and marine invertebrates developed early in his life. In 1870, when he was barely 25 years-old, he was appointed a professor of zoology and comparative anatomy at the University of Odessa; a position he resigned in 1882 because of limited research opportunities in Odessa, and because of political instability in the Ukraine after the assassination of Alexander II. Metchnikoff’s pioneering experiments that year were carried out at a private laboratory in Messina. [Later, during the Soviet Era, Odessa University was renamed Odessa I.I. Mechnikov National University, in Metchnikoff’s honor.]

In 1888 Louis Pasteur recruited Metchnikoff to the Pasteur Institute, where he would spend the remainder of his career. There, under the influence of Pasteur and Emile Roux (with whom he developed a close friendship), Metchnikoff turned his attention from simple organisms to experimental infectious disease and immunity.

By the late 1880s, Metchnikoff’s hypothesis that leukocyte recruitment and phagocytosis played a key role in host defense was garnering considerable attention. However, much of that attention was hostile, mainly because Paul Ehrlich, in Germany, was concurrently promoting the role of antisera in the body’s defenses.  The resulting feud between French scientists at the Pasteur Institute and Ehrlich’s colleagues in Germany was dubbed the “Immunity War.” [The “Immunity War” also may have reflected nationalistic feelings left over from the quite real Franco-Prussian war of July 1970 to May 1971.]

It was not until after Metchnikoff and Ehrlich shared their 1908 Nobel award that immunologists recognized that Metchnikoff’s phagocytes were a feature of “innate immunity,” while Ehrlich’s antibodies were a feature of “adaptive immunity.” Eventually both schools of thought would be integrated into our modern understanding of immunity. Metchnikoff would be recognized as the “Father of Innate Immunity,” while Ehrlich would be recognized as the pioneer of adaptive immunity (see the Aside). But, Metchnikoff’s early dispute with Ehrlich may be one reason why he avoided attending the 1908 Nobel Prize award ceremony. Metchnikoff presented a delayed Nobel lecture in Stockholm in 1909.

[Aside: Innate immunity is so named because it is present at birth and remains unchanged throughout life. It is the body’s first response to an invasive pathogen. Innate immunity is fast because it recognizes molecular patterns that are characteristic of broad classes of microorganisms; doing so via receptors that are encoded in the germ line. In contrast, the adaptive immune system is highly specific, recognizing determinants that are unique to each invader; doing so via receptors that are not encoded in the germ line. The adaptive immune system also has a memory. The price for the adaptive system’s specificity is that activation can take 1 week or longer. Innate immunity is the more primitive of these systems. It is present in primordial invertebrates, including insects, worms and mollusks. In contrast, adaptive immunity is seen only in vertebrates.]

How true to fact is the starfish-based tale of Metchnikoff’s discovery? A recent review by Siamon Gordon (Oxford professor of cellular pathology) suggests that Metchnikoff’s own personal account may not be entirely accurate (2).  For instance, a review of the early scientific literature shows that at the time of Metchnikoff’s discovery, phagocytosis had already been described by others.  Intriguingly, a description of phagocytosis appeared in the 1862 novel Fathers and Sons by Turgenev; an author admired by Metchnikoff. In Turgenev’s novel, “the description is given by a nihilist doctor, Yevgeny Bazarov, who, like Metchnikoff, used the microscope to make his own observations (2).”

Nonetheless, Gordon asserts that Metchnikoff indeed carried out the starfish experiments which led to the discovery. Moreover: “What distinguishes his (Metchnikoff’s) discovery from other early descriptions is that he followed up the initial observation with a program of striking experiments, which convinced him that this was a far-reaching process of general biological significance (2).” [Another review by Gordon summarized Metchnikoff’s many considerable contributions (3), some of which are noted below (see Note).]

The “myth” of Metchnikoff’s discovery, like all such myths, often convey a misimpression of the nature of scientific discovery, since they do not sufficiently acknowledge the intense efforts, sustained over considerable periods of time, which are generally necessary to produce major breakthroughs. But, these myths are fun and they do enhance the lay-public’s awareness of science.

Metchnikoff became somewhat of a public celebrity in his later years when he advocated eating yogurt to promote good health and long life (4). Apropos our larger story, Metchnikoff’s promotion of yogurt consumption was inspired by his interest in phagocytes. It was based on his beliefs that 1) the infirmities of old-age happen when phagocytes are transformed from defenders against infection into destroyers of healthy tissue by autotoxins (i.e., toxins that harm the organisms in which they are produced) derived from “putrefactive bacteria” residing in the colon, 2) that these degenerative changes could be prevented by inhibiting the colon’s putrefactive bacteria, and 3) that the host-friendly lactate-producing bacteria in yogurt would inhibit the putrefactive bacteria in the colon. [Metchnikoff regarded the colon as a “vestigial cesspool,” which does little more than provide a reservoir for putrefactive bacteria.]

Metchnikoff’s yogurt-eating regimen attracted numerous adherents for a time, but it eventually fell out of favor (indeed it even was satirized), since the premises on which it was based were never verified. Nonetheless, the medical community has recently been using Lactobacillus acidophilus to effectively treat several conditions, including pediatric antibiotic-associated diarrhea, acute infectious diarrhea, and persistent diarrhea in children. So, might Metchnikoff also be viewed as the “father” (or grandfather perhaps) of the current probiotics craze?

References:

1. Metchnikoff E: My stay in Messina (Memories of the  past, 1908); in Souvenirs, Editions en Languese Etrangeres. Moscow, 1959 (translated from the French by Claudine Neyen). (w.karger.com/doi/10.1159/000443331)

2. Gordon S. 2016. Elie Metchnikoff, the Man and the Myth. Journal of Innate Immunity, 8:223-227.

3. Gordon S. 2008. Elie Metchnikoff: Father of natural immunity. European Journal of Immunology, 38:3257-3264.

4. Mackowiak P. 2013. Recycling Metchnikoff: Probiotics, the Intestinal Microbiome and the Quest for Long Life. Frontiers in Public Health. 1-3.

Note: “His (Metchnikoff’s) notable observations include proof that organisms were taken up by an active process, involving living, and not just scavenged dead organisms; acidification of vacuoles, digestion and destruction of degradable particles including many infectious microbes including bacteria, spirochaetes and yeasts; uptake of host cells, e.g. erythrocytes, often nucleated for ready identification, from diverse species, as well as spermatocytes; and carmine dye-particles, used as an intravital marker of phagocytosis. Metchnikoff emphasized observations in living systems, combining microscopy and staining with neutral red and other histological labels to evaluate the acidity of vacuoles, viability and fate of ingested organisms. The bacteria examined included Cholera vibrio, Bacillus pyocyaneum, Bacillus anthracis and its spores, Mycobacterium (human, avian and bovine), plague bacilli, Streptococci and Gonococci, and some of these were studied in combination. He demonstrated killing by leukocytic enzymes (‘cytase’). Metchnikoff made important contributions to understanding the entire process of inflammatory recruitment, described at length in his lectures on comparative inflammation. He observed diapedesis through vessel walls, aggregation of leukocytes at sites of inflammation and their tendency to fuse, and he dissected the role of endothelial, epithelial and mesenchymal cells, as well as of lymphatic drainage and nervous elements in the classic hallmarks of inflammation (oedema, rubor, calor, dolor, loss of function) and repair. By using simple organisms, he discovered the central role of phagocytosis in diverse biologic models. This work led naturally to studies on the clearance and fate of organisms after experimental administration via a variety of routes, e.g. intravenous, intraperitoneal, subcutaneous and even the anterior chamber of the eye (3).”

 

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