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An Interview with Professor Manuel Varela: Elie Metchnikoff- Phagocytes and Macrophages.

Nov 19, 2018 by

Michael F. Shaughnessy –

1.Professor Varela, the name Elie Metchnikoff seems to be inextricably linked to phagocytes and macrophages. First of all, tell us about Elie Metchnikoff and where and when he was born and went to school.

Prof. Elie Metchnikoff (Ilya Ilyich Mechnikov) was born on the 16thday of May to Jewish parents Illia Ivanovitch (father) and Emilia Nevahovna (mother)in 1845 in a small village called Ivanovka, which was near the town called Kharkov, known today as Kharkiv, located in the Ukraine, Russia. 

It is reported that as a child his mother greatly influenced his interests in the natural sciences, providing for him a dedicated tutor to accommodate these interests.  In 1856, young Metchnikoff attended the Lyceum located at Kharkov, becoming interested in the biological sciences while there.  Apparently, his mother discouraged a career for him in the field of medicine, but wholeheartedly approved of his pursuing a career as a physiologist and zoologist.

At first, in 1862, he attended university at Wurzburg, but changed his mind about attending the institution when the semester did not start out straightaway.  Upon returning to Kharkiv he attend the university there and majored in the natural sciences, taking his undergraduate degree, in 1864.

He moved to the University of Geissen, focusing on parasitology under the tutelage of Prof. Rudolf Leuckart, taking the advice of the famous investigator Prof. Ferdinand Cohn while Metchnikoff had been at Heligoland studying marine biology and botany. In Dr. Leuckart’s laboratory at Geissen, Metchnikoff studied metabolism within the cellular contents of a nematode flatworm, making what is
considered by many to be his first major scientific discovery of note, in 1865.

Next, he moved to the Naples Zoological Station, where he focused his
investigative studies on cuttle fish (Sepiola) and a crustacean (Nelalia) for his doctoral dissertation. Progress on this project was interrupted, however, by an epidemic of cholera, and he moved, thus, to the university at Göttingen, where he studied for a short while with Profs. J. Henle and W. Keferstein, in 1867.  

Moving to the University of St. Petersburg, Metchnikoff studied invertebrate zoology, finishing his doctorate in 1868, at the age of 23. 

2) Sometimes, he is called the “father of natural immunity”. How did he come by this moniker?

Dr. Metchnikoff is credited with having provided the first detailed experimental evidence for the cellular process known as phagocytosis performed by certain white blood cells called macrophages.

Thus, he widely known as the discoverer of the phagocytes. He found that these specialized phagocytic cells ate fungi microorganisms.  His work provided a mechanism for our understanding of how phagocytosis worked. 

Importantly, Dr. Metchnikoff found that phagocytes play an important role as a prime component of the innate immunity arm of the immune system. Thus, he has been referred to as the father of natural or innate immunity. Others have called this system natural resistance or non-specific immunity. Innate immunity seems to be the prevailing popular term in modern times.

Innate immunity can be envisaged as a series of barriers. The phagocytes that Dr. Metchnikoff discovered partake in a cellular barrier function, a key aspect of innate immunity.  Other cells that
hold this cellular barrier role within the innate immunity system include neutrophils, monocytes, and natural killer cells. 

These macrophage, neutrophil, and monocyte cells bind to certain microbial antigens, and they then internalize the microbes into intracellular endosome pockets called phagosomes. These internal microbe-containing phagosomes then fuse with cytoplasmic membrane-bound lysosomes containing pre-formed hydrolytic proteins, to form phagolysosomes, thus activating the digesting enzymes. These phagolysosomes then digest the internalized microbes into tiny pieces.  The phagocytes then discharge the eaten microbial pieces into the outside of the cell.

Natural killer cells, also part of the cellular barrier aspect of innate immunity, target cells that are infected by viruses and cancer cells, in order to destroy each of them. Sometimes the natural killer cells are recruited by components of the adaptive immune system, a proteinaceous molecule called an antibody, and the natural killer cells then destroy the invading antigens.

Other barriers of the innate immune system include chemical, physical or anatomical, and physiological types. Together, these various innate barrier machineries serve to provide a naturally based protection system in humans against potentially harmful antigens.

3) Let’s start with the immune system and white blood cells. This microbiologist believed that perhaps white blood cells were responsible for the destruction of certain dangerous bodies such as bacteria. Was this theory accepted and was he acknowledged?

Unfortunately, at first Dr. Metchnikoff’s cellular theory of the microbial
destruction by phagocytes and macrophages, proposed in 1888, flew in the face of the popular humoral theory of immunity, a view developed by proponents holding that certain blood (known as one of the four humors) components conferred protection against antigens. His skeptics were quick to point out that it was humoral immunity, with its antitoxins, or antibodies, which recognized antigens and neutralized or destroyed them. Thus, the controversy emerged between investigators in favor of the cellular (innate) immunity versus those keen to the humoral (adaptive) form of immunity.

The opposition to Dr. Metchnikoff’s theory of phagocytosis mediated by
cellular systems was formidable. The advocates of the opposing humoral theory were numerous and included some of the most prominent investigators of the time, such as the great Prof. Louis Pasteur, and even Dr. Robert Koch, himself.

The evidence in favor of Dr. Metchnikoff’s theory of phagocytosis and its implications for its role in innate immunity accumulated with time. Meanwhile, the evidence in favor of the opposing antitoxin theory appeared to accumulate, as well.  Sometimes, to their chagrin, both schools of thought, phagocytes versus antibodies, obtained evidence that seemed to corroborate the ideas of the opposing sides, forcing investigators reluctantly to accept certain aspects of each other’s theories.

The newly emerging ideas become clear:  both sides were largely correct, with the Nobel being conferred, in 1908, to the leaders of both camps, Dr. Metchnikoff, leading the cellular phagocyte camp, and to Dr. Paul Ehrlich, leader of the antibody humoral camp.

4) And now, the difficult questions- what exactly are phagocytes/macrophages- and why study them in microbiology? What is their ultimate importance?

The macrophages constitute a type of phagocyte, which operate to eat
invading foreign antigens.  The phagocytes function to provide a means of defense against pathogenic microbes. The cells of the phagocytes are considered members of the cellular barrier aspect of natural (innate) immunity, providing a non-specific form of defense.

The phagocytes perform their defensive role by first moving to locations within the body that are injured or are replete with invading microbial pathogens.  This cellular migration role is often referred to as chemotaxis. The phagocyte will then bind to their microbial targets, an attachment process sometimes called adhesion or adherence, forming an antigen-phagocyte complex.

The antigen will then be taken into the inside location of the phagocyte,
forming an endosome called a phagosome, a membrane-bound vesicle harboring the enclosed microbial antigens. Sometimes this internalization process is called ingestion.

Next, the phagosome with its enclosed internalized microbes contained within it, will fuse with lysosomes. These lysosomes are also membrane-lined cellular packets, which harbor inactive hydrolytic enzymes.  The fusion between the microbe-containing phagosome and the inactive-enzyme containing lysosome forms a so-called
phagolysosome. In the newly formed phagolysosome, the inactive enzymes become activated. 

The activated enzymes begin the process of digestion. The activated
proteases break apart the microbial proteins. The activated lipases disrupt the microbial membranes. The activated nucleases destroy microbial DNA and RNA molecules.  It takes less than an hour to effectively kill the trapped microbes within the phagocytes.

The phagocytes then egest the broken microbial parts, making their
microbe-killing process almost complete. The phagocytes will often secrete certain messenger molecules to recruit other cells to finish off the remaining vestiges of the invading microbes and to mediate repair of any damaged host tissue.

5) He did win the Nobel Prize, which provided him some consolation- since his personal life was full of strife. What was the prize won for and what transpired, sadly during his life?

Dr. Metchnikoff earned the Nobel for clearly defining the microbe-killing role of the phagocytes.  He provided clear experimental evidence for the role of phagocytes as well as their role in natural immunity.

While working in St. Petersburg, he met Ms. Ludmilla Feodorovitch, whom he married in 1863.  At the time of their wedding, she had been chronically infected with the bacterium called Mycobacterium tuberculosis, the causative agent of tuberculosis, also called
the Great Consumption, because the affliction frequently consumed its patients. It was reported that she was so ill, that she had to sit down during entire wedding ceremony. The illness was long lasting and severe. Sadly, Ludmilla passed away on the 20th of April, in 1873.

The personal loss for Dr. Metchnikoff was too great to endure. He attempted suicide by consuming an overdose of opium but was unsuccessful.

He later remarried.  This time he married one of his students, Ms. Olga Belokopytova, in 1875.  However, in 1885, she acquired a serious case
of the typhoid fever, a disease caused by the Salmonella enterica bacteria. The episode brought about another bout of severe depression for Dr. Metchnikoff, who again attempted suicide, this time by consuming a large dose of a spirochete bacterium, a causative agent of relapsing fever. It had been a ruse, pretending to experimentally evaluate the effects of the relapsing fever microbe in the blood. Though he acquired a severe case of the disease and almost died, he recovered.

6) What have I neglected to ask about this very famous microbiologist and his contributions?

Interestingly, Dr. Metchnikoff studied other topics after the Nobel. For
instance, he studied the transmission of the infectious disease syphilis in primates, working with Dr. Emile Roux to find a treatment for the ailment using a mercury-containing compound.

Dr. Metchnikoff also proposed the theory that bacterial composition
influenced certain aspects of senescence, the process of aging. Namely, he thought that there was a connection between microbes living on the body and senility. He had the idea that bacterial toxins could mediate senility.  To ward off these putative senility-producing bacteria he advocated a new diet consisting of milk that had been fermented by
certain lactic acid producing bacteria. The proposed Metchnikoff diet had been widely practiced. 

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