Author: Ibon Cancio, UPV/EHU Associated Professor in Cell Biology; researcher in the ‘Cell Biology & Environmental Toxicology’ (CBET) research group of the Plentzia Marine Station (PiE-UPV/EHU); Spanish scientific representative in the EMBRC Committee of Nodes

Alexander Onufrievich Kovalevsky and Élie Ilyich Metchnikoff are two of the most recognisable and renowned scientists among all those born in the Russian Empire. Kovalevesky came to life in Vorkovo, now Latvia, on 7 November 1840, while Metchnikoff was born in Ivanovka, now Ukraine, on 15 May 1845. Both were marine biologists, essential to understanding evolutionary embryology and physiology and good friends for nearly 40 years after they first met in Naples, Italy. One worked all his life on marine invertebrates and is remembered as the father of comparative evolutionary embryology. The other one, in essence a marine zoologist, is remembered as the discoverer of phagocytosis, father of cellular immunology and winner of the Nobel Prize in medicine.

Picture of Kovalevsky and Mechnikov
Picture of Kovalevsky and Mechnikov (public domain).

Both scientists had a German university education, at least in part. Kovalevsky initiated his studies at Imperial St. Petersburg University, always focused on zoology with some initial interest in chemistry due to the lectures he received on organic chemistry from Mendeleev (what a professor he must have been as the creator of the periodic table of elements!). Kovalevsky decided to finish his studies in Germany, first in Heidelberg and then in Tubingen, obtaining his diploma in St. Petersburg in 1961. Back in Tubingen in 1863, he initiated his zoological studies, learning histology and microscopy under Franz Leydig, who lent his name to the cells that produce testosterone in vertebrate testes. As for Metchnikoff, he studied natural sciences at Kharkob Imperial University, finishing a four-year degree in two (1862-1864). Then he initiated his German adventure first studying marine invertebrates on the island of Heligoland (Helgoland) and later working at the University of Giessen and at the Munich Academy. At that moment, aged 19 and 24 respectively, the life of both youngsters converged in science and in space, when both initiated studies by the sea in Naples. Imagine the impact of the Neapolitan photoperiod and way of life on the two young scientists. Metchnikoff had obtained a grant from the Russian Academy of Science to conduct zoological research for two years in Naples. Kovalevsky was also to spend the following two years in Naples. Imagine the bonds established between the two researchers during a stay where they endured two cholera epidemics that decimated Naples. In the first one, in 1865, they temporarily left the city, Metchnikoff for the University of Göttingen, Kovalevsky to obtain his master's degree for his Neapolitan work on 'The history of the development of the lancelet - Amphioxus lanceolatus' (1865). This work would turn him into a legend. Then, they returned to work in Naples to fall soon into another cholera outbreak that took the life of the landlady that was renting the rooms they both shared and where they had installed their laboratory.

Both friends decided to return to Russia to occupy academic positions in St. Petersburg and Odessa, and presented their PhD theses in St. Petersburg in 1867. The quality of their Neapolitan work on the development of germ layers in invertebrate embryos, the horseshoe worm Phoronis in the case of Kovalevsky and the cuttle-fish Sepiola and the crustacean Nebalia in the case of Metchnikoff, resulted in a shared first Karl Ernst von Baer prize for both friends. The prize was awarded by the 75-year-old von Baer himself. That very same year, Kovalevsky published a series of studies on the embryology of worms, bryozoans, echinoderms, and ascidians establishing the universality and homologous nature of the germ layers within all animals, ectoderm, endoderm and mesoderm. Precisely, von Baer himself, together with Pander, had described the germ layers in 1828. Both friends were seeking the general in the specifics and based on these studies, Kovalevsky proposed an evolutionary theory of germ layers and argued that the process of gastrulation is homologous among all animals. He also established that ascidians, which were considered molluscs at the time, were a new subphylum, tunicates, through embryological analysis. He discovered that the larval stages of ascidians and lancelets possess a notochord and pharyngeal slits, meaning that they are chordates like vertebrates. Thus, a direct link was established between invertebrates and vertebrates, captivating the minds of researchers at the time. All those findings would become the ABC’s of embryology in the years to come and of modern developmental biology.

Bust of Karl Ernst von Baer
The bust of Karl Ernst von Baer in the fresco room at Stazione Zoologica Anton Dohrn, an honour shared only with Charles Darwin. This illustrious Baltic scientist is the father of the germ layer theory and the discoverer of the blastula, the notochord and the mammalian egg. Kovalevsky and Metchnikoff built the bridge between embryology and evolution, between von Baer and Darwin. Photograph by Ibon Cancio.

Kovalevsky dedicated all his life to education in Russia (in St. Perterburg, Kazan, Kiev, and Odessa), travelling occasionally to the coasts where he could conduct research on the embryological aspects of marine invertebrates: Cnidaria, Ctenophora, Oligochaeta, Polychaeta, Echiurida, Mollusca, Brachiopoda, Arthropoda, Echinodermata, Ascidia, and Phoronida. All these travels resulted in hundreds of specimens that were brought back to Russian universities. He investigated, for instance, cellular division in basket stars, and described the dwarf males of Bonelia, discovering the crawling ctenophore Coeloplana metschnikowii (dedicated to his friend). Kowalevsky was in Naples in 1864-1866, 1868, 1870–1871, 1887 and 1889–1890. Only the last time did he work in the facilities of Stazione Zoologica Anton Dohrn. Kowalevsky spent six months there studying the excretory organs in crustaceans and molluscs and the development of ascidians. In 1893, he founded a Special Zoological Laboratory at the Academy of Sciences in St. Petersburg, the first Russian centre of experimental zoology. He also promoted and supervised the construction of the Sevastopol Biological Station, becoming its director from 1892 to 1901. He also played a role in the establishment of the Russian station at Villefranche-sur-mer (France). A total of 12 years of his life were spent working by the coastline in the Mediterranean (Trieste, Naples, Messina, Villefranche-sur-Mer, Marseille, Banyuls-sur-Mer), Black, Red, Marmara, and Caspian seas, and the Atlantic French coastline (Wimerex and Roskoff).

Lancelet and ascidian larvae
Lancelet and ascidian larvae, the two study models that generated a revolution in embryological and evolution research thanks to Kovalevsky. Pictured: an immature Branchiostoma californiense (CC BY 4.0, 10.3897-zookeys.873.33901) and a tadpole of the ascidian Polysyncraton lacazeikindly provided by Federica Montesanto (University of Bari).

Mechnikoff’s relationship with Russian academia was not for life. He was professor at universities in Odessa (in two different periods) and in St. Petersburg, but he carried out all his work from 1888 until his death at the Pasteur Institute in Paris. His involvement in zoological research was also more intermittent than that of Kovalevsky’s and he is considered the father of cell-mediated immunity, having worked on terrestrial mammals and human infectious diseases. He also developed the earliest concepts in ageing, coining the term gerontology in 1903, and was one of the first crusaders of probiotics defending the use of Lactobacillus.

Image of publication
First publication of the process of phagocytosis in marine organisms by Metchnikoff in the 5th volume of the Arbeiten aus der Zoologishchen Institute de Universität of Wien und der Zoologishchen Station in Trieste edited by Prof Claus. The plate of Asteridea sea stars with a bippinaia larvae (circle) belongs to Haeckel (1904) (public domain).

However, Metchnikoff’s big Nobel Prize-winning discovery, that of phagocytosis, occurred while working with marine invertebrates. His phagocytic and cellular immunity theories were built based on his embryological work and the germ layers theory. In 1882, he resigned from Odessa University due to political chaos after the assassination of Emperor Alexander II of Russia and moved to Sicily, establishing a private laboratory in Messina. There he experimented inserting rose thorns into the transparent body of bippinaria stage larvae of the starfish Bippinaria asterias that do not possess blood vessels or a nervous system. In his microscope he was able to observe cells that moved around the thorns. He realised that in animals that have blood, the white blood cells gather at the site of inflammation, and he hypothesised that this could be the process by which bacteria were attacked and killed. He presented his results to Carl Claus, zoologist at the University of Vienna and director of the zoological station in Trieste, who suggested the term ‘phagocyte’ for such killer cells. Metchnikoff presented his findings at Odessa University in 1883 and published them in the journal of Carl Claus in 1884, yet was met with scepticism from leading specialists. His major supporter was Rudolf Virchow, father of the concept of cellular pathology.

Metchnikoff had become very interested in the study of intracellular digestion, mainly the origin of the digestive tract. Studying medusae, he had observed that the mesoderm kept a primitive digestive function while the gastrulation process was characterised by migration of mobile mesodermic cells. Instead, in triploblastic animals where the gastrula arises through whole epithelium invagination, the endoderm is the precursor of the digestive cavity and extracellular digestion. In any case, the mobile cells of the mesoderm keep the ability to move and conduct digestion intracellularly. As he studied the process more closely, he confirmed that mesodermic cells accumulated around foreign particles introduced into the organism. So, in essence, inflammation consists of the reaction of mesodermic mobile cells in a physiological cellular response against an external agent.

Gastrulation process
Gastrulation process in medusae (Embryologische Studien an Medusen. Ein Beitrag zur Genealogie der Primitiv-organ. Metchnikoff, 1886) (public domain).

Meanwhile, Paul Ehrlich had established the concept of humoral immunity, arguing that immune response is the responsibility of factors that are transported by the circulatory system (humoral factors) such as antibodies or endocrine factors. The floor was set for a war between humoralists (championed by Koch and Ehrlich) and cellularists such as Metchnikoff. In 1887, Metchnikoff observed that leukocytes isolated from the blood of various animals were attracted to certain bacteria. This attraction was soon proposed to be due to soluble elements released by the bacteria. This resulted in the bridging of the opposed positions of the newly-born discipline of immunology. Metchnikoff and Ehrlich would then be jointly awarded the Nobel Prize in Physiology or Medicine ‘in recognition of their work on immunity’ in 1908. A Nobel Prize for scientific peace!

The pathways of our two protagonists and friends diverged geographically and scientifically, although always reverberating on the happy Naples times. Kovalevsky and Metchnikoff were elected together corresponding members of the Imperial Academy of Sciences in 1883. Irremediably most of the relationship between both friends until Kovalevsky’s early death in 1901 was through letters (185 letters are kept written by Kovalevsky to Metchnikoff from 1866 to 1900). The zoological interests of Kovalevsky were focused on excretion processes while those of Metchnikoff were on digestion, and this led him to the Nobel Prize. But they were friends. In the lovely biography ‘Life of Elie Metchnikoff 1845-1916”’ published in 1921 by Metchnikoff’s wife, Olga Metchnikoff, with a preface by Sir Ray Lankester (great marine biologist, promoter and president of MBA at Plymouth), the reflections of the young man on first meeting the also young Kovalevsky in the old city of Naples are published like this:

He found in Kovalevsky a young man with shy but cordial manners and the clear sweet eyes of a pure child, obviously an idealist. He had for science an absolute cult, the sacred fire of the worshipper; no sacrifice was too great, no difficulty too repellent for his ardour. On a closer acquaintance, the small, timid young man proved to be a hard fighter where science was concerned. The two young men formed an excellent impression of each other, and a friendship was started between them which was to last a lifetime. Though very different from each other, they met on common ground, a passion for science’.

The scent of the sea and the hands wet on marine science make friends for life!

Biography
Biography of Metchnikoff written by his wife Olga and prefaced by Ray Lankester who met both Metchnikoff and Kovalevsky and president of Plymouth MBA.
Sabrina Gaber
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