On the 150th anniversary of the birth of Academician of the USSR Academy of Medical Sciences N.N. Petrov

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The Sukhumi period of the life and scientific work of Professor Nikolai  N. Petrov: the study of experimental carcinogenesis in primates. On the 150th anniversary of the scientist's birth (1876-2026)

It is safe to say that all senior Soviet oncologists were, in a sense, N.N. Petrov's students. While many of them came to oncology through different paths and belonged to different scientific schools, the well-known monograph "General Theory of Tumors" (1910) by Nikolai Nikolaevich was the first and most important book on oncology for all of them. Under the influence of the ideas of this book, all interested doctors formed their initial ideas in the field of oncology, on the basis of which they developed their own views and concepts, but the foundation remained the scientific innovative ideas of N.N. Petrov, which were striking in their depth and insight. In 2026, it will be 150 years since the birth of Nikolai Nikolaevich Petrov (Fig. 1). Nikolai Petrov, an outstanding surgeon and thinker of our country, was born on December 14 (December 2, Old Style), 1876, in St. Petersburg, in the family of Nikolai Pavlovich Petrov (1836-1920), a professor of mechanics whose achievements were widely recognized not only in Russia but also abroad.

Fig. 1. Nikolai N. Petrov                                                                                                                           

 Image taken from [https://ppt-online.org/67157]. Author unknown

In 1894, N.N. Petrov graduated from high school with a gold medal and entered the Military Medical Academy (VMA). By the time he entered the Academy, Nikolai Nikolaevich had a brilliant background, knowing not only Greek and Latin, but also French and German, and was fluent in scientific literature in English and Italian. After graduating from the Military Medical Academy in 1899, Nikolai Nikolayevich was assigned to the surgical clinic, headed by Professor M.S. Subbotin, for three years to further his studies and prepare for a professorship. During these years, he wrote and defended his doctoral thesis on the experimental study of the pathogenesis of joint tuberculosis in connection with trauma, and was sent abroad for two years (to France, Germany, and Austria) to work in surgical clinics. Upon his return to St. Petersburg in 1905, after delivering two trial lectures and passing an examination, N.N. Petrov was awarded the title of Associate Professor at the Military Medical Academy, and in 1908, he became an Associate Professor at the St. Petersburg Women's Medical Institute [1]. N.N. Petrov's medical career was progressing rapidly. He was a brilliant healthcare organizer. In 1927, at N.N. Petrov's initiative, the first oncology institute in the country was established in Leningrad (since 1926, an oncology department with 100 beds at the Mechnikov Hospital), which became part of the USSR Academy of Medical Sciences in 1945 and played a crucial role in shaping the country's cancer care strategy and tactics for many years.  According to N.N. Petrov's plan, the Institute was to become an important research center for studying the etiology, pathogenesis, diagnosis, and clinical features of tumor diseases, which would allow for the development of a solid scientific basis for organizing anti-cancer efforts. He also participated in the organization of the Kuban University, the First All-Union Anti-Cancer Congress in Kharkiv (1931), and the International Anti-Cancer Association in Paris (1934). All-Union Congress of Surgeons in Leningrad (1935), Laboratory of Experimental Cancer at the branch of the All-Union Institute of Experimental Medicine (VIEM) in Sukhum (Abkhaz ASSR) (1938), in which he worked fruitfully with his students for more than 18 years [2, 3]. In the spring of 1955, the director of the Leningrad Institute of Oncology of the USSR Academy of Medical Sciences, Academician and Professor A.I. Serebrov (Fig. 2), summoned R.A. Melnikov, then a young junior researcher, to his office and assigned him an extremely important task. The fact was that their common teacher and scientific consultant at the institute, N.N. Petrov, was planning to visit the Sukhum Medical and Biological Station of the USSR Academy of Medical Sciences (a monkey nursery) after a long break (Fig. 3), where unique experiments on the induction of malignant tumors in primates had been conducted in the laboratory of experimental cancer since before the war. Rurik Alexandrovich was invited to accompany Nikolai Nikolaevich on this long journey and to do everything necessary to create favorable conditions for his stay and work in the hot and sultry city of Sukhum (Abkhaz ASSR, Georgian SSR), even during these months. "It is difficult to describe the justified excitement that gripped me during the preparations for the departure," R.A. Melnikov recalled [4, 5]

Fig. 2. Aleksandr I. Serebrov

Image taken from  [https://www.livelib.ru/author/156928/pictures]. Author unknown

Fig.3. Monkey nursery in Sukhumi. Image from [https://ru.wikipedia.org/wiki/Sukhumi Monkey Nursery#/media/Файл:2014_Suchum,_Małpiarnia_(04).jpg].  Distributed under a CC BY-SA 4.0 license.   

Rurik Alexandrovich wrote: "A huge responsibility fell on me. At that time, the train took about two and a half days to reach its destination, with many stops at small stations and a transfer to a local train in Sochi. The spring drafts in the train, the cold nights, and the possibility of catching a cold made me anxious, as Nikolai Nikolaevich, a very sociable and inquisitive person by nature, enjoyed walking at the stops and exploring the station facilities. This also caused me concern, as the schedule was not always accurate, and the train could leave a few minutes earlier, leaving the passenger on the platform. Fortunately, subsequent events did not confirm my pessimistic predictions. Our journey was remarkably successful. Despite the significant age difference (I was 30 years old, while Nikolai Nikolaevich was almost 80), we found a wide range of interesting life and scientific issues to discuss, chatting until midnight on various topics." [4]. It should be noted that over the next seven years (from 1955), Nikolai Nikolaevich and Rurik Alexandrovich came to the Sukhum Nursery for 1-2 months each year to continue important experimental research. R.A. Melnikov recalled: "I remember a time when I realized that Nikolai Nikolaevich trusted me as a doctor. Suddenly, Nikolai Nikolaevich's upper jaw tooth began to ache. Conservative measures, such as applying heat and using various mouthwashes, did not provide the desired effect. In the evening, his temperature rose, and he experienced a slight chill. I examined Nikolai Nikolaevich and offered to arrange a dental consultation. "No way! - said Nikolai Nikolaevich, - tomorrow you will personally extract the tooth in our laboratory." Unfortunately, there were no forceps for tooth extraction in the operating room. Nikolai Nikolayevich decisively chose the pliers that he thought were suitable. The moment of truth had arrived. Without anesthesia, as the surrounding gum was inflamed, I extracted the decayed tooth with a single sharp tug. The scientists gathered around breathed a sigh of relief..." [4]. The small team at the Experimental Oncology Laboratory consisted of a few dedicated and committed individuals. Everyone working in the laboratory, from the professor to the junior highly qualified laboratory assistants, created an atmosphere of friendliness and benevolence. The spirit of selfless service to science and the enormous responsibility for the collective research constantly surrounded N.N. Petrov. "In our rare free time, Nikolai Nikolaevich and I loved to walk around the picturesque places of sunny Sukhumi - the famous Sukhumi Mountain, in the unique botanical garden of the Academy of Sciences of the Georgian SSR," [4] recalled Rurik Alexandrovich. N.N. Petrov's scientific activity was extremely high. His rule was to provide extensive information about scientific achievements. His trips to Sukhumi were accompanied by presentations by each of the scientists, both at the scientific conference of the nursery and at the meeting of the Abkhazian Medical Society. The presentations were of a scientific and theoretical nature or focused on the clinical aspects of cancer in various locations. These presentations were usually highly engaging, and the large hall of the Doctor's House was always filled to capacity on these evenings. A major achievement of Russian experimental oncologists is the development of methods for inducing malignant tumors in monkeys that are the closest to humans in terms of their anatomical and physiological characteristics. Nikolai Nikolaevich Petrov's name runs through these studies like a red thread - he is the founder of experiments on primates, experiments were carried out according to his ideas, and for the first time in the world, a team of experimental oncologists led by N.N. Petrov obtained experimental malignant tumors in monkeys. In 1938, N.N. Petrov came to Sukhumi for the first time, where the monkey nursery of the VIEMA branch is located on the Trapezium Mountain (All-Union Institute of Experimental Medicine). Nikolai Nikolaevich correctly assessed the climatic conditions and the lifespan of monkeys in the kennel, and he established the first laboratory for experimental cancer. At the beginning of its existence, the laboratory was located in an unattended building with a limited staff.   The first studies conducted at the institute focused on solar radiation and the potential development of tumors in rats, as well as viral skin tumors in rabbits. During this period, N.N. Petrov's monograph "Comparative Pathology of Tumors in Animals and Humans" was published, which earned him the USSR State Prize in 1941. These studies laid the foundation for more advanced research on the induction of malignant tumors in monkeys. The first experiments on primates were conducted in January 1939 by N.N. Petrov and his close associates N.A. Krotkina and the head of the laboratory, A.V. Vadova. In 1952, N.N. Petrov and his students published a fundamental work titled "Dynamics of the Origin and Development of Malignant Growth in Monkey Experiments" in the USSR Academy of Medical Sciences (Fig. 4) [5, 6, 7].

Fig. 4. Fundamental work of N.N. Petrov and co-authors (1952).Image borrowed from [https://bigenc.ru/b/dinamika-vozniknoveniia-i-r-db171a] . Author unknown.

It should be emphasized that Nikolai Nikolaevich and his colleagues undertook this scientific research despite the opinions of many researchers from different countries, whose repeated attempts to induce tumors in primates were unsuccessful. The development of malignant tumors in primates has become extremely important due to the fact that monkeys are the closest to humans in terms of their anatomical and physiological characteristics, and they have a longer lifespan than most other mammals (approximately half of the human lifespan). Small laboratory animals commonly used in experimental oncology do not meet these requirements. In this regard, researchers were justified in using monkeys to study the etiology and pathogenesis of malignant tumors. Thus, the researchers at the Oncology Laboratory were faced with the crucial task of selecting a reliable carcinogenic agent and developing a method for its rational administration in order to induce tumors in monkeys. Nikolai Nikolaevich decided to use chemical carcinogens, as well as certain radioactive substances. The concept of chemical carcinogens, or blastomogens, originated from observations of occupational cancer, the first cases of which were described over 250 years ago. Without dwelling on the history of this issue (see the book by A.I. Serebrov and O.L. Donetskaya, Professional Neoplasms, Leningrad, 1976), it is important to note the following. In many types of occupational tumors, it has been firmly established that the tumor arises as a result of prolonged exposure to chemical products such as resins, coke, mineral oils, or intermediate products from the aniline and dye industry. It was quite clear that these agents were exogenous, that they were environmental influences that could cause cancerous tumors in humans (L.M. Shabad). According to the recollections of the laboratory's veterans, there was a period of disappointment in these experiments after five years of unsuccessful observations of the test animals. The administration of the kennel, while not openly expressing their doubts, was also pessimistic about the experiment, given the high cost of maintaining several dozen monkeys and the difficulties of caring for them. Indeed, it seemed that primates were completely resistant to conventional carcinogens. Only Nikolai Nikolayevich remained cheerful, using his lively mind and energy to joke and encourage his colleagues, confident in their success. Once again, Nikolai Nikolaevich's scientific foresight proved accurate, as a major breakthrough occurred in 1948 when the first signs of tumor growth were detected on radiographs in a monkey named Tomilla, who had received 30 mg of methylcholanthrene in a paraffin pill injected into her tibia. As the tumor progressed, the animal's lower limb was amputated to save its life. The morphological analysis of the tumor revealed the presence of a polymorphic cell sarcoma. Thus, for the first time in the world, a malignant tumor (bone sarcoma) was induced in monkeys. Nikolai Nikolaevich Petrov jokingly called this monkey Tomilla the Savior, as the experiments were not only continued, but the increased enthusiasm of the staff allowed for a significant expansion and deepening of these studies. During this period, the laboratory expanded, and the Sukhum Monkey Nursery became part of the USSR Academy of Medical Sciences as the Medical and Biological Station [4]. n 1948, a significant event occurred: a second monkey named Spartan developed bone sarcoma 8 years and 5 months after receiving a tube containing radioactive ore, and in 1949, similar bone sarcoma was observed in monkeys named Vampire and Red. As mentioned earlier, in 1952, a unique and fundamental monograph was published, summarizing the experiments conducted on monkeys: "The Dynamics of the Origin and Development of Malignant Growth in Monkey Experiments." The authors of the study, who were the first in the world to obtain malignant tumors – bone sarcomas – in four monkeys, N.N. Petrov, N.A. Krotkina, A.V. Vadova, and Z.A. Postnikova, were awarded the prestigious Mechnikov Prize for outstanding research in biological science. The authors of this work specifically noted that in monkeys, the bone marrow of long tubular bones is the most favorable object for such experiments as tumor induction, providing both the achievement of malignant growth and the possibility of observing its dynamics of occurrence and development [2]. The study conducted parallels of induced bone tumors in monkeys with bone sarcomas observed in humans. Long-term accumulation of quantitative changes was noted, leading to a new qualitative transformation, followed by a sharp acceleration of the process. The study also highlights the different morphogenesis of induced osteogenic sarcomas in monkeys, which can be fibroblastic, chondroblastic, or polymorphic. It is important to note that the study obtained sarcomas from various carcinogenic agents, including chemical and radioactive agents. The experimentally induced tumors in the two monkeys were well accepted in autotransplantation and did not produce results in homotransplantation. The main conclusion of this outstanding study states: "for the first time, the possibility of experimental carcinogenesis in primates has been definitively proven, both through chemical carcinogens and short-wave rays, and a corresponding methodology has been established" [4, 8]. Under the direct supervision of N.N. Petrov, R.A. Melnikov conducted a new series of experiments in 1955 to induce malignant tumors in the upper jaw of monkeys. In these experiments, new substances were used as carcinogenic agents: radioactive silver (Ag110) and cobalt (Co60), which were injected into the anterior wall of the maxillary sinus to potentially induce both sarcomas and carcinomas. Two and a half years later, in 1958, the first tumors appeared: a polymorphonuclear sarcoma of the upper jaw in a monkey named Snipe and a spindle-cell sarcoma in a monkey named Fraser. In the latter animal, a second malignant tumor, a squamous cell carcinoma of the tongue, was also induced. These experiments on the induction of tumors in the tubular bones, the upper jaw, and the tongue were presented in 1958 by N.N. Petrov and his colleagues at the Seventh International Anti-Cancer Congress in London [3]. The work of Russian scientists E.Ya. Smoilovskaya, A.V. Vadova, M.Ya. Podvalnaya, and I.A. Chachibaya, who used radioactive isotopes to induce breast carcinoma and skin melanoblastoma in monkeys, should be particularly emphasized. In further experiments by R.A. Melnikova and E.M. Barabadze, cancer of the maxillary cavity, fibrosarcoma of the upper jaw and lymphosarcoma of the lower jaw were obtained in monkeys. These studies were reported at the VIII International Cancer Congress in Moscow and the IX in Tokyo (Japan) [8]. N.A. Krotkina and E.M. Barabadze (1964), employees of the Laboratory of Experimental Oncology at the Sukhumi Nursery, gave two more new observations of induced tibial sarcomas in monkeys in an experiment where glass tubes with radium bromide were inserted into the bone. The laboratory worked hard and developed Nikolai Nikolaevich's idea of creating a transferable strain of malignant tumor in monkeys. At the same time, an urgent study was conducted on the relationship of hormonal disorders in the animal's body with the process of carcinogenesis. Unfortunately, these studies were not continued after the death of N.N. Petrov (1964) [2, 9]. R.A. Melnikov wrote (1976): "We were happy to contribute our small brick to the monument to our dear teacher: the monograph "Malignant Tumors in Monkeys" (by R.A. Melnikov and E.M. Barabadze), published in 1968 by the USSR Academy of Sciences, which summarized research on the induction of malignant tumors in primates." [4] Academician A.I. Serebrov, a student and close associate of N.N. Petrov, wrote in his book dedicated to Nikolai Petrov: "N.N. Petrov lived a relatively long life of 87 years, but in order to accomplish the immense work he did, he truly had to work non-stop. He worked from 6 a.m. until late at night, cherishing every minute, without Sundays or days off. N.N. Petrov hardly ever went to the theater, never went to the movies, and never watched TV. This was not because he was indifferent to life and art, but because he simply did not have enough time for it. His only passion, which remained with him until the end of his life, was poetry. He loved poetry and often recited the poems of his favorite poets, especially Fyodor Tyutchev and Aleksey Konstantinovich Tolstoy. He often used poetry to express his feelings in his letters. N.N. Petrov was a vibrant and passionate individual. His aspirations were determined early on, while still a student, and they were all related to science. "A scientist must know a lot, and therefore work hard." This was his motto, which he followed throughout his life." [2].Thus, more than 70 years ago, N.N. Petrov solved a number of complex and controversial issues in oncology in the way they are now included in the concept of the relationship between the tumor and the body. However, in some relevant issues, N.N. Petrov went even further (at least further than most of his contemporaries), particularly in the issue of the reversibility of the properties of tumor cells. The recognition of this possibility led Nikolai Nikolaevich to introduce the new term "malignization and demalignization" (1954), which, in terms of its content, was fully consistent with the concept of "carcinogenesis and anticarcinogenesis."Summing up our brief essay, we would like to note that we have focused on some of N.N. Petrov's priority scientific views in experimental oncology, which provide us with a vivid image of a scientist with a broad erudition who had his own views on all the fundamental theoretical issues in oncology. In defending his views, Nikolai Nikolaevich was not afraid to reconsider and refine his positions under the influence of new data, but the most valuable thing about him was his rare scientific intuition, which helped him to point out further ways for the development of medical science. As a result, many of his progressive thoughts and statements remain relevant today and continue to guide the search for more effective methods of cancer prevention and treatment.

              

                                   

About the authors

Lekso Z. Gurtskaia

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Author for correspondence.
Email: lekso.doc1610@mail.ru
ORCID iD: 0009-0004-4377-9269
SPIN-code: 3101-8876

MD, Cand. Sci. (Medicine)

Russian Federation, Saint Petersburg, Russia

Temuri Sh. Morgoshiya

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Email: temom1972@mail.ru
ORCID iD: 0000-0003-3838-177X
SPIN-code: 5560-2570

MD, Cand. Sci. (Medicine), Assistant Professor, Department of Faculty Surgery named after prof. A.A. Rusanov

Russian Federation, Saint Petersburg, Russia

Daria S. Pavlova

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Email: pavlova.0069@mail.ru
ORCID iD: 0009-0009-0886-4202
Russian Federation, Saint Petersburg, Russia

Anna N. Mirzoyan

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Email: mirzoyananna@bk.ru
ORCID iD: 0009-0004-2031-7723
Russian Federation, Saint Petersburg, Russia

Anna E. Yakovenko

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Email: tidalwave@mail.ru
ORCID iD: 0000-0002-1226-1764
Russian Federation, Saint Petersburg, Russia

Elisey V. Ababurko

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Email: elis.ababurko@gmail.com
ORCID iD: 0009-0007-5523-1307
Russian Federation, Saint Petersburg, Russia

Yulia A. Leshchenko

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Email: iulech@gmail.com
ORCID iD: 0009-0009-7909-8701
Russian Federation, Saint Petersburg, Russia

Angelina A. Burka

Saint Petersburg State Pediatric Medical University, Saint Petersburg

Email: burkaangelina010203@gmail.com
ORCID iD: 0009-0005-3309-7798
Russian Federation, Saint Petersburg, Russia

References

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