The brilliance and poverty of medical genetics

Medical genetics in RussiaA. M. Polishchuk, Doctor of Medical Sciences

"Chemistry and Life" No. 2, 2010
The abridged version is published on the website "Elements"A.M. Polishchuk graduated from the 1st Leningrad Pavlov Medical Institute in 1963 - just when genetics in our country was coming out of hiding.

He studied in postgraduate studies at the Laboratory of Radiation Genetics of the Institute of Cytology and Genetics of the SB Academy of Sciences of the USSR in Novosibirsk under the supervision of Yu. Ya. Kerkis. From 1978 to 1982, he headed the Department of Biology and Genetics of the Tomsk Medical Institute, from where he left under pressure from the KGB (suspected of storing and distributing anti-Soviet literature). A direct participant in the restoration of medical genetics.

Emergence and flourishingBoth in Russia and in the West, medical genetics originated from eugenics, the part of it that set out to prevent the birth of people with physical and mental hereditary defects.

In the early 30s of the last century, this science reached the peak of popularity in society, even reflected in the legislation of many countries of the world. However, at the end of the 30-40s in Nazi Germany, it was replaced by the doctrine of the election of the Aryan race, the purity of which was to be maintained through racial policy. As part of this policy, forced sterilization and mass killings of people who were considered of little value were carried out. All this discredited eugenics, and its very name has long been associated with the concepts of "Nazism" and "fascism". At the same time, the rapid development of genetics has shown a real possibility of diagnosing and preventing hereditary human diseases, which, in fact, was the goal of that part of eugenics, which was called negative. Therefore, it continued to develop as an independent direction, but already under the name "medical genetics". <...>

In Russia, the beginning of the eugenic movement should be dated to 1865. Then in the magazine "Russian Antiquity" were published essays by V. M. Florinsky, in which the ideas of improving the human breed were developed. Eugenics in Russia and the USSR was particularly closely related to genetics, since they were engaged in the same people. They were created mainly by the efforts of two young talented scientists: N. K. Koltsov in Moscow and Yu. A. Filipchenko in Petrograd.

Nikolai Konstantinovich Koltsov.

Russian Russian Eugenic Society was founded in 1920 by N. K. Koltsov in Moscow, at which the "Russian Eugenic Journal" was published. In 1920, a eugenic department was organized at the Institute of Experimental Biology (IEB), headed by N. K. Koltsov, which launched research on human genetics. The first works on inheritance of blood groups, catalase content in the blood, inheritance of hair and eye color, variability and heredity of complex traits using the twin method were started here. The first medical and genetic consultation worked at the department.

In 1921, Y. A. Filipchenko organized a Eugenics Bureau in Petrograd, where, in particular, a unique population-genetic study of human creative abilities was carried out. <...> The vast majority of scientists who made a decisive contribution to the formation and development of medical genetics in our country were either students of Koltsov and Filipchenko, or students of their students.

Yuri Alexandrovich Filipchenko

The official date of the emergence of medical genetics as an independent discipline in Russia should be considered May 15, 1934. On this day, at a conference at the Medical and Biological Institute, its director Grigory Solomonovich Levit made a report "Anthropogenetics and Medicine", in which he defined a new discipline. The historian of genetics V. V. Babkov described its significance as follows: "Levit became the founder of Russian medical genetics, formulated its key principles and ideas." <...> In 1928, he organized the Cabinet of Heredity and Human Constitution at the Medical and Biological Institute in Moscow. In 1930, the Office was expanded to the Genetic Department of the Medical and Biological Institute, and Levit was appointed its director, which allowed him to refocus the institute's topics on human genetics. In 1935, the institution was renamed the M. Gorky Scientific Research Medical and Genetic Institute. The work here developed in three directions: clinical and genetic, twin and cytological. <...>

Solomon G. Levit

In the field of clinical and genetic research, the works of S. N. Davidenkov on the genetics of amyotrophic lateral sclerosis and Leviticus on various manifestations of most pathological mutant human genes were of great importance. Fundamentally important was the remarkable theoretical study of V. P. Efroimson, carried out in 1932, on the balance between the accumulation of mutations and the intensity of selection. In it, the scientist estimated the rate of the mutation process in humans. The "twin" direction was successfully developing. By 1933, the study covered 600 pairs of twins. Interesting results were obtained on the role of heredity and environment in the physiology and pathology of the child, in the variability of the electrocardiogram, in the manifestation of some mental signs. In the cytological direction, it is necessary to name the studies conducted in the laboratories of P. I. Zhivago and A. G. Andres at the Institute of Experimental Biology and at the Medical-Genetic Institute. These include the development by G. K. Khrushchev and E. A. Berlin of a method for culturing blood cells for karyological analysis (analysis of the number and external structure of chromosomes. – Ed. note), as well as the analysis of the fine morphological structure of the human chromosome carried out for the first time in the world by A. G. Andres and M. S. Navashin. Emphasizing the importance of these works, the president of the III International Congress on Human Genetics, L. S. Penrose, said in 1966: "If these laboratories in the USSR had continued to work, most of the discoveries on the human karyotype made over the past nine years could have appeared twenty years earlier."

In Leningrad, medical genetics developed thanks to the activities of a major specialist in nervous diseases S. N. Davidenkov. <...> He began to study the genetics of nervous diseases in Moscow at the institute headed by Levit. In 1932 he moved to Leningrad, where he headed the Department of Nervous Diseases at the Leningrad Institute of Advanced Medical Training. Remarkable works on the genetics of diseases of the nervous system were carried out here. <...>

By the end of the 30s, medical genetics in the Soviet Union, both in theory and in practice, corresponded to the highest international standards. But just at the moment when its powerful take-off was prepared, the development of medical genetics in the USSR was abruptly cut short.<...>

The debacleThe peak of the defeat of medical genetics occurred during the years of the Great Terror (1936-1939), but it began much earlier, and the "unfinished" during this period were repressed after the August 1948 session of the VASHNiL (All-Union Academy of Agricultural Sciences named after V. I. Lenin). <...>

The fate of many geneticists, including S. G. Levit, has tragically developed. In 1936, he was expelled from the party "for associating with the enemies of the people, for pushing hostile theories in the works of the institute and for Menshevik idealism." He was also blamed for signing a letter in defense of an arrested friend, and for trying to criticize the work of T. D. Lysenko at a meeting. In 1937, Levit was dismissed from his position as director, and the institute was closed. A year later, he was arrested, sentenced to death for terrorism and espionage and shot. Levit was rehabilitated posthumously in 1956. <...> V. P. Efroimson was arrested three times. Professor S. N. Davidenkov was also persecuted. His scientific works on medical genetics were not published, and his doctorate at the Leningrad Institute of Advanced Medical Training was closed. Koltsov was dismissed from the post of director of the IEB and died of a myocardial infarction in the same 1940. <...>

During the Great Patriotic War, the repressions subsided noticeably, but intensified again in 1946. <...> The defeat occurred in August 1948 at the session of the VASHNiL, where genetics was branded as "bourgeois pseudoscience". The August session of the VASNIL served as a signal for a large-scale campaign to defeat "idealistic" biology in the Soviet Union. Already on August 24-26, an expanded meeting of the Presidium of the Academy of Sciences of the USSR took place, on September 4 – the Presidium of the Academy of Pedagogical Sciences of the RSFSR, on September 9-10 – the Presidium of the Academy of Medical Sciences of the USSR. At this meeting, the Presidium of the USSR Academy of Medical Sciences officially banned medical genetics. All these meetings of the highest scientific institutions of the country were devoted to the introduction of the "only true", "materialistic" "Michurinsky" biology. Organizational issues followed: the dismissal of geneticists and their replacement by Lysenko's supporters (about 3 thousand scientists were dismissed or demoted), the revision of biology and genetics programs at universities, medical and pedagogical universities, scientific plans at research institutes and laboratories. An official ban was imposed on genetics, which lasted until 1964. <...>

Recovery<...> The development of nuclear energy, nuclear weapons and cosmonautics, despite the prohibitions, stimulated the resumption of work on human cytogenetics.

For these industries, it was necessary to be able to assess the danger of radioactive radiation and develop methods of radiation protection. In 1956, a laboratory of radiation genetics was organized in Moscow at the Institute of Biological Physics of the Academy of Sciences. The well-known geneticist N. P. Dubinin, who worked as an ornithologist in the Urals after the session of VASHNiL, was invited as the head. He gathered geneticists who were excommunicated from science after the 1948 pogrom, and launched work on radiation mutagenesis. The laboratory also conducted a cytogenetic examination of testers preparing to become astronauts.

In 1957, as part of the Siberian Branch of the USSR Academy of Sciences (Novosibirsk) The Institute of Cytology and Genetics (ICiG SB of the USSR Academy of Sciences) was organized. N. P. Dubinin was appointed Director. As in Moscow, he began to collect geneticists expelled from science. In particular, he invited Yu. A. Filipchenko's student, Yu. Ya. Kerkis, to the position of head of the Laboratory of Radiation Genetics. Kerkis and his collaborators were among the first in the world to use human cell culture as an object of research to determine the dose of radioactive radiation doubling the frequency of spontaneous mutations, and showed that this dose is equal to 8-10 X-rays.

In 1958, a commission on medical genetics was established in the Presidium of the Academy of Medical Sciences of the USSR, but it was headed by a faithful Lysenkoist, academician of the Academy of Medical Sciences N. N. Zhukov-Verezhnikov. A microbiologist by profession, he, to put it mildly, was not a major specialist in the field of medical genetics. Therefore, the commission led by him included in the State Plan for the Development of Science for the next five years the problem of "Correcting corrupted genetic information in humans by targeting corrupted genes." Only blatant ignorance could explain such a statement of the problem: in those years there were not even approaches to solve it. Specialists took a lot of effort to convince the Presidium of the AMN to dissolve this commission. Instead, largely thanks to the efforts of A. A. Prokofieva-Belgovskaya and V. P. Efroimson, the Council for General and Medical Genetics was established under the chairmanship of Academician I. D. Timakov. <...>

Alexandra Alekseevna Prokofieva-Belgovskaya

Back in 1958, S. N. Davidenkov organized a Medical and Genetic Laboratory of the Academy of Medical Sciences in Leningrad, which was headed by E. F. Davidenkova after his death in 1961. Another center for the revival of medical genetics in Leningrad was the Institute of Experimental Medicine of the USSR Academy of Medical Sciences. In the early 60s, at this institute, S. A. Neifakh organized one of the first biochemical genetics laboratories in the country, where research on the molecular mechanisms of hereditary diseases began. <...> S.A. Neifakh was one of the first in the world to express the idea of the role of mitochondrial DNA mutations in the etiology of diseases inherited through the maternal line. As a result of studying the biochemical and genetic aspects of phenyl-pyruvic oligophrenia, his student A.M. Shaposhnikov in 1967 created the country's first diet for the treatment of phenylketonuria. <...>

The most rapid revival of medical genetics took place in Moscow, largely due to the activity of A. A. Prokofieva-Belgovskaya. In the late 50s – early 60s, publications appeared abroad about new methods of chromosome analysis that allow us to assess their role in human pathology, as well as to test the mutagenic activity of various influences on cultured human cells. There were practically no personnel with such techniques in the USSR. A. A. Prokofiev-Belgovskaya made a huge contribution to the elimination of this gap. She headed two laboratories: the Laboratory of Karyology at the Institute of Molecular Biology of the USSR Academy of Sciences (1962) and the Laboratory of Cytogenetics at the Institute of Human Morphology of the USSR Academy of Medical Sciences (1964). On the basis of the first one, the chromosomes of testers preparing for space flights were examined. Here, V. M. Gindilis evaluated the quantitative parameters of human chromosomes and obtained quantitative characteristics of individual chromosomes. Before the advent of differential staining methods, this was the only method of identifying human chromosomes. Another employee of this laboratory, A.V. Mikelsaar, for the first time in the USSR investigated the genotype-phenotype correlation in humans, studying the chromosomes of children with multiple malformations. There Prokofieva-Belgovskaya organized courses to train doctors in cytogenetics methods. Dozens of doctors took these courses in 1962-1964.

At about the same time, Professor E. F. Davidenkova conducted similar courses in Leningrad. They were part of a program to create a medical and genetic service, the project of which was worked on by A. A. Prokofieva-Belgovskaya, E. E. Pogosyants, V. P. Efroimson with the participation of young colleagues, K. N. Grinberg and V. M. Gindilis.

In the second laboratory, where K. N. Grinberg, a young geneticist from the Institute of Atomic Energy of the Academy of Sciences, was invited as a deputy to Prokofiev-Belgovskaya, intensive research was launched in the field of the chromosomal nature of a number of diseases and developmental defects in humans. The first specialists in medical genetics who became famous and taught the next generation were brought up in this laboratory: O. Podgugnikova, V. Kukharenko, A. Revazov, G. Mirzayants, Yu. Seleznev, A. Sinkus, A. Kuliyev. In 1963, a Cytogenetics Laboratory was organized at the Institute of Experimental and Clinical Oncology of the Academy of Medical Sciences, in which, under the leadership of E. E. Pogosyants, the study of the cytogenetics of leukemia in humans began. As can be seen, the restoration of medical genetics began mainly with human cytogenetics and took place within the framework of AMN and AN.

The beginning of the restoration of the "clinical part" of medical genetics can be considered the publication of V. P. Efroimson's book "Introduction to Medical Genetics", published in 1964 after a three-year struggle with the Lysenkoites. This book has been the only manual on medical genetics for thousands of Russian doctors for many years.

In September 1965, at a meeting of the Presidium of the USSR Academy of Sciences, the methods and results of Lysenko's activities were openly criticized for the first time, and the ban on genetics was lifted. <...>

In 1967, G. I. Lazyuk organized a Laboratory of Teratology and Medical Genetics in Minsk, which eventually became the largest institution in the country to study the causes and epidemiology of congenital malformations. Later, the laboratory was transformed into a branch of the IMG of the USSR Academy of Medical Sciences. In the same year, V. P. Efroimson became head of the Genetics Department of the Moscow Institute of Psychiatry of the RSFSR. The work on the genetics of oligophrenia, psychosis, epilepsy, schizophrenia unfolded here. In 1969, under the guidance and with the author's participation of Prokofieva-Belgovskaya, the book "Fundamentals of Human Cytogenetics" was published, which became an important textbook for doctors and biologists engaged in medical genetics.<...>

The most important event was the establishment of the Institute of Medical Genetics (IMG) in 1969. N. P. Bochkov, a student of the outstanding geneticist N. V. Timofeev-Resovsky, was appointed director of the Institute. This institute has become the country's leading and coordinating institution for medical genetics. The Laboratory of Human Cytogenetics, headed by A. A. Prokofieva-Belgovskaya, was transferred to it, the Laboratory of General Cytogenetics under the leadership of A. F. Zakharov and the Laboratory of Mutagenesis and Population Cytogenetics, headed by N. P. Bochkov, were organized. In addition, the staff of the Moscow Medical and Genetic Consultation joined the institute, which became the basis of the Laboratory of Clinical Genetics.

In the early years of the institute's existence, cytogenetic laboratories set the tone. In the Laboratory of Human Cytogenetics, research focused on three areas: the phenogenetics of chromosomal abnormalities at the cellular level, the cytogenetics of spontaneous abortions and polymorphism of heterochromatin regions of human chromosomes (a variety of compacted, inactive sections of chromosomes. In the course of these studies, a museum of cultured human cells with chromosomal and gene mutations was created at the Institute, which soon became the basis of the All–Union Collection of Cell Cultures. Another direction – human population cytogenetics – was headed by N. P. Bochkov. Back in 1967, he organized a newborn examination in Moscow to determine the frequency of X-chromosome abnormalities. These studies were continued at IMG. By the beginning of the 70s, 6000 newborns were cytogenetically examined and the frequencies of various chromosomal abnormalities, as well as the frequency of chromosomal and gene mutations in humans were estimated. <...> The Institute began developing screening programs for early diagnosis and prevention of hereditary diseases, research on developmental genetics (V. I. Ivanov) and population genetics of hereditary diseases (E. K. Ginter).

In 1982, on the initiative of N. P. Bochkov, the Tomsk Department of IMG was opened. It included a Laboratory of Human Population Genetics and a Laboratory of Cytogenetics. The head of the department was invited by a young energetic associate professor of the Novosibirsk Medical Institute V. P. Puzyrev. Five years later, he headed the Research Institute of Medical Genetics as part of the Tomsk Scientific Center of the Siberian Branch of the AMN, organized on the basis of the department. <...>

Medical genetics in Leningrad received a new impetus to development in 1987, when V. S. Baranov came to the Institute of Obstetrics and Gynecology of the D. O. Ott Medical Academy, who created and headed the Laboratory of Prenatal Diagnostics of Hereditary and Congenital Diseases. They quickly established all the methods of invasive prenatal diagnosis of hereditary diseases known at that time. One of the main directions was the development of the scientific foundations of genodiagnostics of common hereditary diseases, in particular, methods of DNA diagnostics of cystic fibrosis and Duchenne myodystrophy. Two years later, the Federal Center for Prenatal Diagnosis of Cystic Fibrosis was opened on the basis of the laboratory.

With the advent of domestic computers in the country, genetic analysis of quantitative human traits began to develop, mainly multifactorial diseases (determined by a combination of many factors, both hereditary and environmental factors. In 1969, V. M. Gindilis headed the group of medical genetics at the Institute of Psychiatry of the USSR Academy of Medical Sciences. Here he and his collaborators developed a method of multivariate analysis of genetically determined traits, which allows quantifying the contribution of genetic factors to the development of endogenous psychoses. A little later, in the mid-80s, a well-known specialist in the field of genetic analysis of quantitative traits E. H. Ginzburg from ICIG SB AN turned to the study of the genetics of multifactorial diseases. <...>

Among the theoretical achievements, it should be noted the hypothesis of M. D. Golubovsky about the existence of a dominant mutation in men that causes double (two sperm) fertilization of an egg. This can lead either to triploidy and subsequent miscarriage, or to a bubble drift, or to the formation of chimeras. The hypothesis <...> predicted the existence of a third, hitherto unknown, type of twins – polutorazygous, in which the maternal genomes are the same, and the paternal ones are different. 20 years later, this type of twins was discovered in an independent study.

Genetics – PracticeThe medical and genetic service in the system of practical healthcare was the slowest to recover.

One of the reasons for this was the appalling genetic ignorance of doctors. Already in those years it was known that at least 8% of the population needed medical and genetic counseling. To help them, a wide network of medical and genetic consultations and a good genetic education of doctors are needed, since they are the ones who refer patients for consultation. However, after almost 30 years of prohibition of genetics, there was no need to talk about the competence of doctors in this matter. So, at the end of the 60s, a consultation was held in the Moscow Children's Neuropsychiatric Dispensary to discuss a seriously ill child with multiple malformations. The cytogeneticist present reported that the child had a deletion of the short arm of chromosome 18. To this, one of the doctors remarked: "Well, you know, deletion is deletion, but do not forget that the child underwent surgery for a hernia under general anesthesia." <...>

The results of a survey conducted in 1978 in two districts of Moscow can be considered typical for that time: out of 530 doctors, only two answered questions on medical genetics. It was only in the late 80s and early 90s that specialized departments in medical universities began to be created. In 1988, N. P. Bochkov organized the Department of Medical Genetics at the 1st Moscow Medical Institute. In 1989, E. I. Schwartz created a similar department at the Leningrad Pediatric Institute as part of a scientific and educational complex, including the Laboratory of Human Molecular Genetics of the LIAF of the USSR Academy of Sciences. Students were taught not only general medical genetics and private sections of molecular medicine, but also practical methods of DNA diagnostics. Later, departments of medical genetics began to appear in other medical institutes. <...>

The first medical and genetic consultations arose on the initiative and under the patronage of academic institutions. Thus, specialists in medical cytogenetics began to be trained in the early 60s on the basis of laboratories in Moscow under the leadership of A. A. Prokofieva-Belgovskaya and in Leningrad under the leadership of E. F. Davidenkova. In 1964, Yu. Ya. Kerkis in Novosibirsk (ICiG SB AN) organized one of the first workshops in the country on human karyology, where doctors of Siberia and the Far East were trained in metaphase analysis of chromosomes. He also initiated the creation of a Medical Genetic Consultation (MGK) in Novosibirsk and put a lot of effort into its formation, in particular for the organization of a cytogenetic laboratory at MGK. <...>

In April 1967, an order was issued by the Minister of Health of the USSR on medical and genetic assistance to the population. The first consultations appeared in Moscow at the children's Neuropsychiatric dispensary No. 6 and in Leningrad, on the basis of the 11th children's polyclinic. Then there were consulting rooms on medical genetics at republican, regional and regional hospitals. By 1979, there were 45 such offices in the country, but this was not enough, and three medical and genetic centers were created. <...> Over the next five years, the number of advisory offices reached 85. In Moscow, Leningrad, in the Belarusian and Lithuanian SSR, mass diagnostics of phenylketonuria in newborns was introduced, their treatment and medical examination were organized. More than 700 doctors, including laboratory assistants, have been trained in medical genetics at the Department of the Institute of Advanced Medical Education of the Ministry of Health of the USSR. <...>

The obvious progress still did not meet the needs of practical healthcare. <...> Methods of prenatal diagnosis of hereditary diseases using amniocentesis and chorionic villus biopsy were carried out only in individual research institutes and were never introduced into widespread healthcare practice. The country has not created a system for organizing assistance to patients with hereditary diseases and their families. Therefore, the former medical and genetic centers were abolished, and republican and interregional medical and genetic centers were formed instead. <...> By the time of the collapse of the USSR, 85 medical and genetic consultations and offices were operating in the country, including 10 interregional ones. Departments of medical genetics are organized in seven medical universities. Ultrasound screening of pregnant women was widely used, examination of newborns for congenital hypothyroidism was started.

Lag and new obstaclesDespite the successes, medical genetics in the USSR by the end of the XX century still lagged far behind the Western one.

In 1964-1995, science there stepped far ahead. By the mid-90s, the genes of sixty new human diseases were mapped, the genes of predisposition to breast cancer in women were identified, methods of fluorescent hybridization in situ were developed and put into practice. <..> Soviet medical genetics did not occupy the place in world science where it was in the 30s, and in this sense, she never recovered after the defeat. The main reasons were insufficient financial support, the voluntaristic nature of the distribution of funds and unsatisfactory training in universities. <..> Dissent was suppressed, it was not always possible to publish a work on the history of genetics, the genetics of behavior and the genetic approach to social phenomena. For example, M. D. Golubovsky, for an article published in 1966 in the popular magazine Radio and Television, was accused that his statements were "contrary to the party program, to the fundamental statements of V. I. Lenin, to the fundamental provisions of Soviet legal science." Golubovsky, on the other hand, only argued that intelligence, as well as antisocial behavior, are formed both under the influence of heredity and upbringing, and doubted "that by changing social conditions it is possible to achieve the complete elimination of crime."

Three years later, A. A. Prokofieva-Belgovskaya and K. N. Grinberg published an article entitled "Heredity" in the journal "Health" (1969, No. 11). The article was considered by a special commission of the Presidium of the AMN, created on behalf of the Central Committee of the CPSU. By order of the USSR Academy of Medical Sciences, the authors were put on view for the fact that they lack "a critical assessment of the views of F. Galton and other bourgeois scientists on the determining role of heredity in the formation of mental abilities and forms of human social behavior."

In 1971, an article by V. P. Efroimson "The Pedigree of Altruism" appeared in the Novy Mir magazine. The author argued that such a complex sphere of the human spirit as ethics is formed under the combined influence of heredity and upbringing and that natural selection has contributed to the formation of ethical principles of modern man. The article was accompanied by comments by academician B. L. Astaurov (also a student of Koltsov), in which he supported and explained the main provisions of Efroimson's work. Both articles were discussed at a meeting of the Science Department of the Central Committee of the CPSU, at which academician N. P. Dubinin described the articles as a relapse of bourgeois eugenics in its worst forms. Efroimson's book "Genetics of Ethics and Aesthetics", written in the late 70s, was published only in 1995. The same fate befell his book "The Genetics of Genius", which could not get into print for more than 20 years and was published only in 1998. In 1976, the laboratory of V. P. Efroimson at the Institute of Psychiatry was closed. A tape recording of Prokofieva-Belgovskaya's report on her scientific life, read on the day of her 80th birthday (in 1983) at a meeting of the IMB scientific council, was "arrested", and it was published only ten years later, since the jubilee's report touched on the history of medical genetics.

Gorbachev's perestroika, the collapse of the USSR and the ban on the activities of the CPSU in 1991 had twofold consequences for science. On the one hand, the ideological dictate of the CPSU has stopped, and scientists have gained freedom of creativity. On the other hand, state funding of science has practically stopped. The process of "brain drain" has begun. With this problem, Russian science has entered the XXI century.

The author is grateful to V. S. Akhunov, M. M. Ginzburg, M. D. Golubovsky, N. M. Gorenstein, E. D. Krupnikov and O. A. Podugolnikova for their help, critical comments and interest in the work.

Portal "Eternal youth" http://vechnayamolodost.ru22.06.2010