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является период времени от 12 до 16 часов. Для консультации обратились к профессору Губину, который с неподдельным вниманием и присущей ему научной интуицией указал, посмотрев данные обследования, что наше исследование выполнено грамотно, но требует тщательного математического анализа для подтверждения достоверности результатов. Несмотря на занятость, Геннадий Дмитриевич отправился в вычислительный центр. Там наши первичные данные были заложены в программу Косинор. Пока электронно-вычислительная машина проводила подсчёт результатов исследования и выводила исходные данные на бумагу, мы с ним вели беседу о перспектив-
ности проведённой нами работы. Меня очень вдохновило на дальнейшее проведение исследований то, что полученные машиной расчёты полностью совпадали с тем, что предположил профессор Г. Д. Губин. Иными словами, наше исследование на сто процентов подтвердило его гипотезу о хронобиологическом течении процессов центральной гемодинамики. Как впоследствии оказалось, наиболее благоприятным временем проведения ЛФК у травматологических больных является период от 12 до 14 часов.
Сведения об авторе
Прокопьев Николай Яковлевич, ФГБОУ ВО Тюменский государственный университет, г. Тюмень.
Prokopiev N. Y.
Tyumen State University, Tyumen, Russia
EMINENT RUSSIAN CHRONOBIOLOGIST, MENTOR AND TEACHER GENNADY GUBIN
The first issue of the Tyumen Chronomedical Journal (Journal of Chronomedicine), formerly Tyumen Medical Journal, the team of the Tyumen State Medical University and the Editorial Board dedicate to two remarkable Jubilees - the 90th anniversary of the founder of the Tyumen school of Chronobiology, one of the first researchers of biological rhythms in ontogenesis, the founder of the Department of Biology of the Tyumen Medical University, Gennady Gubin (b. 20.08.1928) and a very recent magnificent Jubilee, the 100th anniversary of Franz Halberg, one of the founders of modern chronomedicine (b. 5.07.1919).
Introducing the articles of the this first issue, most of which are devoted to the scientific heritage of these two outstanding scientists, one of the most fruitful former students of Gennady Gubin, today a prominent Tyumen scientist and biographer, author of multi-volume encyclopedias «Keeping grateful memory», Nikolai Yakovlevich Prokopiev shares his memories of the teacher.
Keywords: daily rhythm, history, chronobiology, circadian, Gubin Gennady, Tyumen, Institute, University.
DOI: 10.36361/2307-4698-2019-21-1-8-13
xGermaine Cornelissen, 2Kuniaki Otuska, 3,4Denis Gubin
1 Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2 Executive Medical Center, Totsuka Royal Clinic, Tokyo Women's Medical University, Tokyo, Japan
3 Department of Biology, Medical University, Tyumen, Russia
4 Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Science, Tomsk, Russia
HONORING GENNADY GUBIN AND HIS LIFETIME ACHIEVEMENTS
Gennady Dmitrievich Gubin (Figure 1) will be remembered primarily for his work on the ontogeny of circadian rhythms, a task continued by his son, Denis Gennadyevich Gubin. The first author first met Gennady in 1989 at a meeting in Halle, GDR. This was a time when ambulatory blood pressure monitors became more readily available. Using this technology, work had started at our laboratory to map the circadian rhythm of blood pressure and heart rate in health from womb to tomb for the derivation of time-specified reference values qualified by gender and age [1-5]. This line of work was in complete alignment with Gennady Gubins interests [6-11]. Not only could we document gender differences and changes in mean value as a function of age, important changes in the circadian waveform also came to light: a damping of the circadian amplitude, an advance in phase, which also became more labile in the elderly, and a more prominent post-prandial dip. A decrease with age of the circadian amplitude of different hormones related to the circulation had also been documented [12-14].
Keywords: Gubin Gennady, chronobiology, chronomedicine, ontogenesis, aging, circadian rhythm, biography.
Gennady Dmitrievich Gubin (Figure 1) will be remembered primarily for his work on the ontogeny of circadian rhythms, a task continued by his son, Denis Gennadyevich Gubin. The first author first met Gennady in 1989 at a meeting in Halle, GDR. This was a time when ambulatory blood pressure monitors became more readily available. Using this technology, work had started at our laboratory to map the circadian rhythm of blood pressure and heart rate in health from womb to tomb for the derivation of time-specified reference values qualified by gender and age [1-5]. This line of work was in complete alignment with Gennady Gubin's interests [6-11]. Not only could we document gender differences and changes in mean value as a function of age, important changes in the circadian waveform also came to light: a damping of the circadian amplitude, an advance in phase, which also became more labile in the elderly, and a more prominent post-prandial dip. A decrease with age of the circadian amplitude of different hormones related to the circulation had also been documented [12-14].
Figure 1. Gennady Dmitrievich Gubin, born on August 20, 1928, in Tyumen, Siberia, Doctor of Medical Sciences, Professor, and Academician of the Russian Academy of Natural Sciences, was the founder of a new scientific direction for the study of chronobiological and chronomedical problems in developmental biology. He was a member of the Problem Commission of the Russian Academy of Medical Sciences on Chronobiology and Chronomedicine, and Head of the Department of Medical Biology and Genetics of Tyumen State Medical Academy
The word ontogeny comes from the Greek ov, on (gen. ovtoq, ontos), i.e., «being; that which is», and from the suffix -geny from the Greek -"ysvaa -geneia, which expresses the concept of «mode of production» (https:// en.wikipedia.org/wiki/Ontogeny). Ontogeny is the origination and development of an organism, usually from the time of fertilization of the egg to the organism's mature form. The term is also used to refer to the study of the entirety of an organism's lifespan. Ontogeny, defined as the developmental history of an organism within its own lifetime, is often contrasted with phylogeny, which
refers to the evolutionary history of a species. While developmental (i.e., ontogenetic) processes can influence subsequent evolutionary (e.g., phylogenetic) processes, individual organisms develop (ontogeny), while species evolve (phylogeny). The term phylogeny derives from the two ancient greek words 9ÜX0V (phúlon), meaning «race, lineage», and "yévsaiq (génesis), meaning «origin, source» (https://en.wikipedia.org/wiki/Phylogenetics). Evidence for phylogeny comes from paleontology, comparative anatomy, and DNA sequence analysis, all leading to a phylogenetic tree or tree of life, a diagram showing a pattern of ancestor/descendent relationships, which continues to be modified as new knowledge accumulates.
These two branches of study were once linked by the theory of recapitulation, also called the biogenetic law or embryological parallelism, often expressed using Ernst Haeckel's phrase «ontogeny recapitulates phylogeny» (https://en.wikipedia.org/wiki/Ernst_Haeckel). Historically, this hypothesis stated that the development of the embryo of an animal, from fertilization to gestation or hatching (ontogeny), goes through stages resembling or representing successive stages in the evolution of the animal's remote ancestors (phylogeny). It was formulated in the 1820s by Etienne Serres, based on the work of Johann Friedrich Meckel. Whereas the theory of recapitulation has since been refuted, Haeckel's concepts of heterochrony and heterotopy, the fact that changes in the timing and positioning within the body of aspects of embryonic development would change the shape of a descendant's body compared to an ancestor's, are two key principles of modern evolutionary developmental (evo-devo) biology [15, 16].
Gennady Gubin deserves credit for his added consideration of time in studying ontogeny, by his careful assessment of circadian rhythm characteristics in inferential statistical terms for determining how they change throughout the lifespan. In the light of our shared research interests, it was not surprising that arrangements were made for his son Denis to come to Minnesota to conduct his Ph.D. thesis. It was a great opportunity for our joined teams to extend work on circadian rhythms to other components of the chronome (broad time structures), now that around-the-clock blood pressure and heart rate records spanning a week or longer were available for analysis from newborns to centenarians [1-5]. The first question examined was to determine how ultradians and infradians (components with periods shorter than 20 hours and longer than 28 hours) changed as a function of age. In view of the records' length and sampling intervals, focus was placed on the weekly and half-weekly rhythms and on harmonic terms of the circadian variation.
In an observational study of 72 individuals 12 to 106 years of age, the decreasing circadian amplitude of blood pressure with age was accompanied by an increase in infradian and ultradian prominence, notably of the weekly and half-weekly rhythms and the 3-hour component, Figure 2 [17, 18]. The day-to-day variability in circadian characteristics was also found to increase with age, indicated by an increase in the width of the
95% confidence interval of the circadian period of blood pressure. A variance transposition from the circadian to the neighboring ultradian and infradian domains was found to characterize the elderly human blood pressure chronome, and was proposed to serve as a new, technically implementable biological, rather than chronological, gauge of human aging. Using the amplitude ratio of the circaseptan versus circadian components, the changes with age found in this transverse study were also documented longitudinally in a unique record of a clinically healthy man spanning several decades [19], Figure 3.
the basic genetic input and the modifying environmental factors requires chronome mapping throughout ontogeny, as begun with Gennady and Denis Gubin.
Figure 2. Multiseptan prominence of blood pressure at extremes of human lifespan. © Halberg Chronobiology Center
The week and half-week had been found to be very prominent early in extrauterine life, documented in hundreds of full-term and premature babies monitored in several cooperating centers worldwide, from Italy, Spain, the Czech Republic, Germany and Russia to Japan and Minnesota, where more recent studies on twins provided evidence for their partly endogenous nature [20]. A resurgence of circaseptan and circasemiseptan components in the elderly constitutes a novel feature of human aging. An understanding of the mechanisms underlying the formation of a collateral hierarchy of rhythms and the elucidation of the relative contributions of
Figure 3. Longitudinal confirmation of changes in the circaseptan-to-circadian amplitude ratio of blood pressure previously observed transversely. Self-measurements from a clinically healthy man. © Halberg Chronobiology Center
The study of mechanisms underlying the biologic week and half week is overdue. Some about-weekly and half-weekly variations, just as circadians, reflect direct or indirect human influences, but they need not be all viewed as mere technogenous or other societal artifacts. About-weekly and half-weekly components have been found to characterize planetary and interplanetary magnetic field disturbances [1], adding to the external factors that need to be specified and considered in biomedicine. Initially, circaseptans and circasemiseptans may have been no more than resonances of living matter with cycles in their environment. But evidence for their partly endogenous nature also stems from their demonstration in early phylogeny in prokaryotic and eukaryotic unicells. In Euglena gracilis (Klebs), the circaseptan observed in cell division of the wild-type may become a circasemiseptan via mutation [21]. Likewise, in Acetabularia, the circaseptan observed in light transmission may become a circasemiseptan after enucleation [22]. There is much further evidence for a partly built-in biologic week, found primarily in relation to growth and repair mechanisms
[23]. In the rat, circaseptans were found to be prominently expressed in dentin accretion, a variable representing growth, even in the absence of a stimulus in continuous light under free-running conditions, and to remain prominent after lesioning of the suprachiasmatic nuclei
[24]. A genetically anchored, environmentally resonant
biological week and half-week in vitro and in vivo intermodulate with other components of broader time structures to reveal rhythmic 3- or more-way feedsideward mechanisms in which, for mammals, melatonin plays the role of modulator via pituitary target gland and/or cellular interactions [25].
of Medical Sciences. It was then presented on July 1, 1997, by invitation at a symposium on environmental adaptation, held in St. Petersburg, Russia, at the XXIII International Congress of the International Union of Physiological Sciences [31]. The aim of such a formalized international womb-to-tomb chronome initiative is the mapping of ubiquitous time structures in health and their alterations in disease, for the consideration of a new chronomedically validated trichotomy of «wellness' (validated by euchronomes) versus «disease risk syndromes' (catachronomes) versus «illness' (dyschronomes). In the BIOCOS resolution, coordinated physiological and physical monitoring is advocated for reasons that are equally pertinent to the mainstream of health care [32-35] and to space research [36-39].
Figure 4. The transyear predominates over the calendar year at birth in the human circulation, whereas the opposite holds true during mid-adulthood. In the elderly, the transyear regains relative prominence over the calendar year. © Halberg Chronobiology Center
Just as circaseptan variations can be more prominent than circadian changes in certain variables and at certain ages, the relative prominence of non-photic components such as the transyear, with a period of about 1.3 years, can also be more prominent than the yearly changes from summer to winter. As in the case of changes in the relative prominence of circaseptans versus circadians in variables related to the circulation of human babies and in the elderly, the relative prominence of transyears versus the calendar year is much larger in early extrauterine life and in the elderly than in mid-adulthood [26] (Figure 4), perhaps because the former are less synchronized with their socioecological yearly cycles [27]. A similar course with ontogeny is thus found for both the circaseptan-to-circadian and for the transyear-to-circannual amplitude ratios of human blood pressure and heart rate. Curiously, the transyear also overshadows the circannual variation in the case of oxygen evolution in Acetabularia [28], Figure 5. Ontogenetic and comparative studies may thus contribute as ontogenetic and phylogenetic memories to locating the sites and time course of life on earth by the sequences of integration of the rhythms into our genome, possibly revealed by their relative prominence in ontogeny and phylogeny [29].
The information to be gained from a systematic and comprehensive mapping of the ontogeny of broad time structures in biota and of the environment in which they evolved led to the project on the BIOsphere and the COSmos (BIOCOS), still ongoing [30]. This project was unanimously endorsed at a meeting called specifically for its discussion, in Moscow on June 30, 1997, under the aegis of and in the main building of the Russian Academy
Figure 5. An about-yearly component is neither the sole nor the largest infrannual variation characterizing Acetabularia's oxygen evolution*. © Halberg Chronobiology Center
The 1994 meeting of the Chronobiology and Chronomedicine Committee in Ekaterinburg, Russia, remains vivid in the first author's memory, where she met Gennady Gubin for the last time. It was on her birthday. He was there with Denis, with whom his legacy is kept alive and with whom cooperation continues to this day. To the association of cardiovascular disease risk with abnormal patterns of blood pressure and heart rate [40], following in his father's footsteps, Denis is uncovering relationships between abnormal patterns of body temperature with progression toward non-insulin dependent diabetes mellitus [41] and with progressive retinal ganglion cell loss in primary open-angle glaucoma [42]. Now that a molecular basis has been uncovered as the foundation of the circadian system, work remains to be done to account for basic mechanisms underlying the many other rhythms that most likely have also entered our genetic makeup.
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'Корнедиссен Ж., 2Отцука К., 3,4Губин Д.
1 Хронобиологический Центр им. Ф. Халберга, Университет Миннесоты, Миннеаполис, США
2 Исполнительный медицинский центр, Королевская Клиника Тоцука, Токийский Женский медицинский университет, Токио, Япония
3 ФГБОУ ВО Тюменский государственный медицинский университет, Тюмень
4 Тюменский кардиологический научный центр, Томский национальный исследовательский медицинский центр РАМН, Томск, Россия
ПОСВЯЩЕНИЕ ГЕННАДИЮ ГУБИНУ И ЕГО ТВОРЧЕСКОМУ НАСЛЕДИЮ
Геннадия Дмитриевича Губина (рис. 1) мировое научное сообщество будет помнить прежде всего за его работы в области исследований онтогенеза циркадианныхритмов, которую продолжает его сын, Денис Геннадьевич Гу-бин. Первый автор (Жермен Корнелиссен) впервые встретилась с Геннадием в 1989 году на встрече в Галле, ГДР. Это было время, когда амбулаторные мониторы артериального давления стали более доступными. Используя эту технологию, в нашей лаборатории была начата работа по картированию циркадного ритма артериального давления и частоты сердечных сокращений в здоровом состоянии от начала до конца жизни человека для получения зависимых от фактора времени референтных значений с учетом пола и возраста [1-5]. Это направление работы полностью соответствовало интересам Геннадия Губина [6-11]. Мы смогли не только зафиксировать гендерные различия и динамику средних значения в зависимости от возраста, но и выявить ключевые возрастные особенности изменений циркадианной организации и структуры вариабельности: затухание цир-кадной амплитуды, смещение фазы, которая также становится более лабильной у пожилых людей, и более выраженное дневное снижение артериального давления. Впоследствии было установлено снижение с возрастом циркадной амплитуды различных гормонов, взаимосвязанных с циркуляцией и гемодинамикой [12-14]. Ключевые слова: Губин Геннадий Дмитриевич, хронобиология, хрономедицина, онтогенез, старение, циркади-анный ритм, биография.
40. Otsuka K, Cornelissen G, Halberg F. Chronomics and Continuous Ambulatory Blood Pressure Monitoring -Vascular Chronomics: From 7-Day/24-Hour to Lifelong Monitoring. Tokyo: Springer Japan, 2016, 870 + lxxv pp. 10.1007/978-4-431-54631-3.
41. Gubin D, Nelaeva AA, Uzhakova AE, Hasanova YV, Cornelissen G, Weinert D. Disrupted circadian rhythms of body temperature, heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus. Chronobiology International 2017; 34 (8):1136-1148.
42. Gubin DG, Malishevskaya TN, Astakhov YS, et al. Progressive retinal ganglion cell loss in primary open-angle glaucoma is associated with temperature circadian rhythm phase delay and compromised sleep. Chronobiology International 2019; doi: 10.1080/07420528.2019.1566741.
Сведения об авторах
Cornelissen Germaine, Хронобиологический Центр им. Ф. Халберга, Университет Миннесоты, Миннеаполис, США.
Otsuka Kuniaki, Исполнительный медицинский центр, Королевская Клиника Тоцука, Токийский Женский медицинский университет, Токио, Япония. Gubin Denis, ФГБОУ ВО Тюменский ГМУ Минздрава России, Тюмень; Тюменский кардиологический научный центр, Томский национальный исследовательский медицинский центр РАМН, Томск, Россия. Адрес для переписки: e-mail: corne001@umn.edu.
