ESSAY｜TOWARD JES 100TH ANNIVERSARY
“Endocrine Supremacism” of new version in the Anthropocene
2023 Volume 70 Issue 3 Pages 233-240
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2023 Volume 70 Issue 3 Pages 233-240
The Japan Endocrine Society (JES) was founded in 1927 by Dr. Kanji Tsuji at the Faculty of Medicine, Kyoto Imperial University. Boasting a long history, second only to the US Endocrine Society, which was founded in 1922, we celebrated the 90th anniversary of the JES in 2017. Currently, we are preparing for our centennial anniversary. The origins of endocrinology in Japan date back to adrenalin crystallization by Dr. Jokichi Takamine in 1900, making Japan a pioneer of this medical field. Owing much to a great many distinguished pioneers, JES now stands as a world leader in endocrinology.
In 2015, I assumed office as its 21st president, advocating the slogan “PAX ENDOCRINOLOGIA Endocrine Supremacism” supporting further prosperity of JES (Fig. 1). This was also the main theme of the 88th Annual Congress of JES in 2015, which I presided over. I appealed to all members to feel proud of the fact: “Hormones are the basic substances for all biological phenomena, and endocrinology is fundamental for the understanding of homeostasis and pathogenesis of all diseases.” At the JES Summer Seminars on Endocrinology & Metabolism and Regional Branch Meetings that followed, this idea was incorporated into the themes “Endocrine Supremacism 2,” “Endocrine Supremacism 3,” and “Endocrine Supremacism—What We Want to Pass to Our Next Generation and What We Want to Learn from Our Pioneers.”
The image of “PAX ENDOCRINOLOGIA Endocrine Supremacism”
The JES should put forward a challenge for new endocrinology as the centenary approaches—based on the secure foundation of the past. In this article, I describe my view on “endocrine supremacism” at next stage.
The 4.6 billion years of history of the Earth is divided into various geological times, and the present time falls in the Cenozoic Era • Quaternary Period • Holocene Epoch, which began 11,700 years ago after the end of the last glacial period. Homo sapiens emerged 200 thousand years ago; our birth occurred at 11:37 pm on December 31 as measured on the basis of the history of the Earth considered as a single year. In 2000, Nobel Laureate in Chemistry, Paul Crutzen and others proposed the Anthropocene (the new era of humankind) as a new geological epoch. This idea emphasizes that while in the past history, humankind was threatened by natural disasters early after its emergence, but, in the course of “human evolution,” human activities themselves have come to threaten nature conversely, and also, the life of humankind to place the humankind in peril, to the same extent as asteroid bombardments, glaciers, and fires, etc. We are now facing the pressing issues which attract the greatest attention, such as climate changes including global warming, loss of biodiversity due to mass extinction, increases in artifacts like waste plastics, or accumulation of residues from fossil fuel combustion and nuclear tests. The COVID-19 pandemic can be in this category, since its persistence is attributable to unavoidably close personal interaction. There are many different opinions on the start of the Anthropocene. Some say that it began with the agricultural revolution 12,000 years ago, and others state that the starting time is around 1900 or after the 1960s.
In her book titled “Transcendence: How Humans Evolved through Fire, Language, Beauty and Time” (Bungeishunju press, 2022), Gaia Vince mentioned four innovations allowing humankind to supersede biological humankind: “fire,” “language,” “beauty,” and “time.” She states that current humankind is going to evolve from Homo sapiens into Homo omnis (“Omni” for short) by these four forces. “Omni” is interpreted as “collective humankind.” It represents a view of “humankind as a super-collaborative super-individual entity” beyond the biological humankind. From this context, I foresee “endocrine supremacism” at next stage or what new endocrinology should be.
It is a well-known fact that “fire” and “language” played major roles in the evolution of humankind. Getting skilled at using “fire,” humankind became able to cook food; they boiled plant roots, which had not been eaten or exploited by other animals, to gelatinize starch to palatable sugar as a readily available rich source of nutrition. Humankind is the only species that cooks. As a result, our brain increased its size, and shared use of fire enabled us to warm ourselves as a group, and to catch animals by acting cooperatively as a group. This cooperative work led to the development of “language,” which served to transmit information needed for game capture. Hence, communication with others allowed humankind to distinguish themselves from others, and to imagine what others are thinking, resulting in “sympathy.”
However, I think that humankind could only have become truly humane because they pursued “beauty” and told a “story.”
Essentially, animals are attracted or charmed by well-balanced materials. I think that this instinct was acquired perhaps as a program of sex hormone-driven emotions in the cerebral limbic system (what is called the old brain) because of the greater likelihood of higher reproductive performance of a well-balanced partner of the opposite sex. Vince insists that the impulse for obtaining beautiful things produced the concepts and innovations of “property and its owning,” “trade and currencies,” “architecture, settlement, and farming,” “hierarchy and society,” and “social norms/rules.” As suggested by books such as “Why do Social Elites Strengthen Their Sense of Beauty?” (S Yamaguchi, Kobunsha shinsho paperback, 2017), the importance of the sense of beauty for social success is nowadays being recognized.
On the other hand, humans became able to memorize past events due to the cognitive power that has been developed by “language.” Humans then attempted to explore the continuity and causality between past history and presently-perceived reality. Thus, there emerged recognition that the present exists only in the context of the past, resulting in the birth of the concept of “time” for humankind. Humankind is the only species able to realize that they will eventually die. The fear of death in turn gave humankind a desire to predict what their future would be. Thus, humankind acquired the habit of telling a “story” from the past to the present and even into the future. Humankind attempted to increase the accuracy of their future predictions by telling individual “stories” to others and exchanging information of their stories. They became more cooperative and increasingly sympathetic, and their “collectivity” was enhanced.
Starting with visceral fat accumulation due to lifestyle derangements, metabolic syndrome is followed by a series of events: diabetes, chronic kidney disease (CKD), and cardiovascular disease occur like dominoes toppling, and in 2003, I named this phenomenon the “metabolic domino” (Fig. 2). I noted that in this “temporal flow” of the occurrence of various diseases, not only the brain, but also all of the other organs of the body can be aware of “time,” i.e., there exist “organ time” and “organ memory” (“Organ Time—How It Goes by Determines Our Longevity,” H Itoh, Shodensha Shinsho paperback, 2013; H Itoh et al., Hypertens Res. 41: 771–779, 2018) (Fig. 3). I would like to predict a person’s future health status from his/her own “story” of metabolic dominoes toppling.
“Metabolic Domino” (H Itoh, 2003)
“Organ Memory” and its formation process (H Itoh, 2018)
With prolongation of human lifespan, there is a concern about the difference between average life span (life expectancy) and healthy life expectancy. In this situation, I proposed the concept of “happy life expectancy” as another dimension of longevity (“Happy Life Expectance: 100 Years Life led by Hormones and Intestinal Bacteria,” H Itoh, Asahi Shinsho paperback, 2018). It is our real desire to feel happy until the last moment of death. I think importance should be attached to how long we can stay feeling happy. Although “happiness” is difficult to define, I consider that it is to “be able to have a hope to live.” I think that hope for life resides in the acquisition of “beauty” and “collectivity” (bonds, sense of ties). Pursuing “beauty” and telling a “story” to possess collectivity are profoundly associated with each other, as I describe later.
Emotional control is mediated by dopamine, oxytocin, and other substances. Hence, hormones serve as the basis for the pursuit of beauty and story narrativity (“Hormones are Almighty!,” H Itoh, Asahi Shinsho paperback, 2015).
I gave a speech titled “Beautiful Endocrinology” at the 2018 JES Summer Seminar on Endocrinology & Metabolism. I placed paramount importance on the ability of good physicians to perceive beauty.
Often described as “the pioneer of medical chemistry” and “Luther in the medical world,” Paracelsus (1493–1541) proposed the “theory of the three essential elements” which constitute all things, that is, mercury, sulfur, and salt. Believing that disease arises from an imbalance of these three elements, he developed a medical drug as a mixture of minerals. However, he said, “Medicine is not only science, but also art. Medicine is not the act of preparing tablets or ointments, but handling the process of life as it is.”
Now that volatility, uncertainty, complexity, and ambiguity (abbreviated to “VUCA”) are drawing our attention, flexibility and creativity are required in medicine for physicians. Good physicians should think more freely, avoiding adherence to nothing more than clinical evidence and guidelines. To this end, I think there is a demand not only for “logic and reason,” but also for “sensibility and intuition,” or more precisely, “a sense of beauty.” Importance should be placed on a sense of balance that allows detection of “something unusual” in the patient, or a feeling of wrongness that cannot be described by words, that is, a medical sense of beauty. Siddhartha Mukherjee said, “Sharp intuition surpasses unreliable testing” in his book under the title of “The Laws of Medicine: Field Notes from an Uncertain Science” (Asahi Press, 2018). Shogi (Japanese Chess) player Yoshiharu Habu reminisces that he can “somehow” preferentially find a good move after being deeply trained. This “somehow” emotion, uneasiness, “intuition,” or what is called “hunch” cannot be possessed by artificial intelligence (AI).
The major principle of endocrinology is the maintenance of “homeostasis.” I think that the “beauty” produced by living organisms resides in the realization of homeostasis. Keeping anything in a given range in any time requires mutually repulsive forces. Hormones have these two opposites, or repulsive effects, preventing biological reactions from large deviations. Homeostasis cannot be achieved by aiming to remain completely constant. Fluctuations over a given range make the system robust. To this end, living organisms have rhythms in hormone secretion and sensitivity. To elucidate biorhythms and hormonal rhythms is key to the understanding of the beauty of living organisms.
“Beauty” is an emotion that cannot be expressed with words. However, some believe that “beauty” can be understood as wonder (novelty) and comfort (pleasure) produced by “order in complexity.” The mathematician Garrett Birkhoff, a friend of John von Neumann, a pioneer in modern computers, proposed that [the value of beauty] = [order] ÷ [complexity], whereas the psychologist Hans Eysenck stated that [the value of beauty] = [order] × [complexity]. Hideaki Kawabata mentions in his book “How Does the Brain Perceive Beauty?—Brain Science of Art” (Chikuma Shinsho paperback, 2012), “Humankind does not feel comfort by receiving information or stimulation that is too simple, but does feel discomfort from things that are too complex; there is an intermediate zone where ‘awakening potential’ reaches to maximize comfort feeling... Hence, comfort is maximized when the stimulation is moderate at the proper level.”
Interestingly, these two factors; “complexity” and “order” or “accuracy” represent the core elements in “free energy principle” proposed by Karl John Friston, a new theory on inference and prediction by the brain, currently in the spotlight (“The Grand Unified Theory of the Brain: What Is the Free Energy Principle?,” T Inui and Y Sakaguchi, Iwanami Shoten press, 2020).
This theory is a hypothesis for comprehensive understanding of all brain functions, including sensations, motions, behaviors, learning, curiosity, volition, and control of organ functions. In this theory, so-called “free energy” is postulated. It is a function of driving cost of the brain. The free energy principle is simple—The brain works and adapts itself to the change of outside world, in order to minimize free energy. To minimize its free energy, the brain does not determine its behaviors and organ functions (control of body temperature, pulse, blood pressure, etc.) after accepting information from exteroception via sensory organs (the five senses), from proprioception (muscular perception, balance perception) or from organ sensations (interoception). Rather, the brain always predicts the next state from experience-based knowledge in advance, and almost simultaneously transmits signals to peripheral organs based on the prediction (referred to as “belief”). The brain functions to minimize the prediction error between actual sensory signals from outside and its predicted signals. This process of inference of the brain is called “active inference.”
I stated in my book “Hormones are Almighty!,” “If blood glucose fluctuations are controlled only by a feedback system in which the brain senses blood glucose fluctuations after sugar absorption in the intestine and actual rise in blood glucose levels and then sends orders to the pancreas to secrete insulin, blood glucose levels should rise and fall more widely. So, a feedforward system also should operate to prevent wide alteration of blood glucose levels. Incretins are secreted just at the time of perception of sweetness by the gastrointestinal tract before the absorption of food sugar.” This system is also known as “allostasis.” Active inference in the brain is a form of allostasis.
Active inference can be defined as an act of the brain to minimize the difference between “the posterior probability” distribution and the “prior probability” distribution made by prediction of an event that is likely to occur in the future, hence minimizing future uncertainty. There are many ways available to minimize uncertainty. They include increasing the sensitivity of perception or changing the modes of moving or action (“action series”) to obtain different kinds of perception from different angles (referred to as “volition”).
The brain attempts to predict more probable future images by getting perceptive information inputs from outside as many as possible by various kinds of efforts. A method or a function to make such a prediction is called a “generative model.” I think that a generative model is a “story” itself, extending from the past to the present and then to the future, which we humans make.
It can be expressed as [free energy] = [generative model (story) complexity] – [generative model (story) accuracy]. Hence, to minimize the free energy is the performance to select the proper action series which can predict the future more accurately with a simpler senario.
Complexity and accuracy or order are important factors for brain functions. As I stated before, these two are the paired elements required for the perception of beauty. Therefore, as the sense of beauty sharpens, it is easier to find better balance between complexity and accuracy, which makes it possible to produce a simpler and more accurate story for our future. I consider that searching for “beauty” and telling a “story” are, thus, closely related to each other.
Periodicity in biorhythms, which is achieved partly by hormone rhythms, supports the resilience and symbolizes the beauty of living organisms. By analyzing it, we can infer and predict what will happen in the future with ease and accuracy. In addition, to evaluate the impact of changing the rhythm (the change of generative models or stories) will make enable us to make a more preferable future story.
People tell their own “stories,” share them with each other, and cooperate together, to increase the accuracy of the prediction of future stories and rewrite the stories to make desired stories of their own. Thus, “collectivity” has emerged, allowing us, humankind to be called “Omni.” Modern predictive medicine based on big data science exists in this context.
Ryugen Matsunami, chief priest of Houdouji Experimental Temple in Kyoto, says that there are two basic ideas in Mahayana Buddhism: yuishiki and chugan.
In yuishiki, yui means only and shiki means know; It is a theory indicating that all existence is subjective and nothing exists outside of the mind (Linguee dictionary, 2022). More precisely, nothing can exist unless recognized by individuals; “self” is defined only in terms of its relationship with all “others” who are not “self.” The idea that existence cannot be recognized without observations seems to be similar to the concept of modern physics (Carlo Rovelli, “Helgoland: Making Sense of the Quantum Revolution” (NHK Publishing press, 2021)).
In chugan, chu means middle and gan means view; it indicates “middle-way” and is related to a concept of ku, Sky, that is “infinity or boundlessness.” The relationship of mankind changes continually, both spatially and temporally, to manifest infinite potentials. This infinite potentials as a whole represent “ku,” which is different from “mu” (vacancy, emptiness), which means nothing exists. “Satori” (enlightenment) is the state that this infinity is intuitively meta-recognized, rather than categorically recognized by language.
The Buddhist term “shiki-soku-ze-ku” (shiki: color, soku-ze: equal ) represents a concept that the colored reality we can perceive is produced from ku world filled with infinite potentials, whereas its reverse term “ku-soku-ze-shiki” shows that the existence of the “colored” reality allows us to infer ku world filled with infinite potentials. I think that this Buddhist philosophy leads to the fundamentals of modern AI-based big data science and its application to precision/preemptive medicine. Ku (Sky) actually indicates “Cloud” in the sky in data science world’s term.
An analysis of human big data on the metabolic dominoes produced in relation to not only the individual’s habits, but also his/her relationships with other members of society, allowing us to predict his/her specific health status with accuracy.
I spoke on “New Internal Medicine to Create a Centenarian Society” at a 2020 symposium of the Japanese Society of Internal Medicine and proposed three keywords for new internal medicine: “Precision Health” (a personalized health management strategy), which will be realized by respecting “Health Diversity” of each individuals, and “Health Sharing” to share health data of the majority of people. Hence, the new modality I proposed may be referred to as “shiki-soku-ze-ku” healthcare.
The phenomenon of entrainment of oscillators with rhythms was observed by pendulum clock inventor Christiaan Huygens and others in 1656. Humankind manifest rhythms and entrainment at different layers of cells, organs, and whole body. Furthermore, at one more higher dimension as a population, we produce strong entrainment to exhibit beautiful rhythms among us. This is the essence of “Omni.” So, I think that the understanding of “Omni” cannot be achieved by the simple approach of end-to-end science based on AI deep learning from big data placed in a black box. It could be realized by performing an analysis of rhythm fluctuations and their entrainment and an evaluation of their beauty.
We propose a new field in endocrinology from the understanding and interventions of “Omni” as described above. Driven by clock genes, the circadian rhythm exists even at the single-cell level, and the entrainment by various oscillators, such as light and food stimuli, produces robust rhythm at the organ and individual levels, resulting in resilience to various perturbations. This rhythm entrainment is related to many hormones such as cortisol; however, it has been difficult so far to understand details of its overall profile. In recent years, however, technologies such as single-cell sequencing, spatial omics, bioinformatic big data analysis, and AI analysis have been developed, enabling us to foresee future trajectories precisely and detect me-byo (pre-symptomatic conditions before the disease onset) in humans by continuously acquiring humoral factor information and conducting wave analysis. In this standpoint, we applied for a group research grant in the 2022 JES Grant for Interdisciplinary Innovative Research, and our project was accepted.
We proposed the research theme, “Digital Endocrinology. Com.” It aims to elucidate the entrainment phenomenon caused by rhythm oscillators acting together in harmony, by analyzing the overall rhythm profile at multi-levels: cellular, organ, individual, and community by endocrinological approach; with the view of communication, commitment, and community, which represent co-existence/symbiosis of living organisms. Specifically, investigations will be made focusing on the inter-generational transmission of non-communicable diseases (NCDs) by mother-child harmonization. Rhythm entrainment and its disorder in mothers with rhythm disorder and their offspring during pregnancy, and the influence on the onset of NCDs in their offspring in adulthood are investigated using basic approaches and clinical study (Fig. 4).
Our research project for “Digital Endocrinology. Com”
Yuval Noah Harari says in his book “Homo Deus” (Kawade Shobo Shinsha press, 2019), “Famine, plague and war, ... have already become manageable issues. ... humanity is likely to make a significant attempt to gain happiness, immortality, and God-like powers.” Future medicine appears to certainly target “immortality” and “happiness.” Endocrinology should play the central role in this future medicine.
Senescence or aging is a “mother disease” that produces many diseases and is underlain by direct involvement of hormones in cell metabolism, inflammation, DNA damage and repair, epigenomic modifications, and other phenomena. Attempts may be made to “cure” senescence, which is deemed to be a disease, using hormones.
In parallel, as stated above, measures to stay happy longer until death (prolongation of “happy life expectancy”) will be also explored. I believe that happiness resided in “BETWEEN (two things).” Therefore, happiness is born between people, “Omni.” Hormones are important for personal linkage, organ-organ communication, symbiosis with intestinal bacteria, and sound inter-generation health transmission.
Humankind is unlikely to become God using AI technology, but healthcare at new dimension surely would emerge with digital transformation (Dx). Big data monitoring and evaluation of lifelong biological activities using various devices, particularly the acquisition and wave analysis of continuous biological data at the individual level (blood pressure, blood glucose, heart beat, sympathetic nerve activity, etc.) and information on hormones in body fluids such as saliva appear to enable us to accurately foresee a personal future trajectory and detect me-byo conditions. Furthermore, it will no longer be a dream to develop an ‟in-body hospital” in which a nanomachine is sent into the body and information is transmitted in real time to topically deliver hormones with appropriate amount to desired areas.
The territories of endocrinology are infinitely large—This is the basic concept of endocrine supremacism. From now on, endocrinology should aim at complete understanding of “Omni,” which pursue “beauty” and tell a “story.” I believe that this goal can be achieved only by the successful fusion of endocrinology with state-of-the art brain science and emerging big data science.
Fig. 5 is an illustration of an imaginary scene that came to me when thinking of the next world of “endocrine supremacism.” The upper portion of this figure is the School of Athens drawn by Rafael, a painter representing the Renascence. Great persons from various historical eras are gathering at a school hall. Standing at the center are Plato and Aristotle. In reality, this Plato is drawn with Leonardo da Vinci’s face. Next to him is Socrates. Pythagoras and Euclid appear in the lower part. Rafael featured his rival Michelangelo at the center of the picture. While Michelangelo and da Vinci were in a cat-and-dog relationship, Rafael as beloved by da Vinci drew himself at the right end of the picture.
“Endocrinology Continuum” and the image of JES towards 100th anniversary
Although Rafael drew great persons in the past, Rafael featured persons of the same generation, including himself, in the same space. I think that he was indicating pride in their own generation. I hope that a similar scene will emerge within JES. It would be wonderful if a culture were to develop in which great people act majestically and are respected by their followers, with young members acting confidently and vigorously in the same space.
However, currently active members are insufficient in JES. The lower part of this picture shows an imaginary scene when the research spaceship Cassini-Huygens arrived at Saturn’s second satellite Enceladus. This satellite has water and heat. Found to have organic matter as well, it is drawing attention because it has an extremely high probability of the existence of extraterrestrial organisms. I hope that newcomers appear one after another in our rich and vigorous culture of JES. Thus, our sustainability will be ensured.
I hope that all members will focus on the “Endocrinology Continuum” as the JES centennial approaches. The term “continuum” represents a concept combining the aforementioned “collectivity” with “time.” The Endocrinology Continuum involves multifaceted continuity in endocrinology.
A human follows a continuum from egg fertilization to individual death. In society, there are various continua in personal relationships such as person-to-person, male-to-female, parent-to-child, and inter-generation relationships. Furthermore, there are other continua, including co-existence with intestinal bacteria and co-existence with AI and robots. These continua are tightly associated with hormones. I hope that a new discipline targeting such diverse continua will emerge and evolve. I also hope for continuous expansion of our activity into unexplored fields in academia and further continued growth of our society.
In closing this essay of mine, I would like to cite the words of William Osler, a Canadian physician who is often described as the Father of Modern Medicine—
“Humanities are the hormones of medicine.”
The ultimate goal we should have as JES members is achievement of the richness of humanity. I hope that all members will endeavor to promote the prosperity of JES in shared common spirit with endocrine supremacism.
Hiroshi Itoh
21st, 22nd President
Professor, Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine
E-mail: hiito@keio.jp
Careers in JES
2019– Director (Academic Affairs and Publication)
2017–2019 22nd President
2015–2017 21st President
2013–2015 President for Kanto-Koshin-Etsu Regional Branch
2009–2015 Director (Finance)
2007–2009 Director (General Affairs)
1995– Councilor
1984– Member
Activities in JES
2015 Chair, 88th Annual Congress of JES
2009 Chair, 9th Annual Meeting of JES Kanto-Koshin-Etsu Regional Branch
JES Awards
2022 1st JES Grant for Interdisciplinary Innovative Research
2020 19th JES Award
1995 15th JES Research Award
Contributions to EJ
2013–2014 Associate Editor-in-Chief
