Two Definitions of Life Will Highlight on Physiological Understanding of Six Meridians

YANG Jie-zuan (杨介钻), FANG Hui (方 辉), XIAO Dang-sheng (肖党生)

1. First Affiliated Hospital, College of Medicine, Zhejiang University, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.

2. Emergency Department, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

3. VIP Ward, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

ABSTRACTTreatise on Cold Pathogenic Diseases is an ancient guideline for traditional Chinese medicine (TCM) clinicians which classified all diseases into six meridians. In Treatise on Cold Pathogenic Diseases, many syndromes are enunciated in simple vocabularies without physiology and pathology, which is always criticized. It seems that a bridge is necessary for physiological and pathological understanding on Treatise on Cold Pathogenic Diseases. In past decade, two definition of life in cell and in our body are presented respectively. In both definitions, energy conversion is the core pathways for all organisms which can be regarded as motion of qi. Moreover, metabolism of energy agents can be seen as yang while gene expression and stem cell proliferation & differentiation (SCPD) should be seen as yin in cell and in our body respectively. The both definitions also outline the physiology and pathology of six meridians in Treatise on Cold Pathogenic Diseases, which can be unveiled as followings: taiyang meridian - elimination of energy and end metabolites; yangming meridian - acquiring energy agents; shaoyin meridian - the conversions of energy agents; taiyin meridian - new born somatic cell attending the metabolism of energy agents and then going to die; shaoyin meridian - storage and activity of stem cell; jueyin meridian - proliferation& differentiation of stem cell to produce somatic cell. These definitions will ignite new physiological and pathological understandings on Treatise on Cold Pathogenic Diseases.

KEYWORDS Metabolism; Stem cell; Yin-yang; Five phases; Six meridians

INTRODUCTION

In the development of Traditional Chinese Medicine (TCM), Inner Canon of Yellow Emperor and Treatise on Cold Pathogenic Diseases are 2 culminations. Inner Canon of Yellow Emperor documented many TCM theories and Treatise on Cold Pathogenic Diseases is an ancient guideline for TCM clinicians. In Treatise on Cold Pathogenic Diseases, many theories and principles are originated from Inner Canon of Yellow Emperor.Although Treatise on Cold Pathogenic Diseases presented many prescriptions which are still utilized in clinic, many TCM theories in Treatise on Cold Pathogenic Diseases are documented in simple vocabularies. Treatise on Cold Pathogenic Diseases was a manuscript of ZHANG Zhong-jing and was finished at the end of the Eastern Han Dynasty.In Jin Dynasty, this manuscript was firstly revised and edited. At that time, TCM clinicians can only read hand copies of Treatise on Cold Pathogenic Diseases. Since then, Treatise on Cold Pathogenic Diseases had been revised, re-edited and copied by hand. In Song Dynasty, Treatise on Cold Pathogenic Diseases was revised and edited officially for the first time and the manuscript of ZHANG Zhong-jing was divided into 2 parts which were named as Treatise on Cold Pathogenic Diseases and Synopsis of Golden Chamber respectively. It is also in Song Dynasty,Treatise on Cold Pathogenic Diseases and Synopsis of Golden Chamber were published officially, which now was called the Song edition of Treatise on Cold Pathogenic Diseases. 700 years later, the Song edition of Treatise on Cold Pathogenic Diseases was nearly disappeared. It is ZHAO Kai-mei who repressed the Song edition of Treatise on Cold Pathogenic Diseases in 1599 AD. Up to date, there are many duplicate manuscripts of Treatise on Cold Pathogenic Diseases in the world but the Song edition is the generally accepted edition for TCM clinicians.

For more than 1000 years, Treatise on Cold Pathogenic Diseases had been the guideline for TCM clinicians. In Treatise on Cold Pathogenic Diseases, ZHANG Zhong-jing not only documented pulse manifestation for diagnosis, but also presented a classification of all diseases according to six meridians. If a TCM clinician can follow this classification, he will take good clinical efficacies for patients. However, the manuscript of ZHANG Zhong-jing was so abstractive that it is very difficult for TCM clinician to follow the thinking pattern of ZHANG Zhong-jing. Moreover, the manuscript of ZHANG Zhong-jing was revised and re-edited for many times and maybe some errors were added in the manuscript even in Song edition. For example,Synopsis of Golden Chamber was departed from Treatise on Cold Pathogenic Diseases and perhaps this is a great error. How to take Synopsis of Golden Chamber back to Treatise on Cold Pathogenic Diseases? This is an interesting issue and still under discussion. Another challenge comes from the west medicine. In Treatise on Cold Pathogenic Diseases,all diseases were delineated on the syndrome or/and pulse manifestation without physiology and pathology, which is always criticized. It seems that a bridge is necessary for physiological and pathological understanding on Treatise on Cold Pathogenic Diseases. Few attempts are made in this field. In past 10 year, two definitions were presented and it was optimizing to take physiological and pathological explanation on the Treatise on Cold Pathogenic Diseases with the two definitions[1,2].

TOW DEFINITIONS OF LIFE

As an open question in biology, what is life is still under discussion[3,4]. Many definitions of life had been published[5]. National Aeronautics and Space Administration (NASA) also publishes a working definition of living for exploring the extraterrestrial life:"Life is a self-sustaining chemical system capable of undergoing Darwinian evolution"[6]. However, these are not working definitions for clinicians. This is not the case in TCM. In the paradigm of TCM, yin, yang,qi and xue are vocabularies to define the life of our body and all physiologies and pathologies of TCM including Treatise on Cold Pathogenic Diseases are based on the interaction of yin, yang, qi and xue. Unequivocal definitions of life will not only take novel understanding on these vocabularies but also are beneficial for translating the core theory of TCM including Treatise on Cold Pathogenic Diseases.

All living organisms can be divided into unicellular organisms and multicellular organisms. A multicellular organism is composed of various kinds of cells while every cell undergoes metabolisms and attends a tiny part of metabolism in the multicellular organism. 10 years ago, two definitions of life were presented in Chinese for unicellular organisms and multicellular organisms respectively. Now, they are modified as following:

A living cell is a chemical system capable of undergoing the metabolisms of energy agents and gene expression for the energy conversions.

A living multicellular organism is a chemical system capable of undergoing the metabolisms of energy agents and stem cell proliferation &differentiation (SCPD) for the energy conversion.

These definitions set 2 frameworks for the physiological understandings of Treatise on Cold Pathogenic Diseases.

THE TWO DEFINITIONS HIGHLIGHT PHYSIOLOGICAL UNDERSTANDING ON YIN-YANG THEORY

Yang and Qi Should be Defined as Energy while the Motions of Qi Should be Defined as Energy Conversion

In both definitions, the energy conversion is seen as the core pathway in all organisms[7]. Living cell is a basic unit for energy conversion. Living cell can only accept heat energy, light energy and chemical energy as extracellular energy source from its surroundings. When heat energy enter cell,they increase the motions of all molecules in cell and drive these molecules to attend biochemical reactions more actively. By photosynthesis, light energy can also enter cell and will be converted into chemical energy carried by glucose after entering living cells. Nearly all of cells accept chemical energy as the main energy source, which are carried by monosaccharides, amino acids and fatty acids. Living cells can also phagocytize many macromolecules such as proteins, polysaccharide,lipids, but they must degrade these macromolecules into monosaccharides, amino acids and fatty acids at first for metabolisms. So, monosaccharides,amino acids and fatty acids should be seen as energy agents and acquiring these energy agents is the initial step for all metabolisms in living cells.

In a living cell, there are 4 pathways for energy conversion with the energy agents as initial mass.The first pathway is that chemical energy carried by energy agents are converted into heat energy by glycolysis, beta oxidation, deamination, tricarboxylic acid cycle and electron oxidation with water, carbon dioxide, urea as end metabolites[8-10]. This pathway outlines a metabolic framework for all energy and mass conversions in a living cell. In this framework,no more 40% chemical energy will be stored in ATP which will be converted into cell membrane potential as well as mechanic motion of cell and these energy will be also dissipated as heat energy.This is the second pathway for energy conversion.In a living cell, the most popular energy conversions are from chemical energy to chemical energy with many organic molecules as the products such as lactic acid, alcohol, neurotransmitters, proteins,polysaccharides, etc[10]. These products can be released as identities of a living cell or return to the first pathway for oxidation. This is the third way for energy conversion, which derives from the metabolic framework. The forth pathway is cell division. A living cell is composed of a variety of organic molecules and can also be seen as the carrier of chemical energy. Although cell division is a complicated process, it should be also acknowledged that producing a daughter cell can be seen as an energy conversion from the chemical energy to chemical energy with a daughter cell as the end product. See Figure 1.

Figure 1. The Flow of Energy in the Living Cell

Our body is composed of a variety of cell and every cell executes a tiny part of energy conversion in our body with some differences. Different from that of a living cell, our body always accepts nutrients as subtracts for energy conversion and these nutrients will be digested into energy agents at first. After being transported to all cells, energy agents will be oxidized into end metabolites with much heat energy being released. This is the first pathways for energy conversion. During the oxidation of nutrition, parts of chemical energy will be converted into mechanical energy, such as walking, speaking,writing and mechanical energy will be converted into heat energy. This is the second pathway for energy conversion. However, in the level of our body, there is no pathway for the conversion from chemical energy to electronic energy. The third pathway is the synthesis and releasing of molecule such as bile pigment, bile acid, hair, nail, and skin keratin. The birth of newborn should also be regarded as the forth pathway for energy conversion from chemical energy to chemical energy.

The energy conversions undergo in all parts of a cell and our body. The arrest of them implies that a living organism is dead. In the paradigm of TCM,yang and qi have the same feature and qi is always seen as yang. So, it should be acceptable that yang can also be defined as the energy conversion or the metabolisms of energy agents with the energy agents as entry substrates.

Yin Should be Defined as Gene Expression in Cell and Stem Cell Proliferation & Differentiation(SCPD) in Our Body Respectively

In a living cell, proteins play the crucial role and function as constructing architectures of a cell, storing chemical energy and playing special functions (including catalyzing biochemistries). Upon the completion of these functions, proteins will be degraded into amino acids for oxidation and the living cell will synthesized new proteins to update the inactive ones by the central dogma[11]. This is the process of gene expression or protein renewal,another essential process in living cells. With this process, a living cell will produce all profiles of proteins and update them for its survival. In the other word, the gene expression or synthesis of proteins is the unique pathway for constructing architectures of a living cell, which has the similar features of yin.So, it is reasonable to define gene expression as yin in a living cell[2].

Cell is structural and functional unite in our body and can also functions as constructing architectures of our body, storing chemical energy and playing special functions. Finishing its functions, cell will go to die and be decomposed into energy agents for metabolism.At this time, our body will produce the new somatic cell to replace the dead one by SCPD. Stem cells are a group of cells with the capacity of self-renewal and producing somatic cells. The functions of stem cell can be abstracted as: growing into an individual; producing somatic cells to replace the dead ones; repairing the damaged tissues and organs[12]. The process of SCPD is the pathway to construct the structure of our body and has the similar feature of yin. On the other hand, SCPD are governed by gene expression and SCPD can also be regarded as a bridge connection genotypes and phenotypes in our body.

In TCM, xue is also similar signification as yin and always translated as bloodTCM. However, blood cells,the contents in blood, are the one of lineages of SCPD.So, it is instructive to translate the xue as SCPD.

THE TWO DEFINITIONS AFFORD A FRAMEWORK TO UNDERSTAND THE TREATISE ON COLD PATHOGENIC DISEASES

In both definitions, energy agents are the entry mass for all metabolisms in a living organism. After entering a living cell, energy agents can be oxidized into end metabolites by glycolysis, beta oxidation,deamination, tricarboxylic acid cycle and electron oxidation. This is the short metabolic pathway in a living cell which is the same as metabolic framework. Energy agents can also attend the gene expression for the synthesis of DNA, RNA and proteins so as to build the architectures of a cell,play some functions and store chemical energy.Finishing these functions, these macromolecules will be degraded into energy agents for oxidation. This is long metabolic pathway with gene expression in the initial part followed by the oxidation of energy agents. In living cells, short metabolic pathway and long metabolic pathway form a metabolic loop.Moreover, there are many metabolic branches in a cell, all of which are derived from this loop and can be seen as the identities of a living cell.

The same metabolic loop is also in our body but more complex. First, our body captures energy agents from nutrition which will first digested in gut with energy agents and feces as end metabolites.After being absorbed, energy agents will be transported to all cells in our body for oxidation with water, carbon dioxide, urea, etc. as end metabolites which will be discharged by excretory organ, such as urinary system, lung and skin. This is the short metabolic pathway, in which stomach, gallbladder,small intestine and large intestine are responsible for the initial step and bladder are responsible for the last steps. In TCM, these organs are named as fu organs. After entering our body, energy agents can also be transported to activate stem cell to proliferate and differentiate for the production of the sufficient somatic cell so as to update dead ones. The dead cells will be decomposed into energy agents for oxidation. This is the long metabolic pathways in our body, in which SCPD is the initial step followed by the oxidation of energy agents. In our body, the long metabolic pathway and short metabolic pathway form a metabolic loop while many metabolic pathways are also originated from the metabolic loop. Moreover, the pathological explanations of diseases in Treatise on Cold Pathogenic Diseases are also based on this metabolic loop.

THE PHYSIOLOGY AND PATHOLOGY OF SIX MERIDIANS IN TREATISE ON COLD PATHOGENIC DISEASES

How to translate the title of Shanghanlun is also a perplexing issue. Shanghanlun is always translated as Treatise on Cold Pathogenic Diseases[13]. This is not precise. One instructive title is Therapies on The Diseases Induced by Hypothermy. In modern medicine, there are some researches on the pathologies induced by hypothermy[14,15]. However, these researches focus only on alterations in physiology or metabolism without therapies and these researches cannot set the relationships between abnormal physiology or metabolism and syndromes or complaints. In

Treatise on Cold Pathogenic Diseases, a series of syndromes induced by hypothermy or cold shock and the shifts between these syndromes are recapitulated. The physiologies and pathologies of these syndromes can be unraveled on the two definitions and the metabolic loops in the living organisms. Now, the first question is what the physiologies of six meridians are.

It is well known that the theories of six meridians are based on yin-yang theory and our model also unravels this relationship between the theories of six meridians and yin-yang theory. Metabolism of energy agents and SCPD are essential pathways in our body and each pathway can be divided into 3 steps so that we can paraphrase the physiology of six meridians. In our body, metabolism of energy agents can be divided into 3 steps: acquiring energy agents,the conversion of energy agents and elimination of energy and end metabolites. SCPD can also be divided into 3 parts: storage and activity of stem cell,proliferation & differentiation of stem cell to produce somatic cell and new born somatic cell attending the metabolism of energy agents and then going to die.In a living cell, metabolism of energy agents and gene expression are also the essential pathways which can also divided into 6 parts: acquiring of energy agents,conversions of energy agents, elimination of energy and end metabolites, the storage and activation of gene, transcription and protein synthesis, the new proteins to play their function and degraded into energy agents after finishing their functions. The relationship between six meridians and six metabolic parts will be listed as following. See Table 1.

Table 1. The Physiologies of Six Meridians in Our Body and in a Cell

Taiyang Meridian

Both in cell and in our body, elimination of end metabolites and energy is the terminal step for all metabolisms. The general viewpoints is that in our body, excretory organs such as urinary system,respiratory system and skin are responsible for the excretion of end metabolites while no organelles in cell are responsible for this physiology and end metabolites will only be release by diffusion. In our body, conduction, convection, radiation and sweating are the pathways for expenditure of heat energy and few researches was paid on the expenditures of heat energy in a cell. However, in our model, Newton's laws of motion and thermodynamic law will be introduced to explain the physiological phenomenon.Let us study the following equation:

This equation uncovers that a moving object will carry energy which is proportional to its mass and square of its motion velocity. The laws of collision and inertia in physics also uncover that a molecule with the small molecular weight will be easier to get high velocity. These physical principles endow water (H2O), the most stable and smallest molecule in cell, with the capacity to get high velocity more easily than other molecules and water should be regarded as an important carrier of heat energy. So, the discharge of water will be coordinated with the expenditure of heat energy,which can be thought as waterTCMrestricting fireTCMor fireTCMcounter-restricting waterTCM. Heat energy driving water off an organism by urine and sweating is the normal physiology of Taiyang meridian and abnormality of any factors will result in diseases which are called taiyang disease. For example,the attenuated water dissipation will result in the accumulation of heat energy which will lead to the increasing of temperature in organisms. If this phenomenon appears in our body, we will get fever. On the other hand, in case that no sufficient heat energy is released in organism, water will not be driven off the cell or our body which will lead to the edema in cell or in our body. So, abnormal dissipation of heat energy and water is the causality of all Taiyang diseases which is recapitulated in

Treatise on Cold Pathogenic Diseases.

Yangming Meridian

Acquiring the sufficient energy agents is the first step for the survival of all living organism. Both for unicellular organism and our body, there are two way to obtain energy agents. A living cell will get energy agents by capturing the energy agents from its surrounding and breakage of the macromolecules in cell. Our body will get energy from nutrition which will be digested into energy agents in gut and the dead cell in our body which will also be decomposed into energy agents. The two ways are antagonistic and will keep equilibrium so that an organism will be in stable state. However, the equilibrium can be broken so as to result in yangming disease. For example, a cell can get over-sufficient energy agents so that the breakage of macromolecules will be attenuated. In this condition, the energy agents will be accumulated in cell and used for the synthesis of proteins, lipid, even RNA and DNA while the cell will grow even go in mitosis. For our body, the accumulation of energy agents is the initial force for growth. However, the over-accumulations of energy agents are the causality for blood stasis syndrome and food accumulation syndrome which should also be classified as yangming disease. On the other hand, in case that no sufficient energy agents are afforded to a living cell, the cell will degraded more macromolecules for its energy metabolism so that the cell cannot synthesize sufficient proteins for updating, which may result in the death of the cell. Same pathology can also appear in our body. In case that our body cannot get sufficient nutrition, more somatic cell will go to death and be decomposed into energy agents for metabolism and the SCPD in our body will be attenuated with less somatic cell being produced, such as dystrophy.These can also be classified as yangming diseases.

Shaoyang Meridian

The physiology of shaoyang meridian is a bridge connecting taiyang meridian and yangming meridian. From the metabolic framework, it can be asserted that both in a living cell and in our body, acquiring energy agents is the physiology of yangming meridian and the excretions of heat energy and end metabolites are the physiology of taiyang meridian. Now, all metabolisms of energy agents in a living cell and in our body are the physiology of shaoyang meridian. The physiologies of shaoyang meridian can be divided into two parts. The first parts include the oxidation of energy agents and the conversions from chemical energy to chemical energy. The second part includes the synthesis of proteins and cell division for gene expression playing the central roles. In our body, the oxidation of energy agents with the energy conversions from chemical energy to heat energy and mechanical energy are seen as the first part while the energy agents activating the stem cells and surging them to go into proliferation & differentiation are belonged to the second part for gene also playing its central role in this process.

Here, an interesting issue is presented. Gene expression and SCPD are defined as yin and most of parts of two processes are the physiology of shaoyang. No ancient documents of TCM delineated this viewpoint. This novel viewpoint will derive many conclusions on TCM, for example the interaction and conversion between yin and yang. In Treatise on Cold Pathogenic Diseases, the chapter of shaoyang diseases is the simplest with one prescription and without blood level syndrome. This is a puzzle. This novel viewpoint extrapolates an acceptable answer.In our body, metabolisms and SCPD share the same substrates: energy agents. After being absorbed,energy agents will be distributed into oxidation and SCPD. So, another physiology of shaoyang meridian is to regulate the distribution of absorbed energy agents. The abnormal distribution of energy agents will disturb the oxidation or SCPD, all of which will be seen as shaoyang disease. However,the abnormality of oxidation should be seen as the qi level disease of shaoyang meridian while the abnormality of SCPD should be seen as the blood level syndrome. The interesting issue is that in our body, SCPD are defined as yin and the abnormalities of SCPD should be seen as yin diseases including shaoyin diseases, jueyin diseases and taiyin diseases. This implies that shaoyin diseases, jueyin diseases and taiyin diseases are the blood level syndrome of shaoyang meridian.

Taiyin Meridian

Gene expression and SCPD are the essential processes in living cell and our body respectively,all of which are defined as yin. In living cells, energy agents attend the synthesis of protein are the physiology of taiyin and in our body, energy agents attend the production of somatic cell is also the physiology of taiyin meridian. In case that too many energy agents accumulate in our body and cannot activate the stem cell to produce somatic cell, this is classified as taiyin disease, for example obesity and overnutrition. The accumulation of energy agents in cells is the cellular pathology of taiyin disease.

Shaoyin Meridian

Life in a cell stem from the gene expression and life in our body stem from the SCPD. DNA carries the genetic information and governs the gene expression and SCPD. Double helix of DNA has the two exclusive functions: storing genetic information and expressing gene information. Closed-chain DNA is beneficial for the storage of genetic information while unwound DNA will activate replication or transcription. A living cell must keep the balance between Closed-chain DNA and unwound DNA so as to keep the balance between the storage of genetic information and the synthesis of proteins by closing or unwinding DNA. The breakage of this balance will result in the disturbance of metabolisms and the gene expression, which is the molecular physiology of shaoyin disease.

In our body, not all stem cells go on proliferation& differentiation to the produce progenies at the same time. Stem cells have two states: quiescence and activity. When stem cells are in quiescence,most parts of DNA are closed with small part of gene being activated for updating of proteins according to the central dogma. When stem cells are activated,more DNA in these stem cells are unwound and transcription and replication will be generated, so stem cells will go on trajectory to proliferate and &differentiate. However, the details on the activation of stem cells are still under researching, and this activation should be defined as the physiology of shaoyin meridian in our body. Our body will keep a balance between the quiescent stem cell and activated stem cell so as to avoid the exhaustion of stem cells, which is also the physiology of shaoyin meridian. The abnormal activation of stem cell will take many diseases to us, which should be defined as shaoyin disease.

Jueyin Disease

A living cell must synthesize all profiles of proteins continuously to update the inactivated ones for its survival and adaption in the surrounding.The synthesis of proteins depends on the central dogma with energy agents as subtracts, which can be defined as the physiology of jueyin. In our body, stem cell will produce billions of somatic cell to replace the dead cell by proliferation &differentiation so that our body will keep our body in stability. SCPD depends on the gene expression and supply of energy agents so as to maintain the balance between the newborn somatic cell and dead cell. The breakage of this balance will take many diseases which are defined as jueyin disease.

SUMMARY

In TCM, yin, yang, qi and blood are the vocabularies to define the life of our body. Now, the definitions in this paper take physiological explain on these vocabularies and present an optimizing model for pathological understanding on the six meridians.Here, the physiology and pathology of six meridians are outlined. More researches should be carried out to enunciate the pathology of every syndrome.