Introduction
The global science pattern has been changing along with the development in science and technology. This pattern includes concept updating, changing the thinking models, building theoretical frameworks, and developing practical action guidelines [
1]. The medical science updates find expression in the changing medical models and updates in health ideas. In 1996, the World Health Organization (WHO) predicted that medical science in the 21st century will develop from “disease medicine” to “health medicine” and from group therapy to individual therapy. Thus, health medicine, with human health as the research object and practical objective, as well as individualized medicine emphasizing on individual differences in a given population, will gradually constitute the developing direction of medicine.
The present paper maintains that individualized treatment fully emphasizes the individual differences of people based on human-based concepts to formulate individual medical designs and adopt optimal and targeted therapeutic interventions that enhance the effectiveness and safety of the design. Thus, the design is developed as an individualized healthcare and considers the entire process of human life, including the early stages, to realize the change from disease medicine to health medicine. The purpose of establishing individualized medicine is to create awareness of individual differences and find the optimal treatment program for a particular patient, which can facilitate the choice for more targeted and appropriate drugs.
The concept of individualized treatment accommodates medical development and the needs of the times. The basic objectives of medical science to cure diseases can be achieved, and medical science can be redirected toward preventive measures against diseases and the improvement of the quality of health. However, the main purpose of medical science remains curative. The individual treatment for individual differences is still in the process of exploration and has yet to be practiced. The manner of implementing individualized treatments is a matter of public concern in Chinese and Western medicine and multidisciplinary fields. Its key point is to find the proper method and path in evaluating health conditions. The objective and accurate evaluation of health and its related indices is of particular importance.
Modern health medicine and individualized treatment
Medical models serve as the initiating factor of individualized treatment
The reductionism-based Western medicine of the 20th century relies on the biomedical model, which is centered on diseases. At one point, this model played a dominant role in the research on external cause-oriented diseases. However, at the beginning of the 21st century, the disease map has changed from infectious to chronic diseases, whereas non-infectious diseases, hypertension, cardiovascular diseases, diabetes, tumors, and other multigene diseases have become the principal contradiction. The etiological factor has changed from singularity to complexity and from biologic to multi-factor. Several epidemiological studies revealed that the biologic factor does not play a dominant role in the etiological factors of diseases (e.g. cardiovascular disease, cancer) that pose serious threat to human life and health. Moreover, the transition of life science to molecular and submolecular levels did not change the essence of biologic medicine. Even if biologic medicine is well-developed, it is limited in its role in the epidemics in modern society. Therefore, the shift of the medical model from biologic medicine to new medicine, which combines physiology, psychology, society, and environment, is inevitable [
2].
Changing the medical model infers changing the research object, particularly the change from diseases of the people to people with the disease. For several years, medical science has regarded diseases as the research priority, with emphasis on the disease of people while disregarding the people with the disease. More than 30 000 kinds of diseases have been discovered to date. The antagonistic therapy for a single cause cannot effectively manage several other diseases, such as allergic, immunological, metabolic, and psychosomatic diseases, among others. Moreover, a number of not-so-healthy people are in a state between being sick and healthy. Meanwhile, a non-discretionary approach brought about by treatments based on disease identification impedes the improvement of clinical effects to a certain extent. Disease treatment and healthcare need individualization. The medical model centered on the study of diseases is passive and is characterized by a considerably high level of confusion. Thus, the medical model must change its focus from disease medicine to health medicine and from population medicine to individual medicine to achieve human-based health objectives.
Development and current situation of modern individualized therapy
The currently proposed term, “Individualized Medicine,” was first used in
Biochemistry Individuality written in 1956 by Williams, who was then the director of the Research Institute of Biochemistry of America. However, the concept failed to draw enough attention [
3]. In the 1970s, terms such as individualized medicine, individualized treatment, individualized care, individualized health care, and tailor-made medicine, became popular. In the late 1990s, Western medicine refocused the concept of personalized medicine. The impetus was provided by the Human Genome Project, which America, Britain, Japan, France, Germany, and China participated in. In 2001, significant developments in genomics again emphasized the importance of individualized medicine [
4]. Consequently, the 4P (predictive, preventive, personalized, and participatory) medical model was proposed in recent years. With it, a modern individualized medical era has begun, with its main thrust centered on every patient [
5].
To date, individualized medicine is mainly established on the basis of individual genome information and the differences in single nucleotide polymorphisms (SNPs). Individualized medicine consists of individualized diagnosis and treatment. General individualized diagnosis includes conducting disease risk assessment based on the individual genome information. Modern medical research has found that all diseases (except for trauma) are almost always genetic in nature. Thus, a susceptibility gene is closely related to the occurrence of diseases. When a susceptible population (which carries the disease susceptibility gene) comes in contact with or is exposed to an adverse factor or environment, the incidence of diseases in the population can be up to 12 times higher than that of a population without the disease susceptibility gene. Thus, conducting a disease risk assessment using individual genome information can improve the living and working environments as well as the dietary structure of a person to prevent the occurrence of diseases, prolong the survival time, and improve the quality of life.
The hereditary features of individual genes and SNPs are closely related to clinical disease phenotypes and play an important role in predicting the response of individuals to drugs [
6,
7]. These features provide scientific bases for individualized disease treatment. Thus, the so-called translational medicine, which is the transition from laboratory to bedside practice, emerged. At present, the practical applications of individualized treatment are mainly in tumor treatment and the management of diabetes, as well as in hypertensive patients [
8-
10]. In particular, the application of antineoplastic drugs has been developed for genetic testing in patients to achieve the expected therapeutic effect and prevent serious toxic reactions. With the continuous discovery of human genetic markers, as well as the relationship between the genotype and phenotype of drug use, genetic labels have been attached to more than 100 categories of drugs after approval from the US FDA. These labels are used to indicate the possible therapeutic effects and toxicity of these drugs when applied to patients with different genotypes [
11].
In recent years, numerous countries have launched related technological initiatives to study the pathogenic mechanism, molecular staging, and individualized treatment of serious non-infectious diseases. These include the Personalized Medicine Project of Japan and the Life Gene Project of Sweden, which are population-based prospective studies, as well as the Malaysian Cohort Project, Sharing Plan of the US, and the Molecular Typing and Individualized Treatment of Serious Diseases Project (“863” Project) of China launched in 2006. The main objectives and research content of these projects involve three aspects. The first is the establishment of a high-quality biologic resource library (e.g. DNA, blood serum, tissues, hair, nail, urine) and a clinical information database that can meet the requirements of research. The second aspect is the performance of molecular staging of diseases, which uses known genomic SNPs and the analysis of gene expression profiles to formulate a correlation analysis of the relationship between all kinds of phenotypes in disease development. This method can facilitate the identification and discovery of the genes related to susceptibility to complex diseases and those related to clinical phenotype vesting, as well as the molecular targets directly for diagnosis and drug effects. For example, Japan conducted a screening on the associative relationship between 250 000 SNPs and major diseases, which lasted until October 2005. The summarized data may be used to identify the corresponding disease gene and confirm an individualized treatment. The third aspect is the promotion of individualized treatment of major diseases. Based on these aspects, the present work intends to achieve the following objectives: (1) to find the disease susceptibility gene and the gene sensitive to all kinds of drugs (valid or invalid); (2) to identify specific molecular targets, which can be the basis for the research and development of new drugs or the formulation of new usage of old drugs, and to propose a new diagnostic program; (3) to identify important genetic information, which can be used to determine individualized treatments; and (4) to study the interaction between genes and the environment and use the results in the prevention of diseases.
Existing problems in the modern individualized treatment
The popularization of individualized medicine relies on DNA sequencing. However, at its current stage, DNA sequencing technology is beset with problems, such as its high cost, difficult quality control, and difficulty in promoting the technology to the population, among others. Moreover, the role of epigenetic markers of certain major diseases remains limited. For example, whether differences in the same epigenetic marker applied in different populations exist, the generally predicted effect of multi-genetic markers on the same individual remains unclear. In the same manner, the relationship between environmental factors and genetic risks remains to be determined. Research results vary because of different research conditions, different races, living areas, and living habits of the research object.
Meanwhile, not all SNPs have clinical significance. A complex disease results from a combination of genetic factors, individual susceptibility, and environmental factors. Currently, the most effective way of finding a minor gene in multigene diseases is to use the DNA marker related to the disease gene. This is known as relational analysis on the basis of SNP. The obviously higher frequency of a genetic marker in a patient than in a non-patient indicates that this marker is related to the disease. By comparing and analyzing their haplotypes and finding the unbalanced linkages, relational analysis can locate any unknown pathogenic gene in a genome. However, around 30 000 to 300 000 SNPs with clinical significance are needed to achieve this purpose. Individualized medicine faces the major challenge of finding functional SNPs with clinical significance from several million genes.
Individualized treatment and health medicine of Chinese medical science
Chinese medical science believes that health is ruled by harmony and unity — a dynamic balance between human, nature, and society. That is, “Yin and Yang are in balance, Essence-spirit is normal,” as described in
Huangdi Neijing[
12]. Individualized treatment also hinges on the theory and practice of the Chinese medical therapeutic system. For example, the basic idea of “individuality-concerned treatment,” “different treatment for the same disease,” and “the same treatment for the different disease” in Chinese medical treatment is to establish a targeted adjustment based on the situation of individual patients. The treatment system based on syndrome differentiation works out all kinds of change regularities caused by constitution, body reaction, and other factors in the occurrence and development of diseases. However, a treatment based on syndrome differentiation using traditional Chinese medicine could not stray from the premise of “disease” and would not reflect the principle of individualized treatment. The constitutional theory in Chinese medicine developed in the 1970s combined the “prevention before disease onset” concept of health medicine with the “individuality-concerned treatment” of individualized treatment. It covers a series of important breakthroughs, such as concept updating, building of theoretical framework, and practical clinical application and achieves a breakthrough for Chinese health medicine and individualized treatment.
Constitutional study in Chinese medicine reflects the “individuality-concerned treatment” and the individualized medicine thinking, leading to methods and tools for individualized treatment
The core issue of individualized treatment is the question of “what is individualized?” Thus, individual differences are considered and population convergence is emphasized. Moreover, the correlation of different individuals to diseases and other issues should be paid attention to. The diversity of genetic factors and the complexity of acquired factors cause obvious differences between individual constitutions. Even the constitutional characteristics of the same individual are dynamic and variable. Thus, constitutions have obvious individual differences and exhibit polymorphism. Meanwhile, the genetic backgrounds and external conditions of a population with the same social background and are located in the same region, or for a population with the same types of food and shelter, are similar. The constitution of a specific population forms the common characteristics of group phenomena, indicating convergence. Moreover, the population shows different constitutional characteristics at different times, and individual differences and group convergence are thus unified. No “constitution” can be differentiated in the absence of individual differences, and no “category” can be classified if group convergence is absent [
13].
Therefore, the constitutional classification study of the Chinese constitutional theory divides populations into different constitutional types based on constitutional individual differences and group convergence. This classification probes into the relationship between constitution, disease, and the action mechanism of constitution intervention and disease prevention and reflects the idea of “individuality-concerned treatment.” In addition, the Chinese constitution was divided into nine basic categories based on the four dimensions of biological differences in population, individual genetic differences, individual mental differences, and natural and social adaption differences. The divisions are as follows: A type (Ping-he), B type (Qi-xu), C type (Yang-xu), D type (Yin-xu), E type (Tan-shi), F type (Shi-re), G type (Xue-yu), H type (Qi-yu), and I type (Te-bing). Except for the A type (Ping-he), the other eight kinds of constitutions belong to biased constitutions, indicating that although they do not possess definite diseases, individual constitutions show related unbalanced statuses of Yin and Yang, Qi and blood, and fluid and humor [
14]. Some biased constitutions are proven to be the “no disease” statuses of some related diseases.
A total of 21 948 large samples were prepared for an epidemiological study in the natural population on a national scale. The results show that the aforementioned nine types of constitutions exist in the population. Ping-he accounts for the majority at 32.75%, whereas the other top four biased constitutions are Qi-xu, Shi-re, Yin-xu, and Qi-yu [
15]. The present study investigated the biologic connotation of constitutions on a microlevel. For example, Yang-xu, Yin-xu, Tan-shi, and Ping-he were found to have the same characteristic gene expression profile [
16]. Moreover, after detecting PPARD, PPARG, and APMI gene polymorphisms, these four types of constitutions were found to have the same distribution of specific SNP polymorphisms and haplotypes [
17]. The present study established that the expression of thyroid hormone receptor β of Yang-xu is downregulated. This observation provides a molecular biological explanation for the cold intolerance of Yang-xu [
18]. All these results provide objective evidence for constitutional classification. The present study has shown that different constitution types in Chinese medicine have unique molecular characteristics and genetic bases. Considering that the worldwide population is 6.5 billion, individualized treatments based on gene sequencing may be difficult to implement. However, the population can be classified based on their constitutions, which can result in the identification of convergence of individual differences and improve the promotion in a large area.
Study of the correlation of constitutions to diseases and constitutional adjustments provides the principle for regulation and treatment as well as the methods for different constitutions and related diseases
The constitutional status indicates integrity and determines the occurrence of a disease. It is closely associated with the occurrence of numerous specific diseases. The differences of individual constitutions are susceptible to several causative factors because their classification is based on congenital and acquired factors. Thus, they can be easily affected by some diseases, from which other kinds of diseases can be formed. The constitutional status is also an important basis for predicting the development, vesting, and prognosis of diseases. The constitutional characteristics of populations in different areas are related to certain disease maps.
In recent years, scholars have studied the relationship between constitution type and disease. For example, the study on the Tan-shi-related diseases shows that people with Tan-shi constitutions are more likely to suffer metabolic syndrome, hypertension, coronary heart disease, and diabetes than people with other constitutions. The copy number and SNPs of the differential expression gene in Tan-shi vary from that of the Ping-he constitution based on genomic DNA testing. Further functional analysis of related genes shows that people with the Tan-shi constitution generally have metabolic disorders [
19]. A multi-step, logistic-regressive analysis shows that the Tan-shi constitution is the primary constitutional factor affecting essential hypertension, followed by Yin-xu and Qi-xu [
20].
The present study on the metabolic basis of Yang-xu and Yin-xu demonstrates their specific relationship to the hypofunction of the hypothalamic-pituitary-adrenocortical axis and the hypothalamic-pituitary-thyroid axis, as well as the dysfunction of the cyclic nucleotide and immune systems [
21].
The constitution is relatively stable and dynamically variable. Each individual is subject to the effects of many internal and external factors, including the natural environment, spirit, nutrition, exercise, and diseases during the course of life. Therefore, constitution can be changed. This concept is the theoretical basis of adjustable constitution, whereas correcting the imbalance of Yin-Yang, Qi-Blood, and fluid-humor through drugs and related treatment methods is the practical basis. The present study established a method of reducing humidity and removing phlegm, which can reduce fat generation, change the lipid metabolism, lower the blood viscosity, and improve the Tan-shi constitution. These effects can reverse pathological fatty liver conditions and prevent fibrous degeneration. In cooperation with the Johns Hopkins University of the US, the Guominkang capsule was developed to alleviate allergic diseases and was proven to reduce the antigenic specificity of rat IgE and inhibit the mast-cell histamine release in sensitized rats. This study has significant effect on the treatment and prevention of allergic diseases and has proven that a biased constitution can be improved by Chinese herbal prescriptions [
22].
Emphasizing the internal relationship between different constitutions, diseases, and syndromes and focusing on the differences in the response of different constitutions to drugs and other treatments are the specific practices with which to implement the individualized treatment and the idea of “individualized treatment.” The different constitutional types or statuses can improve Qi, invigorate Yin, moderate Yang, release Shi, open Yu, or dredge blood to balance Yin and Yang and the dynamic and stable states as well as reverse the unbalanced trend to embody the human-based treatment principle of treating diseases from the root. Early diagnosis and intervention of the biased status of a constitution can facilitate a constitutional adjustment to prevent diseases and pathological changes preclinically and clinically and promote “non disease” treatment using Chinese medical science.
Constitution identification shows the direction and provides the core technology for health status evaluation
Chinese medical science places health and disease into the context of natural and social environments for a comprehensive study, which includes the full unity of the structure and function of the human body itself, as well as the correlation between spirit and body and the adaptation of humans to the natural and social environment, among others. It has many similarities with the concept of health in modern medicine. Health can be achieved if the health status can be correctly distinguished and described. The study of the health status should cover at least four aspects, namely, building a theoretical health status system, developing a methodology to evaluate the health status and a system to assess the methodology, and conducting a comparative study of the health status in Chinese and Western medicine.
The interpretation of the health status based on Chinese medical science includes the following aspects: the related constitutional stability; the theory of the relative Yin-Yang balance; the ascending and descending order, the coming and going of Qi activity, and the circulation of Qi and blood; and the unified internal and external environments (the holistic concept). However, the scientific evaluation of health is a challenge and remains an important concern that Chinese medicine needs to address. Traditional Chinese medicine requires further studies on methodologies that determine the health status. Moreover, it has no precise and replicable data, materials, and related elements to use as standards. Constitution identification based on the constitutional theory in Chinese medicine is the method of health status evaluation with the widest application and clinical operability among all current evaluation methods [
23].
Constitution identification is designed to encompass the totality of health and disease factors from the constitutional status as well as the classification characteristics of the different constitutions by regarding the constitution of a human being as a cognitive object. A principle of prevention and treatment is then formulated, and the corresponding treatment, prevention, and healthcare methods are chosen for the implementation of “individuality-concerned treatment.” The constitution is the reactive state of Yin-Yang, Qi-blood, and fluid-humor changes. It is the relatively stable and comprehensive natural characteristic of morphology and structure, physiologic function, and psychological state, inherently formed and acquired throughout life. Therefore, the Ping-he constitutional status reflects a balanced Yin-Yang, Qi-blood, and fluid-humor health states. As previously stated, the classification and identification of health statuses was performed based on the Chinese medicine constitutional theory, which provides guidance. The core technology is the Constitution Scale in Chinese Medicine based on rule nine of the Chinese medicine constitution. As the measurement tool of constitution classification, the scale can provide a quantitative evaluation of population and individual constitutions for standardization and operability. Based on a scientific evaluation of the reliability and validity of the scale, the Chinese Medicine Standard for Constitution Classification and Identification was established following several discussions by experts and based on a large epidemiological survey sample and statistical analyses [
24]. It was formally published by the China Association of Traditional Chinese Medicine on April 9, 2009. In the same year, the “Constitution Identification of Chinese Medicine” was listed in the National Public Health Service Standards. At present, approximately 0.3 billion health archives have been established in China.
Conclusions
In the past 30 years, with the development of modern medicine toward the molecular level, an interesting phenomenon emerged out of the human genome project: the faster that medical science delves into the microlevel, the more effort should be exerted to implement individualization. One of the efforts to achieve this goal is the “tailor made” pharmacogenomics proposal to cure each patient using individualized treatments [
25]. Moreover,
Environmental Genomics proposed the interaction of humans and the environment. Chinese and Western medical systems create common concepts of individualized treatments based on macro- and microlevel developments. All these efforts promote the diagnosis and treatment of human diseases using individualized projects.
Although Chinese and Western medicine agree on the concept of health medicine and individualized treatment, differences in value orientations, thinking style, and directions of study remain because of their respective historical and cultural backgrounds. The developmental direction of modern individualized treatment is toward building a human gene info-database (including an SNP database) and to develop a biomedical informatics method of effectively analyzing gene-typing data. In particular, the method involves the analysis and calculation of SNP data related to diseases and pathogenic factors. Once a pathogenic gene is determined, the effective drugs for this gene are researched and developed. When polymorphisms, gene expression profiles, and other biologic characteristics are closely related to drug reactions, the optimal treatment for an individual can be realized [
26]. The development of Chinese medicine individualized treatment should form a multi-dynamic, open, and new model of Chinese medicine treatment that can fulfill the modern scientific specifications of a Chinese medical clinic and confirm the importance of a treatment based on syndrome differentiation. Based on clinical practices, a treatment based on individual differentiation, syndrome differentiation, and disease differentiation should be adopted. Combinations and complementarities of these methods can then be created to establish a diagnostic and treatment model by differentiating individuals, diseases, and symptoms. In addition, the development of modern biological technology should be maximized to establish a research platform for Chinese medicine and individualized treatment and to provide a new model for individualized treatments and health medicine for the international medical community.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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