Towards to Intelligent Function-reversible Network Medicine

--Future Medicine Arivial？

Changzhong Fang,   Jingwang Tan ([email protected])

With the development of natural science, modern medicine has played a huge role in resisting a variety of infectious diseases or “simple” diseases with obvious external factors and made great contributions to humankind's health. However, the profile of diseases is changed significantly with social development. “Non-linear” complicated systems of all sorts of complex diseases such as cancer are different from “linear” simple systems[1,2]. If the “linear determination” manner is still used for treatment, obviously medical tasks cannot be finished. The modern cancer medical model of “removal etiological treatment”, which is dominated by surgical chemoradiotherapy, lacks a holistic view. The diagnosis and treatment method for simple diseases followed manifests as “uncertain curative effect” in theory and huge harm in the practice. According to Global Cancer Survey Report published by the International Agency for Research on Cancer (IARC) in early 2014: Cancer incidence, mortality and other related data in 184 countries or regions worldwide showed that 14 million cancer patients increased newly with 8.2 million deaths worldwide in 2012[3,4]. The deaths caused by tumors exceeded the total deaths from all coronary heart disease and stroke. Additionally, it is predicted that cancer mortality will be increased to 13 million per year in 2030. The survival rate and cure rate of many malignant tumors such as hepatoma, lung carcinoma and colorectal cancer are not significantly improved. Most cancer patients suffered enormous pain in the final short survival period, and some even had fatal organs removed. The consequence was especially distressing. Modern tumor research is in-depth, investment is huge and technology is very developed but it is regrettable that prospect is pessimistic in a certain period of time. In the final analysis, modern medicine cannot achieve the “efficacy prewarning” to provide a deterministic treatment for different individuals. There is a severe problem in strategic thought. As Einstein said, “If the mode caused the problem is still adopted to solve it, you are doomed to failure”[5]. So is the development of cancer science. The human body is an extremely complex giant network system. Only by the method of large-scale networked data mathematical modeling can an interactive complex giant network model between tumor super-organisms and the human body be constructed. Further the “intelligent prewarning” of cancer curative effect is achieved through artificial intelligence technology. It is the only way to defeat cancer[6,7].

1. Planck, a well-known international physicist and the founder of quantum theory, once said, “Scientific inner as wholeness is decomposed into isolated parts, independent of the essence of things, subject to the limitation of human cognitive ability”. More and more scientists are aware of the limitation of the modern medicine lacking a holistic view. Academician Fan Daiming, a famous medical expert in China, has been advocating the holistic integration medicine for more than a decade[8,9]. As early as 2016, the author put forward an integrated “diversified” mini-Invasive or non-invasive  treatments for tumors，preserving function-reversible. Today it only is the most reasonable method to save a good many later and end-stage patients, and makes impossibility into possibility. Besides, the author pointed out that “toward intelligent function-reversible via integrated mini-Invasive and non-invasive approach ” is the only way for future cancer medicine. The author discussed the inevitability of intelligent function-reversible medicine as future human direction by the scientific theory of complex network system, especially the theoretical basis of intelligent function reversible medicine, and the inevitable requirement for achieving intelligent function-reversible medical system[9,10].

Systematization or Holism(Complex  Life Network) 

Firstly,medicine must return to holism or “Nature and Man in One” network medicine[10,11].Human beings live in the realm of nature, they are constantly surrounded by it and interact with it Humans evolved from nature, return to nature, human beings constantly evolve to adapt to nature. The human body is composed of various compounds and organic matter come from of carbon, hydrogen, oxygen, nitrogen, phosphorus and other elements in  nature.In essence, the human being interacting with nature and everything, form the "Unity of Man and nature"of the complex physical system and correspondence between man and nature with electromagnetic resonance.So the biosphere is not a chaotic conglomeration of natural phenomena and formations. By a seemingly objective logic everything is taken into account and everything mutually adapts with the same obedience to proportion and harmony that we discern in the harmonious motion of the heavenly bodies or the integral paintings of the great masters.  Losses of living energy from our organism are constantly compensated by various forms of energy flowing from the vast expanses of the universe.[11,12] The human body is an open and indivisible dynamic network system, which contains lots and lots of subsystems or sub-network, which also contains lots and lots of lower sub-systems or sub-network at different levels. Human beings are difficult to understand the characteristics and progression rules of cancer complex biosystem as a dynamic whole, and often only recognize local and partial features of a stationary complex system through “fragmentation” and “cross-section” to make decisions and obtain valuable data on the basis of big data due to the limitation of thinking ability. The cancer forms as the results of long-term exchange between inside and outside material information of the human body, and own functional action of the human system, by no means a local cause of the organ where the cancer is located. However current therapies mainly aim at locals. Taking surgical resection as an example, not only cannot cure cancer once and for all, but also brings more new problems, even at the cost of life, not worth the candle[3,12].

Fig.5  Complex Human Body  Network

Geneticization or Molecular Network  Medicine(Taxonomy According to Gene Network) 

Secondly, , in which, cancer forms as a result of the long-term evolution of a series of multi-step gene mutations[12,13]. The past decades have brought remarkable advances in our understanding of human disease . While progress on the genetic and proteomic aspects has been impressive  , most aspects of the relation between genotype and phenotype still remain unclear, especially for complex diseases . Heterogeneity, polygenicity and pleiotropism are major factors that are hampering the progress , as well as diffuse boundaries between diseases , as they can have multiple causes and be related through several dimensions . A number of resources have been constructed aiming to understand the entangled relationship between diseases,often in the form of networks. Postgenomic protein function determines the heterogeneity of cancer cell. Scientists gradually focus on functional genomic research with the progress of genome sequencing. The studies of gene expression and regulation, structure and function of gene and its product, molecular interaction, and a correlation between genotype and phenotype at the genome-level promote a series of genome-level testing technology platforms, mainly including genomics, transcriptomics, proteomics, metabolomics, interactomics, phenomics and so on（Fig. 5)[13,14]. These high-throughput omics experimental platforms constitute mega-scientific engineering in systems biology. The biological function of cancer as a super-organisms network system depends on the protein core functional network module. Thus it is different from the past through finding key gene or protein as the main way to recognize disease. The most different measure of intelligent medicine is to explore the overall state and behavioral characteristics of the core functional network that cause cancer and cancer biological characteristics from core network functional block.Network-based approaches to human disease have multiple potential biological and clinical applications. A better understanding of the effects of cellular interconnectedness on disease progression may lead to the identification of disease genes and disease pathways, which, in turn, may offer better targets for drug development. These advances may also lead to better and more accurate biomarkers to monitor the functional integrity of networks that are perturbed by diseases as well as to better disease classification. Here we present an overview of the organizing principles that govern cellular networks and the implications of these principles for understanding disease. These principles and the tools and methodologies that are derived from them are facilitating the emergence of a body of knowledge that is increasingly referred to as network medicine[13,14,15].

A new data network that integrates emerging research on the molecular makeup of diseases with clinical data on individual patients could drive the development of a more accurate classification of diseases and ultimately enhance diagnosis and treatment. The "new taxonomy" that emerges would define diseases by their underlying molecular causes and other factors in addition to their traditional physical signs and symptoms. The book adds that the new data network could also improve biomedical research by enabling scientists to access patients' information during treatment while still protecting their rights. This would allow the marriage of molecular research and clinical data at the point of care, as opposed to research information continuing to reside primarily in academia.Toward Precision Medicine notes that moving toward individualized medicine requires that researchers and health care providers have access to very large sets of health- and disease-related data linked to individual patients. These data are also critical for developing the information commons, the knowledge network of disease, and ultimately the new taxonomy[15,17].

Mathematization (Mathematical Modeling or ArticialIntelligence)

Thirdly,  mathematical modelingor mathematics is the most beautiful language(Fig.6). All kinds of mathematical methods are applied to establish mathematical models. The subject of the disease cannot be directly observed so people can only establish the mathematical model to “approach” the true law of things development through the external appearance of the disease itself, i.e. biological information (“visceral sign” named by Chinese medicine). The human body is a complex giant network system with infinite dimensions and cannot be thoroughly described by modern technology. Only by the “decomposition” method, i.e., a painstaking investigation level by level with various clues can behavioral characteristics of key functional blocks of cancer be understood[18,19]. The application of the network mathematical model will be of great significance to the overall quantification of clinical medical diagnosis and treatment path. In clinical practice, systems with similar functional blocks are found by disease, syndrome, psychological, and nutrition and metabolic characteristics and other differentiation for the human body, in essence, induction-analysis (classification) and then induction once more. It is beneficial to the reduction in the dimension of the complex system. The mathematical model of diagnostic network is established to further deepen the cognition for the disease, and more importantly provide an accurate path for personalized medicine[16,21,22].

Fig.7 Mathematical Modeling

Quantization or Bioelectromagnetic Method

Fourthly, Quantization or Bioelectromagnetic method is to translate life activety with bioelectromagnetic wave messure. The human body is a physical system of “integration of man and nature” on the basis of complex network giant system formed by the inter- and intra-interaction of atom-molecule-gene-protein-cell-tissue-organ-system-natural societal environment and other material levels in the human body composed of carbon, hydrogen, oxygen, nitrogen, phosphorus and other main elements[23,24]. Today the mainstream clinical medicine is mainly based on the analysis of material components, that is, the pathophysiological lesion of the human body is “translated” by the change in various components. Essentially, the universal gravitation of the earth is used to measure and explain life motions, ignoring the interaction among various substances (quanta) in the system. The intrinsic error of modern medicine is to only pay attention to the existence of the earth electromagnetic attraction. Theoretically, the “quantum measurement” method should be applied to explore the electromagnetic interaction between matters. The decipherment of life secret in the future will definitely require the help of electromagnetic measurement (“quantum ruler”) with the development of quantum science(Fig.7). In theory, the construction of an intelligent noninvasive medical system for cancer must first establish the exchange between the cancer super-organisms-human body system and external matter, energy and information, including the network mathematical model of interaction. In fact, the so-called matter, energy and information are the interaction of electromagnetic wave (quantum), and the model of network mathematics is equivalent to that of quantum mechanical action[1,23,25].

 Fig. 8 Quantum experiment Verifies”Spooky Action at a Distance”

Synergistic Function-reversible  Treatment 

Thousands of human medicine to form a variety of traditional Chinese and western medicine treatment methods, especially the development of modern Western medicine has made full progress, has formed a variety of local treatment methods for different levels of the human body, such as warm therapy，traditional Chinese medicine prescription,and and so on ; There are various treatments at the organ level, such as surgical excision and ablation; More targeted therapies are targeted at each target or targeted region of the biomolecular network.Based on the view of life network system, Chinese and western medicine must be integrated[16,26,27,28]. 

Based on network science theory, there are mainly two kinds of network-based target discovery strategies, namely central hit strategy and Network influence strategy. The guiding ideology of the former is mainly by attacking a few key points and a devastating blow to the network, these key points are also often become targets of therapy, including wedge hub center node points such as the top of the hierarchy in the network nodes The latter's guiding ideology is to overcome the system robustness, the network recover from disease state to normal state of health Nodes with a moderate number of connections, such as network Bridges, are often ideal targets for this strategy. In addition, network influence strategies often target network segments, such as disease-related modules, which are more similar to hubs in terms of network structure They form a rich region, form a network bridge between different functional modules, behave like a bottleneck, and form specific signal connections between key nodes or network segments, which makes them more robust to network disturbances as people interact with network nodes' characteristics[28,29] .

The complex life network of the body was established, and various statistical information of the network was calculated to mine the clinical data, that is, the mutual information method based on information entropy was used to evaluate the correlation, and the non-parametric test method (random permutation text,RPT) was introduced to automatically determine the significance of the correlation degree[30].In recent years, the combination of bioinformatics technology and network pharmacology method has become one of the important methods in the study of mechanism of TCM compound compound. The research on TCM compound compound based on this model has broken the bottleneck of traditional mechanism research of TCM compound compound compound and made the mechanism which was difficult to be qualitative previously predicted and verified This research method is suitable for the study of TCM compound/monomer treatment mechanism of various diseases. The network pharmacology theory method is used to screen the effective components of TCM compound and predict the target, and to explore the relationship between component-target-target-disease target-signal pathway, and make the network relationship diagram. The target of action of TCM monomer components was predicted in a variety of ways, and the mechanism was analyzed. Bioinformatics database was used to associate gene expression profile data with drug mechanism, and bioinformatics method was used to analyze the mechanism of action of TCM compound/monomer, so as to associate disease, drug and mechanism Gene expression regulation network - biological networks - the point of view of traditional Chinese medicine network to explore the role of the relationship between traditional Chinese medicine compound with the, to study the traditional Chinese medicine compound multicomponent, multiple targets for treatment of internal relation and mechanism to build the body complex network model of how to use the mathematical model of complex network computing cooperative multi-level diversification sequential multiple targets (target Systemic) the effect of the treatment on the cancer system and the influence of normal body system, so as to achieve the goal of synergistic disease removal and functional reversibility.[31,32,33]

Towards to Intelligent Function-reversible Network Medicine

As a product of the evolution of the universe, human body is a physical system composed of carbon, hydrogen, oxygen, nitrogen, phosphorus, sulfur and other atoms in different order and spatial structure. It is the most complex cellular automation in the universe[32]. All life activities are the self-operation and self-performance of living substances The reductionist idea that the sum of complex living systems focuses on removing causes has serious defects, and the curative effect is full of uncertainty and harm. Medicine must return to wholeness, to humanity! The holistic view of traditional Chinese medicine and the theory of yin-yang and the Five elements are the earliest complex system theoretical model of human beings. The holistic view of traditional Chinese medicine is based on modern Western medicine which is based on reductionism and the holistic view of traditional Chinese medicine which is based on the holistic view of the unity of man and nature[15,33]. The two are highly complementary through the integration of mathematics, physics, chemistry and biomedicine Multidisciplinary methods, such as, information and computation science, from a kind of new biological network dynamics Angle to study the phenomenon of life, including molecular and cellular organ entities such as biological organisms and environment system under the mutual relationship between various components of the phenotype of function and behavior So it combines the characteristics of biology and information science In general, biological information flows in the following directions :DNA, mRNA, protein, protein interaction, network, cell, organ, individual, population. It's important to note here that information at each network level provides useful insights into the functioning of living network systems Functions of the important tasks of medical network is to get as far as possible each level network of information and to integrate them Under the background in the era of big data, through mathematical modeling, digital really prompted the fusion of Chinese and western medicine, implementation of traditional Chinese medicine for the body, for western medicine to use the intelligent function of reversible medical network, its essence is using thermal oxidation reduction and so on to promote the whole body is short of imbalance, Away from the equilibrium state, and realize intelligent early warning collaborative treatment, functional reversible network medical system[34,35].

The huge changes in the era come toward us at unprecedented acceleration. The fifth intelligent industrial revolution sweeps across the globe. The rapid development of big data, quantum computation and information, artificial intelligence and Internet of Things ushers in an unimaginable revolution for human society. In the research and practice of medical theories, the research and application of artificial intelligence have made great progress. Medical treatment in the future is humanized and noninvasive undoubtedly by virtue of artificial intelligence. Only by relying on artificial intelligence can noninvasiveness be achieved. Human medical treatment cause with respect to human health is the top priority. We should make every effort to go into action and greet the arrival of wonderful tomorrow.

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