Traditional Chinese medicine should not beignored during the development of precision medicine with Chinese characteristics

Hong-Cai Shang,Xiong-Zhi Wu,Rui-Jin Qiu,Ya-Han Wang,Yong-Yan Wang

1China Academy of Chinese Medical Sciences,Beijing,100700,China.2Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Beijing University of Chinese Medicine,Beijing,100700,China.3 Huan-Hu-Xi Road,He-Xi District,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,300060,China.

Introduction

On January 20,2015,President Barack Obama announced Precision Medicine Initiative(PMI).In March,2015,Ministry of Science and Technology of the People’s Republic of China(MOST)held a conference of experts of precision medicine strategy for the first time.The experts proposed to promote the development of precision medicine,which indicated the advent of the era of precision medicine in China[1].In March,2016,the MOST released the application guideline for key project of precision medicine research.The aims of the precision medicine research are:(a)to develop natural population national large health queue in more than one million people and develop serious disease special queue;(b)to establish multi-layer precision medical knowledge base system,and safe and stable biomedical big data sharing platform,which is workable and can break through the new generation of life omics clinical application technology and biomedical big data analysis technology;(c)to build an innovative and large-scale experiment and analysis technics system research of biomarkers, cardiovascular and cerebrovascular disease,respiratory system disease,metabolic disease,rare disease,malignant tumor,immunological disease,nervous and mental disease,etc[2].Actually,the concept of Precision Medicine(PM)which takes different precautionary measures and therapeutic measures based on individual variability,is not a new term.In 2011,the National Academy of Sciences,the National Academy of Engineering,the Institute of Medicine,the National Research Council of USA presented “toward precision medicine”,to build a knowledge network for biomedical research and a new taxonomy of disease[3].PM can be defined as treatments targeted to the needs of individual patients on the basis of genetic,biomarker,phenotypic,or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations[4].Compared with the previous medical concepts,the progress of PM is crossing the mechanisms of disease and biological large data and information science,classifying disease and diagnose accurately,providing targeted and valid treatment measures for patients(especially for patients with breast cancer or leukemia),integrating biological big data and targeted individualized diagnosis and treatment of disease,as well as advanced real-time detection.

Though the concept of PM was proposed several years ago,PM has already been implemented in some clinical fields such as breast cancer and leukemia,which is based on the patients’genetic trait.For example,the treatment of breast cancer is based on the molecular subtypes,which is the result of estrogen receptor(ER),progesterone receptor(PR),human epidermal growth factor receptor-2 (HER-2) in accordance with immunohistochemistry,including type of Luminal A(HER2-negative,ER-positive and/or PR-Positive), Luminal B (ER-positive and/or PR-Positive,HER2-positive,or HER2-negative with Ki-67>14%),Triple negative/basal-like(ER-negative,PR-negative,HER2-negative)and HER2 positive(ER-negative, PR-negative, HER2-positive). The clinical manifestation,treatment measures,therapeutic effect and prognosis are different in different sub-type breast cancers.Studies showed genetic polymorphism of CYP2C19 relating to clopidogrel resistance and cardiovascular events:a study enrolled 2208 patients presenting with an acute myocardial infarction and receiving clopidogrel therapy,the results showed that who carried any two CYP2C19 loss-of-function alleles(*2,*3,*4,or*5)had a higher event rate than those with none(21.5%vs.13.3%)[5].A systematic review showed in the patients of cardiovascular disease receiving clopidogrel therapy after undergoing percutaneous coronary intervention(PCI),compared with CYP2C19*1 carriers,CYP2C19*2,*3 carriers had a higher risk of stent thrombosis in clopidogrel-treated patients,but there were few differences in cardiovascular and bleeding events between the two carriers [6].A prospective,randomized,proof-of-concept trial of point-of-care genetic testing for personalization of antiplatelet treatment showed that none of the 23 CYP2C19*2 carriers given personalized treatment with prasugrel had high on-treatment platelet reactivity,compared with seven(30%)of 23 received standard treatment(P=0.0092)[7].We can conclude that the genetic factors affect the efficacy of precision treatment tremendously.

The individualized treatment on the basis of genotype is similar to“treating the same disease with different methods”of Traditional Chinese Medicine(TCM).“Treating the same disease with different methods”means curing a disease with diverse therapeutic methods because of different etiology and pathogenesis,various pathological factors,diverse stages of disease,different seasons and territories in the same disease.For rapid arrhythmia,it can be discriminated as phlegm-fire confusing heart syndrome,Qi and Yin deficiency syndrome,fire excess from yin deficiency syndrome,yang qi exhaustion syndrome.It can be treated with add and subtract Huanglian Wendan decoction, Huanglian Ejiao decoction and Shengmai powder,Shengmai powder and Tianwang Buxin Dan,Shenfu decoction and Zhenwu decoction respectively[8].Though the theory and remedy are different between TCM and western medicine(WM),both TCM with treatment based on syndrome differentiation and WM with treatment based on genomics and proteomics reflect the characteristics of PM.

However,there are numerous problems remaining to be worked out to make PM come true.Scientists have identified 3600 genes for rare mendelian disorders,4000 genetic loci related to common diseases,and several hundred genes that drive cancer,but it is hard to be applied in practice[9].The expansion of phenotypic spectrum because of clinical heterogeneity of single-gene disorders and pleiotropic phenotypes,defining phenotype by specific mutation types,phenotype modified by allelic interactions,all these make it more complex to evaluate medicine based on phenotype[10].The challenges of PM include:(a)huge demographic characteristic determines that the accurate sequencing needs a long time;(b)gene sequencing cannot reflect the characteristics of life entity;(c)gene sequencing cannot achieve the prospection of disease control and prevention[11].Precise and individualized diagnosis often limited by current knowledge of disease etiologies and phenotype diagnosis methods,which result in limitation of treatment[10].And now it is needed in a broad research program to encourage creative approaches to PM,test them rigorously,and ultimately use them to build the evidence base needed to guide clinical practice[12].In China,it is a tremendous burden in manpower,material and financial resources to make PM come true.The equipment manufacture and technology of gene sequencing originating from abroad,and the exorbitant price of gene sequencing means that it will be a prolonged aim for China to realize precision medicine.

TCM has existed for thousands of years in China.The effect and efficacy of TCM should not be ignored.Syndrome differentiation and treatment present the characteristics of individualized therapy.TCM should not be neglected during the development of PM with Chinese characteristics.It will contribute much to Chinese PM if accurate prevention,diagnosis and therapy can be achieved.This paper will discuss how to develop PM with Chinese characteristics from the following several aspects(Figure 1).

Figure 1 The discussion about Chinese PM

1.Precision Prevention

The Huangdi Neijing puts forward theory of preventive treatment for the first time.Prevention of disease includes three aspects:prevention before disease onset,preventing disease from exacerbating,prevention of the recrudescence of disease.Prevention before disease onset should be the key point in the beginning,to avoid sufferings of the patients and reduce the economic burden of patients and society.Individualized therapy with TCM characteristics reflects the theory of adjusting to changing circumstances,adjusting measures to local conditions,and treatment chosen according to the variability of an individual.Developing PM with TCM characteristics can be in accordance with three categories of etiological factors system.

1.1 Adjusting to Changing Circumstances

Holistic view,means harmonious unification in human and the nature,which occurs throughout the process of TCM treatment.The physical change will be affected by nature,and the change of nature can also affect the people's physiological pathology.The Huangdi Neijing showed yang qi rising in spring,growing in summer,being restrained in autumn and hiding in winter.People should conform to the changes of the season to keep in good health.Those who go against the way of yang qi rising in spring may suffer from injuring liver system functions and may be attacked by cold syndrome in summer.Those who disobey the way of yang qi growing in summer may suffer from injuring heart system functions and may be attacked by malaria in autumn.Those who have breached the way of yang qi being restrained in autumn may suffer from injuring lung system functions and may be attacked by swill diarrhea in winter.While violating the way of yang qi hiding in winter may result in injuring kidney system functions and disordered circulation of vital energy in spring.Therefore,people should realize the changes of seasons and climates,and adjust diet,daily life activities and emotions in different seasons to prevent certain diseases.

1.2 Adjusting Measures to Local Conditions

People in different areas with various residential environments and dietary habits present different incidence trends.Those living in the east eat fish and salty food so frequently that they tend to develop large carbuncle. Those dwelling in the west prefer flavorsome diet,and therefore catch internal diseases more easily.Those residing in the south prefer much sour food and tend to get hypertonic impediment.Those living in the midland eat much sundry food and do few activities,thus resulting in disordered circulation of vital energy,cold,or heat.Therefore,adjusting dietary habits in different areas may prevent certain regional diseases.

1.3 Choosing Treatment According to the Variability of an Individual

The tendency of disease is closely related to age,gender,heredity,living environment,life style,social status and constitution.For instance,children,old and weak people are susceptible to infectious diseases,while female are susceptible to gynecopathy on account of unique physiological characteristics.Wang Q[11]presented the concept of Nine-constitution medicine and divided constitution into nine sections such as gentler constitution,qi deficiency constitution,yang deficiency constitution, yin deficiency constitution,qi depression constitution,phlegm-damp constitution,damp-heat constitution,blood stasis constitution,and the specific endowment constitution.Each section of them contains physical traits,molecular biology characteristics,mental profile,social adaptation ability,susceptibility to disease,and intervention for this constitution type.Therefore,certain diseases may be prevented according to these demographic characteristics.

The system of three categories of etiologic factors should be an entirety in the prevention of disease.From the overall understanding to diseases,once genetic indicator and biological indicator have been acquired,TCM characteristic will be brought into full play,and precision prevention will come true in both individual and special groups.

2.Precision Diagnosis

Diagnosis is the precondition of treatment.Precision treatment is based on precision diagnosis.However,PM is based on costly gene sequencing,which is hard to be popularized.The large population number means that it will be a long time to acquire everybody’s genome information and find driving factors from gene regulatory network of disease.TCM diagnosis type means integrating differentiations of diseases and syndromes.All these existing problems give rise to inexact diagnosis in TCM clinical practice and researches.

2.1 Precision Disease Differentiation

In clinical practice of TCM,there is a phenomenon of attaching great importance to the syndrome differentiation while ignoring disease differentiation.Generally,the name of a disease can be diagnosed explicitly in WM,but is usually general and indistinct in TCM.

The term of syndrome differentiation and treatment is deriving from Treatise on Febrile Diseases.However,due to the restriction of previous medical conditions,disease differentiation of TCM is always based on symptoms of a disease and the patient’s signs.For example,abdominal pain refers to the pain below gastral cavity and above the pubis hairline,where includes liver, bravery, kidney,intestine, small intestine,bladder and viscera.Abdominal pain may indicate pancreatitis,cholecystitis acute and chronic enteritidis.TCM disease names originated from analogism,such as typhoid fever.The concept of typhoid fever has broad sense and narrow sense.The broad sense of typhoid fever refers to all kinds of the exogenous febrile diseases,while the narrow sense of typhoid fever refers to diseases attacking instantly from exogenous wind-cold.There are many kinds of febrile diseases caused by exogenous factors,including exogenous disease caused by bacteria,viruses or fungi.However,the clinical manifestation,pathological features and prognosis are discrepant in diseases caused by different pathogenic bacteria.It could be difficult to speculate the etiology,pathogenesis,pathological and prognosis of diseases from the general TCM disease names.Similarly,diseases diagnosed definitely by modern medical may have different meanings from those recorded in the ancient medical literatures.For example，chronic renal failure in modern medicine can be named as guan ge(obstruction and rejection),shui zhong(edema),long bi(retention of urine),ni du,shen lao (kidney overstrain),or shen feng(wind-associated kidney)in TCM.The non-standard and skimble-scamble TCM disease names have impeded our understanding of the characteristics of diseases and therefore,restricted our clinical researches and the development of TCM.One of the missions for TCM precision diagnosis is to develop normative and unified TCM disease names.

2.2 Precision Syndrome Differentiation

Syndrome differentiation,the essence of TCM,is based on various disease symptoms.Syndrome refers to the pathological generalization of a disease in certain stage,which is the principal contradiction at the time.The explicit characteristics of symptoms provide guidance for specific therapeutic target,thus promoting precision treatment.There are some problems existing at present.

2.2.1 Different Syndrome Classification Criteria

Syndrome classification is the base of syndrome differentiation and treatment.However,the syndrome classification criteria are disunity now. For example, there are various standards in The National Standard of the People's Republic of China·Disease Syndrome Classification and Code of TCM·The Name of Syndromes and Classification Code,TCM Industrial Standard of the People's Republic of China·Disease of TCM Syndrome Diagnosis Curative Standard,National Standard of the People's Republic of China·Syndrome of TCM Clinical Diagnosis and Treatment Term,Compile for Universal Use in Colleges and Universities Teaching Material· Diagnostics of TCM and Syndrome Standardization in TCM edited by Deng Tietao[13].This is restriction for the development of TCM clinical research. Some researchers [14]presented the principle of Chinese medicine syndrome differentiation and disease classification:acquire all of the phenotypic information of TCM syndrome and find out the relations among them on the basis of precision diagnosis with modern medical means，on which those syndromes can be reclassified,and as a result,patients will receive more elaborate diagnosis and more precise treatment.For the past few years,multivariate statistical analysis has been wildly used in the research of TCM syndrome classification.

Although there are some problems existing,it is still effective for the objective research of TCM syndrome classification identification[15].Obviously,in order to make the precision TCM syndrome classification come true,we should master multidisciplinary method and deepen the research of TCM syndrome classification,which will benefit the medical therapy,clinical research,evaluation of therapeutic efficiency,and even designing new drugs.All these efforts will make TCM more influential and acceptable on a global scale.

2.2.2 Inconsistent Syndrome Name

Syndrome differentiation is based on patients’symptoms and signs,so it tends to be subjective in syndrome naming.Take atrial fibrillation for example,its syndrome names in literature include pathogenic water attacking heart,phlegm stagnation obstructing meridian,deficiency of qi and blood,yin deficiency of heart and kidney, deficiency of pectoral qi,simultaneous occurrence of cold and heat,qi deficiency and blood stasis,fire excess from yin deficiency,heart blood stasis syndrome,yin deficiency and yang excess,qi deficiency of heart and lung,heart-kidney yang deficiency,stagnation of phlegm-damp,deficiency of liver-yin and kidney-yin,insufficiency of heart yin, deficiency of the kidney-yang,deficiency of both qi and yin.These various names have brought about difficulty in TCM clinical researches and the evaluation of curative effect.With the development of modern medicine,pathological examination,the golden standard of diagnosis,helps a lot in the practice of diagnosing diseases such as early-stage cancer that has few clinical symptoms in early phase.Other modern techniques such as biochemical test help a lot in early-stage metabolic syndrome diagnosis,a disease without specific syndrome characteristics.So unifying syndrome name is also a problem need to be solved.

2.2.3 Nonstandard Syndrome Diagnosis

The methods of syndrome differentiation consist of eight principal syndrome differentiation,six-meridian syndrome differentiation,differentiation of tri-jiao,viscera syndrome differentiation, defensive energy-nutrient-blood syndrome differentiation,differentiation of qi-blood-body fluid.These methods are macroscopical and nonrepresentational.It is very important to develop standard syndrome diagnosis in TCM to achieve precision syndrome differentiation,which will affect the repeatability and comparability of scientific researches and improve the level of clinical diagnosis and treatment directly[16].

Basing on epidemiology,Liu N[17]has developed standardized specification syndromes of TCM for Alzheimer's disease in Taiyuan.But it is not representative.Some researchers [18]also have suggested combining diseases with symptoms to study the standardization of TCM syndrome,including developing macroscopical diagnostic criteria of syndrome,setting up new system of syndrome differentiation on the basis of syndrome element,researching single syndrome in the guideline of scale.Data mining[19]is an edge discipline resulting from the development and intersection of artificial intelligence and database technology,dedicating to find essence and development trends hiding in data.Li JS,etc.[20]have developed standard syndrome diagnosis of diabetes mellitus type 2 in TCM with the method of “primary symptom and secondary symptom”based on data mining.Wang XW,etc.[21]have found out seven key symptoms of blood stasis syndrome on the basis of data mining.The accuracy rate of simple bayesian classifier model,established in line with these key symptoms for diagnosis of blood stasis syndrome has gone up to 96.6%.Further research is needed in achieving normative and precise standard for TCM syndrome diagnosis,in order to guide TCM clinical practice and research better.

3.Precision Treatment

Treatment based on syndrome differentiation and holistic view is individualized therapy method in TCM.In precision therapy,it is also need to adjust the therapeutic measures in accordance with changing circumstances,local conditions and variability of an individual.For syndrome differentiation,because of the skimble-scamble syndrome classification criteria,different syndrome names and nonstandard syndrome diagnosis,as well as the syndrome evolving in the progress of disease,the complexity of the syndrome and the subjectivity of the diagnosis,inaccurate syndrome differentiation seem to be inevitable.As a result,individualized treatments cannot be precise enough.To achieve precision therapy,some researches can be developed.

3.1 Precision Corresponding of Prescription and Medicine

Sun XL,etc.[22]have presented that there were a series of sub-sets of compositing symptoms signs during the spontaneous evolving based on the theory of topological structure.Those sub-sets of the syndromes can be related to corresponding therapeutic methods and recipes precisely.For instance,for the syndrome of spleen qi deficiency, invigorating spleen and supplementing qi should be taken to treat the signs of fatigue,weak breath and speak less,and the corresponding prescription is Sijunzi decoction,which consists of Dang Shen(Radix Salviae Miltiorrhizae),Bai Zhu (R hizoma Atractylodis Macrocephalae),Fu Ling(Poria),and Gan Cao(Radix Glycyrrhizae);to treat the signs of low appetite and indigestion,invigorating spleen should be taken, and the corresponding prescription is Jianpi pill,which consists of Dang Shen(Radix Salviae Miltiorrhizae),Bai Zhu(R hizoma Atractylodis Macrocephalae),Shan Zha(Fructus Crataegi),Chen Pi(Pericarpium Citri Reticulatae),Zhi Shi(Fructus Aurantii Immaturus),and Mai Ya(Fructus Hordei Germinatus);to treat the signs of abdominal distension,obstructions in the flow of vital energy should be removed by corresponding herbal medicines like Chen Pi(Pericarpium Citri Reticulatae),Mu Xiang(Radix Aucklandiae),Hou Po(Cortex Magnoliae Officinalis);to treat the signs of loose stool,dampness in human body should be removed to cure diarrhea,and the corresponding prescription is Shenling Baizhu powder,which consists of Dang Shen(Radix Salviae Miltiorrhizae),baizhu(Rhizoma Atractylodis Macrocephalae),Fu Ling(Poria),Gan Cao(Radix Glycyrrhizae),Lian Zi(Semen Nelumbinis),Yi Yi Ren(Semen Coicis),Sha Ren(Fructus Amomi Villosi),Bai Bian Dou(Semen Dolichoris Album),Jie Geng(Radix Platycodonis),and Shan Yao(Rhizoma Dioscoreae);to treat the signs of loose and slow pulse or weak pulse,pale tongue with whitish fur,spleen should be invigorated and qi should be supplemented through herbs like Dang Shen(Radix Salviae Miltiorrhizae) and Bai Zhu (R hizoma Atractylodis Macrocephalae).Patients suffering from all those symptoms above should be treated by invigorating spleen to promote digestion,drying dampness to stop diarrhea,and removing obstructions in energy flow through Jianpi pill and Shenling Baizhu powder adding other herbs such as Chen Pi(Pericarpium Citri Reticulatae),Mu Xiang(Radix Aucklandiae),Hou Po(Cortex Magnoliae Officinalis).As mentioned above,this will become an innovative approach in the research of accurate corresponding connections between prescriptions and drugs,but its popularization and clinical efficacy still need to be verified.

3.2 The Correspondence of Prescription and Syndrome

The correspondence of prescription and syndrome refers to that the indications and principles of prescriptions correspond to the primary symptoms and pathogenesis demonstrating in patients.This is widely applicable in clinical practice and recommended by many medical experts.

A published paper[23]studied the relations between prescriptions and syndromes through literature information data mining and concluded the core pulse and symptoms corresponding to xiaoqinglong decoction,which included fever with aversion to cold,cough and asthma,white tongue,glossy tongue fur,and floating pulse,the core herbs are Ma Huang(Herba Ephedrae),Gui Zhi(Ramulus Cinnamomi),Shao Yao(Radix Paeoniae Alba),Wu Wei Zi(Fructus Schisandrae Chinensis), Gan Jiang (Rhizoma Zingiberis),Xi Xin(Herba Asari),Ban Xia(Rhizoma Pinelliae),and Gan Cao(Radix Glycyrrhizae).The result demonstrated the precise relations between prescriptions and syndromes of Xiaoqinglong decoction.Another clinical data mining research of 1105 hypertension patients[24]in correspondence of prescriptions and syndromes showed that the essential syndrome of hypertension was hyperactivity of yang due to yin deficiency,and accompanied by five specific syndromes including hepatorenal yin deficient syndrome,liver-fire excess syndrome,excessive accumulation of phlegm dampness syndrome,syndrome of deficiency of heart and kidney,liver depression and damaging shen syndrome.Basic prescription for this disease was Tianma Gouteng decoction,while the five specific syndromes should be treated by Qiju Dihuangwan decoction,Longdan Xieganwan decoction, Banxia Baizhu Tianma decoction,Qifu decoction,and Chaihu Shugan powder,respectively.

The reasonable clinical use of the proprietary Chinese medicines that has been approved by Chinese Food and Drug Administration(CFDA)has been viewed as a paradigm of correspondence of prescription and syndrome due to its quantitative compositions and dosage easy to be evaluated.For example,qiliqiangxin capsule [25] has obvious curative effect and is exactly safe in the treatment of mild-to-moderate chronic heart failure caused by hypertension or coronary heart disease manifested with syndromes like yang qi deficiency,blood stasis and water stagnation.Another multicenter,randomized,double-blind,parallel-group,placebo-controlled study of 512 chronic heart failure patients has shown that qiliqiangxin capsule reduced the level of NT-proBNP[26].In addition,Shensongyangxin capsule is effective and can be widely used in clinical treatment of premature ventricular contractions (PVC) with manifestations of qi and yin deficiency,heart-collateral obstruction. However, due to its low-quality methodology,small sample size and high clinical heterogeneity,evidence in its curative effect on PVC[27,28]is weak,as the meta-analysis concluded.These problems are also impeding the development of clinical research of TCM.In the future,some steps should be taken,such as reasonable design,multicenter and large sample studies and developing core outcome sets in clinical trials of TCM,establishing standard reporting items, reducing clinical heterogeneity between outcomes reported in different trials,to enhance the quality of evidence[29].

3.3 Clarifying the Relation of Dose-Effect/Toxic-Effect in TCM

Different dosage leads to multifarious therapeutic effects.The characteristics of Chinese herb dosage include:(a)efficacy differs in various dosages;(b)dosage differs in various individual constitutions,ages,genders or illnesses;(c)dosage changes with disparate herbal formulations and preparations;(d)dosage changes with herbal qualities and traits;(e)dosage varies according to its effective dose and modern pharmacological researches [30]. However, the existing problems in TCM dosage include:(a)there is no standard stipulation of dosage;(b)the formulated dosage ranges cannot be applied in clinical application;(c)there are great disparities among the formulated D-values of TCM dosage;(d)some herbs dosage has fractional part;(e)overuse in clinical practice[31].These existing problems, starting lately in dose-effect/toxic-effect researches in TCM,lacking enough experimental data,as well as the complexity of Chinese herbal medicine itself,all have enhanced the difficulty of researches.Since medicine dosage influences the therapeutic effect greatly,even though the syndrome differentiation is precise,treatment effects still cannot be ensured.Low doses of herbs may result in futile treatment,while high doses of herbs may result in toxic and side effects.Therefore,developing researches in dose-effect/toxic-effect and setting up herb dosage standards should be the key mission to PM,as well as to achieve modernization and internationalization of TCM.

3.4 New Drug Design and Creation

Network pharmacology has been developing in TCM for a few years.Network pharmacology is a new discipline based on systematic biology and poly-pharmacology,which analyzes the network of biological system and chooses special signal nodes for drug molecular design of multiple targets [32].Combining network pharmacology with systematic biology to study the interaction between chemical system of TCM formula and the biological system of human body,Li S[33]has presented the concept of network target, which helps to find out the pharmaceutic rule of TCM and their effective substances and give out further explanation for their correlative mechanism to be used in future precise TCM compositions and researches.This will be a key point to study the mechanical network of TCM integrally,to instruct clinical prescription.Also,it is an innovative approach [34]to study the relations between drugs and symptoms,and construct herbal molecule-symptom network,which is a new approach to screen drug-likeness and discovery new drugs independently to abnormal training data,and providing evidence for the development of new drugs.Definitely,the results from network pharmacology need experimental validation.

3.5 Improving the Quality Standard of TCM

The quality of TCM is related to curative effect and safe.The low quality of TCM would affect the efficacy,no matter how precise of diagnosis and treatment are,However,the quality standard of TCM is existing a lot of problems,such as(a)the mode of new drug design and creation copied the mode of chemical medicine,the ingredients that need to be detected in the quality standard is not related to the actual effect;(b)the limit scope of ingredients is inaccurate and lack of dose-effect/toxic-effect experiment;(c)the low level of TCM quality standard;(d)the limitation of TCM quality standard research method;(e)the defect of TCM chemical fingerprint study[35].Therefore,it is necessary to establish high quality standard of TCM with pharmacodynamics indicators or metabonomics technology in the future[36].Overall,there should be a long way to go for us to develop the PM,during which TCM cannot be neglected.Moreover,more advanced techniques will be needed in the future to make the prevention,diagnosis and treatment of TCM more precise and effective and to improve the international influence of Chinese medicine.

Competing interests

The authors declare that they have no competing interests.

Acknowledgment

Supported by Key Project of National Natural Science Foundation of China(No.81430098).

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