美国《Science》2014年12月19日推出中医药特刊，刊登北京中医药大学校长的文章：《Zheng: A systemsbiology approach to diagnosis and treatments》
为便于学习，现为大家提供我科林玮涛的译文一篇，供大家参考。
“证”?? 疾病诊疗的系统生物学方法
传统中医学是一种古老的医疗实践体系。它强调人体自身的统一性和人与自然环境的统一性。作为中医学的一个重要概念，“证”是人体在特定的内在或外在条件下的生理或病理概括，通常是由中医师将四诊（望、闻、问、切）所收集的资料，包括临床症状和体征，运用中医学理论进行综合分析并概括出来的疾病本质。正确辨证是疾病诊断和治疗的基础。
在西方医学中，疾病是指一种特定的病理状态，影响着人体的局部或整体，并具有特定的症状。相比之下，“证”是中医对疾病的独特定义，涵括了患者所有的症状。由于人体自身内部的高度统一和谐，从分子水平上完全独立地对不同疾病进行研究是十分困难的。证候的研究亦如此。再者，证候是动态变化并可相互兼夹的。有史以来，“证”一直是中医确定治法、处方遣药的重要准则。证候方面的研究缺乏，使得其潜在的生物学原理及证候、疾病和处方药物之间的联系难以被理解。既往有学者尝试将中医辨证与现代生物医学的诊断方法相结合，但其结果并未尽如人意。许多众所周知的经方，如六味地黄丸、金匮肾气丸，已经久为中医师辨证治病所用，但这类以证候为导向的治疗在证候和疗效方面仍缺乏循证医学依据。从分子水平上多尺度地对“证”的生物学基础进行研究，使其在生物学和机械论的角度上难以被理解。因此，我们提出构想，建立一种综合的证候图，以分子细胞学联系为依据，将所有的“证”联结在一起。另外，我们建议创立名为“证候组学”(Zhengome)的组学新领域，以网状结构为基础单位，从分子水平和系统水平来研究人体的层次结构。全面地理解“证候组学”，需要引入大量的证据来源，从基因共享到蛋白质相互作用、环境因素共享、共同的治疗、临床表现，目的是为把握不同证候之间的关系。“证”通过阴阳、表里、寒热、虚实来描述患者的病理状态，从而为处方遣药提供依据。现代组学技术通过系统生物学的方法，结合生物信息学和生物网络模型，已被应用于证候间的差异性研究和寻找新的生物标记物。例如，有研究显示，辨证为“热证”和“寒证”的类风湿性关节炎患者具有基因和代谢组学上的差异??热证患者的细胞凋亡比寒证患者更活跃。再者，有学者通过采用一种以网状结构为基础的计算模型，从神经-内分泌-免疫的角度理解证候的涵义，结果发现寒证和热证与代谢-免疫失衡密切相关。有人对黄疸患者的尿液代谢组学及“阳黄”(急性)与“阴黄”(慢性)两种分型进行研究，并找出几种生物标志物代谢产物。然而，目前大多数研究仅仅依靠一种或两种指纹图谱技术的方法，而缺乏一种能将来自不同组学的数据整合在一起的方法。这些研究没有将分子水平数据的分析与临床变量结合在一起，由此可能失去了产生更具说服力的结论的机遇。鉴于既往研究的局限性，未来我们需致力于对大量不同证型患者的数据进行各类组学水平的综合分析，并需涵盖疾病预后和治疗工具方面的研究。再者，将患者的临床信息和分子水平数据结合在一起，可以为证候的理论解释提供循证依据。证候可以随着疾病的进展而动态变化。在疾病的各个不同阶段进行正确辨证，能为及时调整方药提供有利依据。采用动态的网状结构模型，疾病病程可以被定位为网状结构中的时空变化。
动态调整处方治疗后所发生的证候变化可用于辨别动态生物网状结构中的重要因素。正确的网络微扰模型和稳健性及拓扑分析可以揭示疾病进展或演变潜在的相关基因和治疗靶点。在建立模型和模型的过程中，需将疾病在特定证候中不同方面的表现（例如主症和并发症）、心理因素、社会因素和环境因素之间的关系考虑在内，旨在揭示复杂疾病的动态属性。“证候组学”与动态模型的结合，对建立精准量化的证候研究模型、创立新的疾病研究系统有着潜在意义。
尽管基因组学、转录组学、蛋白质组学和代谢组学已取得较大进展，合理的药物设计和新药研发仍经常遭遇失败，耗费巨大，阻碍着现代药物的研发。
纵观中医药发展史，在传统药物的研发中，以证候为导向的药物研发取得了巨大的成就。但是这对于西方医学来说是一种全新的模式。因此，如何将以证候为导向的药物研发融入到现代药物研发的潮流中，将是一大难题。在此，我们提出在系统药理学框架中建立“从证到中医”和“从中医到证”的策略，旨在研究生物系统和开发新型的治疗方法。“从证到中医”为从证候的诊断到中药处方之间提供了渠道，包括证候的辨别、证候和相关的基因、蛋白及药效反向定位的识别、网状结构系统的构建与分析和最终找出有效的中药疗法。实际上，这样的策略可作为一种反向定位和筛选的途径，从适用于多种证型及相关疾病的天然药物中寻找并研发新药，目的是为了帮助研究者找出药用植物、多成分中药处方或复方合剂的活性成分。而这种新策略已经成功应用于我们的一个研究中。我们在补益气血的中药中找到其有效成分、靶点及在治疗气血不足证中的作用途径。“从中医到证”是指从中药或中药复方到证候辨别的整个系统评估的过程，包括中药的采集与分类，药物吸收、分布、代谢、排泄和具有毒性的成分，药物靶向的检查和组织定位，构建和分析网状结构系统，最终辨别证候/疾病。这种策略可能有助于在天然药物中找出新型的多靶点药物。举个非常显著的例子，就是冠心病气虚血瘀证和相应辨证用药的系统分析，结果提示该类用药中的活血药具有扩张血管、改善循环、降低血液粘度、调节血脂的作用，而补气药具有促进能量代谢和抗炎的疗效。“从中医到证”的策略有助于阐释中药及其复方的药理学作用。在我们正在开展的“脾虚证”研究中，我们采用SAPAS、RNA测序、脂类代谢组学、蛋白质代谢组学和转录组学的方法对患者提供的标本进行分析，以解释脾虚证的发病机制和人体复杂反应。
我们准备根据“从中医到证”的策略，从药物研发的角度，系统地研究广泛用于治疗脾虚证的四君子汤，目的在于探讨此方为何能够调节免疫反应、促进血液循环和改善胃肠道功能。
尽管以证候为导向的药物研发已经取得一定进展，但其未来的发展仍需要多学科技术的结合和创新。这将促进对疾病的多因素理解和新型疗法的发展。
（译者后记：粗略翻译的一篇文章，供大家参考学习。学识尚浅，对于文中的不足之处，敬请各位老师、同学、专业人士批评指正！谢谢！）
附原文：
Zheng: A systems biologyapproach to diagnosis and treatments
TraditionalChinese medicine (TCM) is an ancient medical practicesystem which emphasizesregulating the integrity of the human bodyand its interrelationship withnatural environments. As a keyconcept in TCM, Zheng (meaning syndrome orpattern)is the overallphysiological and/or pathological pattern of the humanbody inresponse to a given internal and external condition, which usuallyisan abstraction of internal disharmony defined by a comprehensiveanalysis ofthe clinical symptoms and signs gathered by apractitioner using inspection,auscultation, olfaction,interrogation, and palpation of the pulses (1).Correctlyidentifying the Zheng is fundamental for the diagnosis andtreatmentof diseases.to systems level is important for advancingthe identificationandtreatment of these syndromes, and forproviding more objective and quantitativediagnostic criteria.
In Western medicine, a disease is a particular abnormal andpathological conditionthat affects part or all of the human bodyand is often construed as a medicalcondition associated withspecific symptoms. By contrast, Zheng puts forth avery differentdefinition of a disease and encompasses all of the symptomsapatient presents.
Becauseof the highly interconnected nature of the humaninteractome, it is difficultto study different diseases at themolecular level completely independent ofone another (3), and thisissue also applies to Zhengs. Moreover, Zhengs aredynamic withchanging boundaries, overlapping symptoms,Moreover, Zheng hasbeenhistorically applied as the key pathological principle guidingthe prescriptionof herbal formulas (Figure 1).
A lackof research on Zheng has left us with little understanding ofits underlyingbiology or the relationships between differentZhengs, diseases, and drugs.Moreover, there have been attempts tointegrate Zheng differentiation withmodern biomedical diagnosticmethods, though these efforts have not achievedthe desired results(2). Many well-known herbal recipes, such as Liu Wei DiHuang Wanand Jin Kui Shen Qi Wan, have long been used for theclinicaltreatment of Zheng disorders; however, Zheng-guidedtreatments are still scarcedue to the lack of evidence-basedinterpretations of syndromes and treatmentefficacies. Thus,investigating the biological basis of Zhengs from a molecularand amultiscale nature, which makes them difficult to understand atabiological and mechanistic level. Thus, we propose that acomprehensive Zhengmap be constructed that links together all theZhengs based on their molecularand cellular relationships. Further,we suggest creating the “Zhengome” as a new 'omics field, in whicha networkis the basic research unit used to investigate thehierarchy present in thehuman body,from the molecular to thesystems level. Acomprehensiveunderstanding of the Zhengome requiresus to bring togethermultiple sources of evidence, from shared genesto proteinprotein interactions,shared environmental factors, commontreatments, and phenotypic and clinicalmanifestations, in order tocapture the relationships between the differentZhengs.
Zheng uses the Yin-Yang, exterior-interior, cold-heat, anddeficiency-excessdefinitions to describe patients’ conditions,which are then managed byZheng-specific recipes (Figure 1). Modern'omics techniques combined withbioinformatics and bionetwork modelsthrough a systems biology approach havebeen applied to investigatethe differences between Zhengs and to identifynovel biomarkers. Forinstance, rheumatoid arthritis (RA) patients differentiatedon thebasis of “hot” and “cold” Zhengs have been shown to beassociatedwith different underlying genomic and metabolomicprofiles, with the RA hotgroup showing more apoptotic activity thanthe cold group (4). Additionally, Liet al. used a network-basedcomputational model to understand Zheng in thecontext of theneuro-endocrine-immune network and found that cold and hotZhengswere closely related to a metabolism-immune imbalance (5). Wangandcolleagues investigated the urine metabolome of patients withjaundice syndromeand its two subtypes of Yang Huang (acute) and YinHuang (chronic), andidentified several biomarker metabolites (6).However, most of the currentstudies have relied on only one or twoapproaches for molecular profiling and havelacked an efficientmethod to integrate data obtained at different 'omiclevels. Thesestudies also did not look at combining the analysis ofmoleculardata with clinical variables, possibly missing anopportunity to generate moreconvincing conclusions. Considering thelimitations of past studies, futureefforts should integrate ananalysis for all levels of 'omics (e.g., genomics,transcriptomics,epigenomics, and proteomics) data from a large number ofpatientsamples for different Zhengs and include an investigation oftheprognostic and therapeutic utilities of the data as a whole.Moreover,combining these molecular data with patients’ clinicalinformation could provideevidence-based theoretical interpretationsfor Zhengs and enable an assessmentof Zheng-based therapeuticapproaches.
Zhengs may change dynamically during disease progression.Differentiating the specificZheng involved in each stage of adisease could provide valuable guidance forprescribing a dynamictherapeutic recipe. Using dynamic network modeling, adiseaseprocess can be conceptualized as spatio-temporal changes innetworkstructures. The changes associated with a Zheng underdynamic therapy can beused to identify the key factors in thedynamic biological networks. Appropriatenetwork perturbation modelsand subsequent robustness and topology analysiscould help unveilpotential disease-related genes or therapeutic targetsinvolved in adisease’s progression or evolution (7). Therelationships betweenthe different aspects of a disease (e.g., main symptomsversuscomplications) in a specific Zheng as well as the psychological,social,and even environmental factors should be taken into accountduring the modelingand simulation process in order to uncover thedynamic nature of complexdiseases.Combining a Zhengome approachwith dynamic modeling has the potentialfor establishing an accurateand quantitative Zheng research model, as well asfor creating a newsystem for performing disease research.
Despite considerable progress in genome, transcriptome,proteome,and metabolome-basedhigh throughput screening methods and inrational drug design, drug discoveryoften encounters considerablecostly failures that challenge the fidelity ofthe modern drugdiscovery system. Zheng-driven drug discovery has showntremendoussuccess for traditional drug discovery throughout Chinesemedicine’s history. However, since this concept iscompletely new toWestern medicine, it is no easy task to incorporateZheng-drivendrug discovery into modern drug discovery workflows. Here,wepropose the “Zheng to TCM” and “TCM to Zheng” strategies withinthe framework of systemspharmacology to investigate biologicalsystems and develop new therapeutics(Figure 2). The first strategy,Zheng to TCM, proposes developing a pipelinefrom Zheng diagnoses toTCM drugs,including differentiating Zhengs,identifyingZheng-related diseases and the associated genes andproteins, reverse targetingof drug effects, constructing andanalyzing network/systems, and finally identifyingeffective herbalmedicines (8). In effect, this strategy can be considered areversetargeting and screening approach that is designed to uncover drugsfromnatural products that can target multiple Zhengs or relateddiseases. The goalof this method is to help researchers identifythe active components withinmedicinal plants and multi-ingredientsynergistic herbal formulas or drugcombinations (9). In fact, thisnovel strategy has already been successfullyapplied in a qi-bloodstudy, where we identified the active compounds in theqi-enrichingand blood-tonifying herbs, their targets, and thecorrespondingpathways involved in the treatment of qi and blooddeficiency syndromes (8).The second strategy, TCM to Zheng,consists of a wholesystem evaluation processstarting with herbs orherbal formulas and culminating in identifying theZhengs. Thisprocess includes the initial collection and classification ofherbalmedicines; screening the ingredients for absorption,distribution,metabolism, excretion, and toxicity (ADME/T);performing targeted drugscreenings and tissue localization;constructing and analyzing networks; andfinally identifyingZhengs/diseases (10). Using this strategy, it is possibletoidentify novel multitarget drugs in natural products (11). Oneparticularlystriking example is the systematic analysis of bloodstasis and qi deficiencysyndrome in coronary heart disease and theherbal drugs used to treat thesyndromes.The results indicate thatthe herbs for eliminating blood stasis havepharmacological activitythat acts to dilate blood vessel, improve themicrocirculation,reduce blood viscosity, and regulate blood lipid, whileqi-enhancingherbs have the potential for enhancing energy metabolismandantiinflammatory activity (12). The TCM to Zheng strategy canalso help toelucidate the pharmacological effectiveness of herbsand formulas.
In ourongoing work investigating Pi-deficiency syndrome(PDS) in thecontext of Zheng,we are analyzing patient samples using thesequencing alternativepolyadenylation sites (SAPAS) method, RNAsequencing (13), lipid metabolomics,proteomics, and transcriptomicsin order to decipher the pathogenesis andcomplex responses of thehuman body to PDS. From a drug developmentperspective, we plan tosystematically investigate the Si Jun Zi decoction, awidely usedherbal recipe for PDS, within the framework of the “TCM to Zheng”strategy, so as to understand why thisrecipe can regulate theimmune response, stimulate blood circulation, andadjustgastrointestinal digestive functions. Despite the progressinZheng-guided drug discovery, its future success requires theintegration ofmultidisciplinary technologies, together with furtherinnovations in thesetechnologies, to facilitate the understandingof multifactorial diseases andthe development of new therapies.
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发表于 2015-1-14 21:12:08
