美國《Science》2014年12月19日推出中醫藥特刊，刊登我校校長徐安龍的文章，全文如下：
Zheng: A systems biology approach to diagnosis and treatments
Traditional Chinese medicine (TCM) is an ancient medical practice system which emphasizes regulating the integrity of the human body and its interrelationship with natural environments. As a key concept in TCM, Zheng (meaning syndrome or pattern) is the overall physiological and/or pathological pattern of the human body in response to a given internal and external condition, which usually is an abstraction of internal disharmony defined by a comprehensive analysis of the clinical symptoms and signs gathered by a practitioner using inspection, auscultation, olfaction, interrogation, and palpation of the pulses (1). Correctly identifying the Zheng is fundamental for the diagnosis and treatment of diseases. Moreover, Zheng has been historically applied as the key pathological principle guiding the prescription of herbal formulas (Figure 1).
A lack of research on Zheng has left us with little understanding of its underlying biology or the relationships between different Zhengs, diseases, and drugs. Moreover,there have been attempts to integrate Zheng differentiation with modern biomedical diagnostic methods, though these efforts have not achieved the desired results (2). Many well-known herbal recipes, such as Liu Wei Di Huang Wan and Jin Kui Shen Qi Wan, have long been used for the clinical treatment of Zheng disorders; however, Zheng-guided treatments are still scarce due to the lack of evidence-based interpretations of syndromes and treatment efficacies. Thus,investigating the biological basis of Zhengs from a molecular to systems level is important for advancing the identification and treatment of these syndromes, and for providing more objective and quantitative diagnostic criteria.
Zheng-guided disease research
In Western medicine, a disease is a particular abnormal and pathological condition that affects part or all of the human body and is often construed as a medical condition associated with specific symptoms. By contrast, Zheng puts forth a very different definition of a disease and encompasses all of the symptoms a patient presents.
Because of the highly interconnected nature of the human interactome, it is difficult to study different diseases at the molecular level completely independent of one another (3),and this issue also applies to Zhengs. Moreover, Zhengs are dynamic with changing boundaries, overlapping symptoms,and a multiscale nature, which makes them difficult to understand at a biological and mechanistic level. Thus, we propose that a comprehensive Zheng map be constructed that links together all the Zhengs based on their molecular and cellular relationships. Further, we suggest creating the “Zhengome” as a new 'omics field, in which a network is the basic research unit used to investigate the hierarchy present in the human body,from the molecular to the systems level. A comprehensive understanding of the Zhengome requires us to bring together multiple sources of evidence, from shared genes to proteinprotein interactions, shared environmental factors, common treatments, and phenotypic and clinical manifestations, in order to capture the relationships between the different Zhengs.
Zheng uses the Yin-Yang, exterior-interior, cold-heat, and deficiency-excess definitions to describe patients’ conditions,which are then managed by Zheng-specific recipes (Figure 1).Modern 'omics techniques combined with bioinformatics and bionetwork models through a systems biology approach have been applied to investigate the differences between Zhengs and to identify novel biomarkers. For instance, rheumatoid arthritis (RA) patients differentiated on the basis of “hot” and “cold” Zhengs have been shown to be associated with different underlying genomic and metabolomic profiles, with the RA hot group showing more apoptotic activity than the cold group (4). Additionally, Li et al. used a network-based computational model to understand Zheng in the context of the neuro-endocrine-immune network and found that cold and hot Zhengs were closely related to a metabolism-immune imbalance (5). Wang and colleagues investigated the urine
metabolome of patients with jaundice syndrome and its two subtypes of Yang Huang (acute) and Yin Huang (chronic), and identified several biomarker metabolites (6). However, most of the current studies have relied on only one or two approaches for molecular profiling and have lacked an efficient method to integrate data obtained at different 'omic levels.These studies also did not look at combining the analysis of molecular data with clinical variables, possibly missing an opportunity to generate more convincing conclusions. Considering the limitations of past studies, future efforts should integrate an analysis for all levels of 'omics (e.g., genomics,transcriptomics, epigenomics, and proteomics) data from a large number of patient samples for different Zhengs and include an investigation of the prognostic and therapeutic utilities of the data as a whole. Moreover, combining these molecular data with patients’ clinical information could provide evidence-based theoretical interpretations for Zhengs and enable an assessment of Zheng-based therapeutic approaches.
Zhengs may change dynamically during disease progression.Differentiating the specific Zheng involved in each stage of a disease could provide valuable guidance for prescribing a dynamic therapeutic recipe. Using dynamic network modeling, a disease process can be conceptualized as spatio-temporal changes in network structures. The changes associated with a Zheng under dynamic therapy can be used to identify the key factors in the dynamic biological
networks. Appropriate network perturbation models and subsequent robustness and topology analysis could help unveil potential disease-related genes or therapeutic targets involved in a disease’s progression or evolution (7). The relationships between the different aspects of a disease (e.g.,main symptoms versus complications) in a specific Zheng as well as the psychological, social, and even environmental factors should be taken into account during the modeling and simulation process in order to uncover the dynamic nature of complex diseases. Combining a Zhengome approach with dynamic modeling has the potential for establishing an accurate and quantitative Zheng research model, as well as for creating a new system for performing disease research.
Zheng-driven drug discovery
Despite considerable progress in genome, transcriptome,proteome, and metabolome-based high throughput screening methods and in rational drug design, drug discovery often encounters considerable costly failures that challenge the fidelity of the modern drug discovery system. Zheng-driven drug discovery has shown tremendous success for traditional drug discovery throughout Chinese medicine’s history.However, since this concept is completely new to Western medicine, it is no easy task to incorporate Zheng-driven drug discovery into modern drug discovery workflows.
Here, we propose the “Zheng to TCM” and “TCM to Zheng” strategies within the framework of systems pharmacology to investigate biological systems and develop new therapeutics(Figure 2). The first strategy, Zheng to TCM, proposes developing a pipeline from Zheng diagnoses to TCM drugs,including differentiating Zhengs, identifying Zheng-related diseases and the associated genes and proteins, reverse targeting of drug effects, constructing and analyzing network/systems, and finally identifying effective herbal medicines (8). In effect, this strategy can be considered a reverse targeting and screening approach that is designed to uncover drugs from natural products that can target multiple Zhengs or related diseases. The goal of this method is to help researchers identify the active components within medicinal plants and multi-ingredient synergistic herbal formulas or drug combinations (9). In fact, this novel strategy has already been successfully applied in a qi-blood study, where we identified the active compounds in the qi-enriching and blood-tonifying herbs, their targets, and the corresponding pathways involved in the treatment of qi and blood deficiency syndromes (8).
The second strategy, TCM to Zheng, consists of a wholesystem evaluation process starting with herbs or herbal formulas and culminating in identifying the Zhengs. This process includes the initial collection and classification of herbal medicines; screening the ingredients for absorption,distribution, metabolism, excretion, and toxicity (ADME/T);performing targeted drug screenings and tissue localization; constructing and analyzing networks; and finally identifying Zhengs/diseases (10). Using this strategy, it is possible to identify novel multitarget drugs in natural products (11). One particularly striking example is the systematic analysis of blood stasis and qi deficiency syndrome in coronary heart disease and the herbal drugs used to treat the syndromes. The results indicate that the herbs for eliminating blood stasis have pharmacological activity that acts to dilate blood vessel, improve the microcirculation, reduce blood viscosity,and regulate blood lipid, while qi-enhancing herbs have the potential for enhancing energy metabolism and anti-inflammatory activity (12). The TCM to Zheng strategy can also help to elucidate the pharmacological effectiveness of herbs and formulas.
In our ongoing work investigating Pi-deficiency syndrome (PDS) in the context of Zheng, we are analyzing patient samples using the sequencing alternative polyadenylation sites (SAPAS) method, RNA sequencing (13), lipid metabolomics,proteomics, and transcriptomics in order to decipher the pathogenesis and complex responses of the human body to PDS. From a drug development perspective, we plan to systematically investigate the Si Jun Zi decoction, a widely used herbal recipe for PDS, within the framework of the “TCM to Zheng” strategy, so as to understand why this recipe can regulate the immune response, stimulate blood circulation,and adjust gastrointestinal digestive functions. Despite the progress in Zheng-guided drug discovery, its future success requires the integration of multidisciplinary technologies,together with further innovations in these technologies, to facilitate the understanding of multifactorial diseases and the development of new therapies.
References
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4. H. van Wietmarschen et al., J. Clin. Rheumatol. 15, 330 (2009).
5. S. Li et al., IET Syst. Biol. 1, 51 (2007).
6. X. Wang et al., Mol. Cell. Proteomics 11, 370 (2012).
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“證”—— 疾病診療的系統生物學方法
翻譯：林瑋濤
傳統中醫學是一種古老的醫療實踐體系。它強調人體自身的統一性和人與自然環境的統一性。作為中醫學的一個重要概念，“證”是人體在特定的內在或外在條件下的生理或病理概括，通常是由中醫師將四診（望、聞、問、切）所收集的資料，包括臨床癥狀和體征，運用中醫學理論進行綜合分析并概括出來的疾病本質。正確辨證是疾病診斷和治療的基礎。
在西方醫學中，疾病是指一種特定的病理狀態，影響著人體的局部或整體，并具有特定的癥狀。相比之下，“證”是中醫對疾病的獨特定義，涵括了患者所有的癥狀。由于人體自身內部的高度統一和諧，從分子水平上完全獨立地對不同疾病進行研究是十分困難的。證候的研究亦如此。再者，證候是動態變化并可相互兼夾的。有史以來，“證”一直是中醫確定治法、處方遣藥的重要準則。證候方面的研究缺乏，使得其潛在的生物學原理及證候、疾病和處方藥物之間的聯系難以被理解。既往有學者嘗試將中醫辨證與現代生物醫學的診斷方法相結合，但其結果并未盡如人意。許多眾所周知的經方，如六味地黃丸、金匱腎氣丸，已經久為中醫師辨證治病所用，但這類以證候為導向的治療在證候和療效方面仍缺乏循證醫學依據。從分子水平上多尺度地對“證”的生物學基礎進行研究，使其在生物學和機械論的角度上難以被理解。因此，我們提出構想，建立一種綜合的證候圖，以分子細胞學聯系為依據，將所有的“證”聯結在一起。另外，我們建議創立名為“證候組學”(Zhengome)的組學新領域，以網狀結構為基礎單位，從分子水平和系統水平來研究人體的層次結構。全面地理解“證候組學”，需要引入大量的證據來源，從基因共享到蛋白質相互作用、環境因素共享、共同的治療、臨床表現，目的是為把握不同證候之間的關系。“證”通過陰陽、表里、寒熱、虛實來描述患者的病理狀態，從而為處方遣藥提供依據。現代組學技術通過系統生物學的方法，結合生物信息學和生物網絡模型，已被應用于證候間的差異性研究和尋找新的生物標記物。例如，有研究顯示，辨證為“熱證”和“寒證”的類風濕性關節炎患者具有基因和代謝組學上的差異——熱證患者的細胞凋亡比寒證患者更活躍。再者，有學者通過采用一種以網狀結構為基礎的計算模型，從神經-內分泌-免疫的角度理解證候的涵義，結果發現寒證和熱證與代謝-免疫失衡密切相關。有人對黃疸患者的尿液代謝組學及“陽黃”(急性)與“陰黃”(慢性)兩種分型進行研究，并找出幾種生物標志物代謝產物。然而，目前大多數研究僅僅依靠一種或兩種指紋圖譜技術的方法，而缺乏一種能將來自不同組學的數據整合在一起的方法。這些研究沒有將分子水平數據的分析與臨床變量結合在一起，由此可能失去了產生更具說服力的結論的機遇。鑒于既往研究的局限性，未來我們需致力于對大量不同證型患者的數據進行各類組學水平的綜合分析，并需涵蓋疾病預后和治療工具方面的研究。再者，將患者的臨床信息和分子水平數據結合在一起，可以為證候的理論解釋提供循證依據。證候可以隨著疾病的進展而動態變化。在疾病的各個不同階段進行正確辨證，能為及時調整方藥提供有利依據。采用動態的網狀結構模型，疾病病程可以被定位為網狀結構中的時空變化。
動態調整處方治療后所發生的證候變化可用于辨別動態生物網狀結構中的重要因素。正確的網絡微擾模型和穩健性及拓撲分析可以揭示疾病進展或演變潛在的相關基因和治療靶點。在建立模型和模型的過程中，需將疾病在特定證候中不同方面的表現（例如主癥和并發癥）、心理因素、社會因素和環境因素之間的關系考慮在內，旨在揭示復雜疾病的動態屬性。“證候組學”與動態模型的結合，對建立精準量化的證候研究模型、創立新的疾病研究系統有著潛在意義。
盡管基因組學、轉錄組學、蛋白質組學和代謝組學已取得較大進展，合理的藥物設計和新藥研發仍經常遭遇失敗，耗費巨大，阻礙著現代藥物的研發。
縱觀中醫藥發展史，在傳統藥物的研發中，以證候為導向的藥物研發取得了巨大的成就。但是這對于西方醫學來說是一種全新的模式。因此，如何將以證候為導向的藥物研發融入到現代藥物研發的潮流中，將是一大難題。在此，我們提出在系統藥理學框架中建立“從證到中醫”和“從中醫到證”的策略，旨在研究生物系統和開發新型的治療方法。 “從證到中醫”為從證候的診斷到中藥處方之間提供了渠道，包括證候的辨別、證候和相關的基因、蛋白及藥效反向定位的識別、網狀結構系統的構建與分析和最終找出有效的中藥療法。實際上，這樣的策略可作為一種反向定位和篩選的途徑，從適用于多種證型及相關疾病的天然藥物中尋找并研發新藥，目的是為了幫助研究者找出藥用植物、多成分中藥處方或復方合劑的活性成分。而這種新策略已經成功應用于我們的一個研究中。我們在補益氣血的中藥中找到其有效成分、靶點及在治療氣血不足證中的作用途徑。“從中醫到證”是指從中藥或中藥復方到證候辨別的整個系統評估的過程，包括中藥的采集與分類，藥物吸收、分布、代謝、排泄和具有毒性的成分，藥物靶向的檢查和組織定位，構建和分析網狀結構系統，最終辨別證候/疾病。這種策略可能有助于在天然藥物中找出新型的多靶點藥物。舉個非常顯著的例子，就是冠心病氣虛血瘀證和相應辨證用藥的系統分析，結果提示該類用藥中的活血藥具有擴張血管、改善循環、降低血液粘度、調節血脂的作用，而補氣藥具有促進能量代謝和抗炎的療效。“從中醫到證”的策略有助于闡釋中藥及其復方的藥理學作用。在我們正在開展的“脾虛證”研究中，我們采用SAPAS、RNA測序、脂類代謝組學、蛋白質代謝組學和轉錄組學的方法對患者提供的標本進行分析，以解釋脾虛證的發病機制和人體復雜反應。
我們準備根據“從中醫到證”的策略，從藥物研發的角度，系統地研究廣泛用于治療脾虛證的四君子湯，目的在于探討此方為何能夠調節免疫反應、促進血液循環和改善胃腸道功能。盡管以證候為導向的藥物研發已經取得一定進展，但其未來的發展仍需要多學科技術的結合和創新。這將促進對疾病的多因素理解和新型療法的發展。
美國Science期刊于1880年由著名發明家愛迪生投資1萬美元創辦，1894年成為美國最大的科學團體“美國科學促進會”(AAAS)的官方非盈利性刊物。
（宣傳部）