【汇科研】徐大大发表在《Science》中医药特刊的论文,翻译有奖!-百语文学网

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《Science》杂志连同英国的《Nature》杂志被誉为世界上两大最顶级杂志，代表了人类自然科学研究的最高水平。2014年12月19日《Science》杂志推出中医药特刊。北京中医药大学徐安龙校长刊发文章Zheng: A systems biology approach to diagnosis and treatments。以下为该文章全文：

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.to systems level is important for advancing the identificationand 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,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 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 comprehensiveunderstanding 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 antiinflammatory 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.

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