PheWAS and Pharmacophenomics in Precision Medicine and Traditional Chinese Medicine

[Speaker] Dayue Darrel Duan:1,2
[Co-author] Lingyu Linda Ye:1, Si-jin Yang:1
1:Center for Phenomics of Traditional Chinese Medicine, and the Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University, Luzhou, Sichuan, China, 2:Department of Pharmacology, University of Nevada Reno School of Medicine, Reno, Nevada, USA

The current practice of Western medicine is organized with a system- or organ-based definition of disease based on an average phenotype of a given disease observed in hundreds or thousands of patients and identification of a particular treatment of a corresponding disease based on randomized clinical trials (RCTs). Since RCTs offer an average statistical benefit and adverse effects on a particular phenotype when compared with a placebo in heterogeneous populations who are at most demographically similar but not truly identical, some individuals may have a profound benefit; others may have no benefit at all or even detrimental effects. Therefore, the current phenotype-based taxonomy of disease and RTC-based therapeutics and treatment programs are too narrow by definition and imprecise by design for a variety of conditions, including cancer, diabetes and cardiovascular diseases. In recent years, we are witnessing an ever increasing endeavors to change the current clinical practice toward a more personalization and precision by developing predictably successful therapy of corresponding diseases. For example, the searching for specific targeted therapy of individual tumors based on the understanding of single nucleotide polymorphisms (SNP) as risk factors or modifiers of cancer has provided novel insight into the expression and progression of specific cancer biomarkers in particular demographic groups and has led to the application of some successful targeted therapeutics. Although genome-wide association studies (GWAS) may help to apply these unique genomic characteristics to larger populations, the potential for this to happen is limited if the current phenotype-based taxonomy of disease remain unchanged. It is now emerging that precision medicine may lead to optimal targeted individualized treatment and prevention that takes into account individual variability not only in patients’ genetic profiles but also in their environment and lifestyle at the phenomic level. Obviously, a phenome-based taxonomy of disease and phenome-wide association studies (PheWAS) are urgently needed for disease redefinition and precision medicine.
In traditional Chinese medicine (TCM), abnormal and diseased conditions have been defined as Zheng-hou, a unique disease definition system in the context of holism. For over 3000 years the clinical practice of TCM has been under the guidelines of “bian-zheng-lun-zhi”. The diagnosis of a Zheng-hou decides the use of a correspondingly-individualized Zheng-targeting treatment. The main clinical treatment method for TCM therapeutics has been Fang-ji, a TCM medicinal formula usually composed of several herbs and medical materials. The compositions of Fangji are based on the principles of “jun-chen-zuo-shi”. However, the modern approach to the study of Fang-ji pharmacology has ignored the principles of Fang-ji composition and has been focusing on the isolation and identification of individual active components for cellular and molecular targets. Although this approach has led to the development of many new monomers purified from Fangji as new drugs widely used in clinical practice such as the antimalarial artemsinin, which has earned a Nobel Prize, the pharmacological bases of these purified effective monomers or active components have lost the TCM characteristics and are far different from the pharmacological theory and clinical applications of Fang-ji, in terms of the principles of “bian-zheng-lun-zhi” and “Jun-chen-zuo-shi”. Here we introduce the emerging pharmacophenophenics as a systematical paradigm for the pharmacological study of Fang-ji.
Pharmacophenomics studies the orchestrated multi-target pharmacology of combination therapy [1]. With well-defined molecular mechanisms of Zheng-hou at the level of multi-omics and a suite of new phenomics technologies and platforms, the pharmacophenomics may be used to characterize the drug-response phenome of Fang-ji and to identify the corresponding multiple therapeutic targets according to the TCM theory of jun-chen-zuo-shi. Pharmacophenomic study of Fang-ji will also lay out a theoretical foundation for the new science of precision medicine.[2,3]

[1] Duan DD. Han Y-S, Li L, Zhao J-Z, Wang Z. Pharmacophenomics: a new paradigm for pharmacology, toxicology, and personalized medicine. Chin J Pharmacol Toxicol. 28 (1):1-9; 2014
[2] Duan DD, Wang Z, Wang YY. New omic and network paradigms for deep understanding of therapeutic mechanisms for Fangji of traditional Chinese medicine. Acta Pharmacol Sin. 2018 Jun;39(6):903-905. doi: 10.1038/aps.2018.42.
[3] Zhang YP, Zhang YY, Duan DD. From Genome-Wide Association Study to Phenome-Wide Association Study: New Paradigms in Obesity Research. Prog Mol Biol Transl Sci. 2016; 140:185-231. doi: 10.1016/bs.pmbts.2016.02.003. Epub 2016 May 14. PMID: 27288830
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