Department of Pharmacology, Vertex Pharmaceuticals Inc., Cambridge, MA, United States.
Profectus Pharma Consulting Inc., San Jose, CA, United States.
Biochem Pharmacol. 2014 Jan 1;87(1):4-24. doi: 10.1016/j.bcp.2013.09.011. Epub 2013 Sep 23.
Pharmacology is an integrative discipline that originated from activities, now nearly 7000 years old, to identify therapeutics from natural product sources. Research in the 19th Century that focused on the Law of Mass Action (LMA) demonstrated that compound effects were dose-/concentration-dependent eventually leading to the receptor concept, now a century old, that remains the key to understanding disease causality and drug action. As pharmacology evolved in the 20th Century through successive biochemical, molecular and genomic eras, the precision in understanding receptor function at the molecular level increased and while providing important insights, led to an overtly reductionistic emphasis. This resulted in the generation of data lacking physiological context that ignored the LMA and was not integrated at the tissue/whole organism level. As reductionism became a primary focus in biomedical research, it led to the fall of pharmacology. However, concerns regarding the disconnect between basic research efforts and the approval of new drugs to treat 21st Century disease tsunamis, e.g., neurodegeneration, metabolic syndrome, etc. has led to the reemergence of pharmacology, its rise, often in the semantic guise of systems biology. Against a background of limited training in pharmacology, this has resulted in issues in experimental replication with a bioinformatics emphasis that often has a limited relationship to reality. The integration of newer technologies within a pharmacological context where research is driven by testable hypotheses rather than technology, together with renewed efforts in teaching pharmacology, is anticipated to improve the focus and relevance of biomedical research and lead to novel therapeutics that will contain health care costs.
药理学是一门综合性学科,起源于大约 7000 年前的活动,旨在从天然产物中寻找治疗方法。19 世纪,人们集中研究了质量作用定律(LMA),证明了化合物的作用是剂量/浓度依赖性的,最终导致了受体概念的产生,这个概念已有一个世纪的历史,至今仍是理解疾病因果关系和药物作用的关键。随着药理学在 20 世纪通过连续的生化、分子和基因组时代的发展,人们对受体功能在分子水平上的理解越来越精确,虽然提供了重要的见解,但也导致了明显的简化论强调。这导致产生了缺乏生理背景的缺乏数据,这些数据忽略了质量作用定律,也没有在组织/整体水平上进行整合。随着简化论成为生物医学研究的主要焦点,它导致了药理学的衰落。然而,人们对基础研究工作与批准新药治疗 21 世纪疾病海啸(如神经退行性疾病、代谢综合征等)之间的脱节感到担忧,这导致了药理学的重新出现,它的兴起,往往是以系统生物学的语义伪装出现。在药理学培训有限的背景下,这导致了实验复制的问题,生物信息学的强调往往与现实的关系有限。在药理学背景下整合新技术,使研究由可测试的假设驱动,而不是由技术驱动,同时重新努力教授药理学,预计将提高生物医学研究的重点和相关性,并导致新的治疗方法,从而控制医疗保健成本。