AUTHOR=Leak Rehana K. , Schreiber James B. TITLE=Mechanistic Research for the Student or Educator (Part II of II) JOURNAL=Frontiers in Pharmacology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.741492 DOI=10.3389/fphar.2022.741492 ISSN=1663-9812 ABSTRACT=

This two-part series describes how to test hypotheses on molecular mechanisms that underlie biological phenomena, using preclinical drug testing as a simplified example. While pursuing drug testing in preclinical research, students will need to understand the limitations of descriptive as well as mechanistic studies. The former does not identify any causal links between two or more variables; it identifies the presence or absence of correlations. Parts I and II of this educational series encourage the student to 1) ensure the sensitivity and specificity of their measurements, 2) establish or optimize an appropriate disease model, 3) find pharmaceutical drug doses/concentrations that interfere with experimental disease processes, 4) leverage the literature and exploratory datasets to craft a mechanism-oriented hypothesis on drug binding and downstream effects, 5) and design a full-factorial experiment to test the hypothesis after sketching potential outcomes and imagining their interpretations. These creative goals facilitate the choice of the appropriate positive and negative controls to avoid false data interpretations. Here, Part II describes in detail how to test for a causal link between drug-induced activation of biological targets and therapeutic outcomes. Upon completion of this two-part series, the new student will have some of the tools in hand to design mechanistic studies, interpret the outcomes of their research, and avoid technical and theoretical pitfalls, which can otherwise decelerate scientific progress and squander human and financial resources.