Mechanistic Research for the Student or Educator (Part I of II)

Many discoveries in the biological sciences have emerged from observational studies, but student researchers also need to learn how to design experiments that distinguish correlation from causation. For example, identifying the physiological mechanism of action of drugs with therapeutic potential requires the establishment of causal links. Only by specifically interfering with the purported mechanisms of action of a drug can the researcher determine how the drug causes its physiological effects. Typically, pharmacological or genetic approaches are employed to modify the expression and/or activity of the biological drug target or downstream pathways, to test if the salutary properties of the drug are thereby abolished. However, experimental techniques have caveats that tend to be underappreciated, particularly for newer methods. Furthermore, statistical effects are no guarantor of their biological importance or translatability across models and species. In this two-part series, the caveats and strengths of mechanistic preclinical research are briefly described, using the intuitive example of pharmaceutical drug testing in experimental models of human diseases. Part I focuses on technical practicalities and common pitfalls of cellular and animal models designed for drug testing, and Part II describes in simple terms how to leverage a full-factorial ANOVA, to test for causality in the link between drug-induced activation (or inhibition) of a biological target and therapeutic outcomes. Upon completion of this series, students will have forehand knowledge of technical and theoretical caveats in mechanistic research, and comprehend that “a model is just a model.” These insights can help the new student appreciate the strengths and limitations of scientific research.