Terminology summary
G protein selectivity (NOT ‘natural bias’) : The repertoire of G proteins that a receptor can engage. The term ‘natural bias’ should not be used as it is an oxymoron i.e., is self-contradictory.
Physiology-biased ligand/signaling: Ligand/signaling that is biased relative to a receptor’s principal endogenous agonist, and therefore bears the meaning that signaling is non-physiological/unnatural.

Unambiguous description of ligand bias – experimental evidence

Recommendation 5: Our foremost recommendation is to describe ligand bias unambiguously by including the major information in an initial statement, e.g.: “ligand L displays [recruitment/signaling…] bias towards pathway P1 at time point TP1 over pathway P2 at time point TP2 and relative to reference ligand A at receptor R in cell line C” .
Of course, reference ligand A must be measured under identical conditions as ligand L at each pathway. Like any definition, this should be mentioned at the first mention of the biased ligand – also in articles that reference data from another, original article. Additionally, we recommend that authors tabulate experimental details critical to the unambiguous description of ligand bias (a template is provided in Table 2). The suggested tabulated experimental details extend the above single-sentence statement with information about temperatures, signal detection techniques and the measured molecules. The time points refer to data collection times (see section Kinetics and choosing measurement time points).
Reason: All the above information is necessary to interpret ligand bias correctly and to separate it from system bias (Figure 1). Hence, the mention of a ‘biased’ or ’unbiased’ ligand as short terms are only meaningful after the prior definition of this information. The recommended statement and tables will facilitate meaningful comparisons of ligands and avoid different definitions leading to different conclusions from different researchers. The more consistent and comprehensive information provided in this statement will also greatly improve clarity and transparency while easing the annotation of biased ligands for review articles or databases.
Disclaimer: It follows from our recommendation 5 that assays that do not use the same reference agonist for bias or the same experimental conditions do not “disprove” biased agonism.

Unambiguous description of ligand bias – quantification models and raw data

Strategies used to quantify ligand-bias are all based on, and derived from, the principles of classical theory of receptor action (Furchott, 1966; Stephenson, 1956). The common objective of all these methods is to separate ligand-dependent parameters from the system-dependent ones in observed responses. However, there is still different views of how to best quantify bias and strategies for quantification are still being developed/improved. Hence, there are numerous models that could be used as long as pathways are measured with consistent pharmacological parameters and in similar systems and assays with corresponding levels of downstream processes and kinetics (see below sections). Of note, even with the most detailed models it is not possible to directly compare quantitative estimates of bias across different studies.