Breaking Through the Bottleneck: Krogh's Principle in Behavioral Neuroendocrinology and the Potential of Gene Editing

In 1929, August Krogh wrote that for every question in biology, there is a species or collection of species in which pursuing such questions is the most appropriate for achieving the deepest insights. Referred to as "Krogh's Principle," these words are a guiding force for many biologists. In practice, Krogh's principle might guide a biologist interested in studying bi-parental care to choose not to use lab mice, in which the female does most of the parenting, but instead study species in which bi-parental care is present and clearly observable, such as in certain poison dart frogs. This approach to pursuing biological questions has been fruitful, with more in-depth insights achievable with new technologies. However, up until recently, an important limitation of Krogh's principle for biologists interested in the functions of certain genes, was certain techniques were only available for a few traditional model organisms such as lab mice, fruit flies (Drosophila melanogaster), zebrafish (Danio rerio) and C. elegans (Caenorhabditis elegans), in which testing the functions of molecular systems on biological processes can be achieved using genetic knockout (KO) and transgenic technology. These methods are typically more precise than other approaches (e.g., pharmacology) commonly used in nontraditional model organisms to address similar questions. Therefore, some of the most in-depth insights into our understanding of the molecular control of these mechanisms have come from a small number of genetically tractable species. Recent advances in gene editing technology such as CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats)/Cas9 gene editing as a laboratory tool has changed the insights achievable for biologists applying Krogh's principle. In this review, we will provide a brief summary on how some researchers of nontraditional model organisms have been able to achieve different levels of experimental precision with limited genetic tractability in their non-traditional model organism in the field of behavioral neuroendocrinology, a field in which understanding tissue and brain-region specific actions of molecules of interest has been a major goal. Then, we will highlight the exciting potential of Krogh's principle using discoveries made in a popular model species of social behavior, the African cichlid fish Astatotilapia burtoni. Specifically, we will focus on insights gained from studies of the control of social status by sex steroid hormones (androgens and estrogens) in A. burtoni that originated during field observations during the 1970s, and have recently culminated in novel insights from CRISPR/Cas9 gene editing in laboratory studies. Our review highlighting discoveries in A. burtoni may function as a roadmap for others using Krogh's principle aiming to incorporate gene editing into their research program. Gene editing is thus a powerful complimentary laboratory tool researchers can use to yield novel insights into understanding the molecular mechanisms of physiology and behavior in non-traditional model organisms.