Snark-Hunters Once More: Rejuvenating the Comparative Approach in Modern Neuroscience
By Jeremy Borniger
65 years ago, the famed behavioral endocrinologist Frank Beach wrote an article in The American Psychologist entitled ‘The Snark was a Boojum’. The title refers to Lewis Carroll’s poem ‘The Hunting of the Snark’, in which several characters embark on a voyage to hunt species of the genus Snark. There are many different types of Snarks, some that have feathers and bite, and others that have whiskers and scratch. But, as we learn in Carroll’s poem, some Snarks are Boojums! Beach paraphrases Carroll’s writing outlining the problem with Boojums:
If your Snark be a Snark, that is right:
Fetch it home by all means—you may serve it
And it’s handy for striking a light.
But oh, beamish nephew, beware of the day,
If your Snark be a Boojum! For then,
You will softly and suddenly vanish away,
And never be met with again!
Instead of the Pied Piper luring the rats out of town with a magic flute, the tables have turned and the rat plays the tune and a large group of scientists follows. (From Beach, 1950)
Beach provides this metaphorical context to describe a problem facing comparative psychologists in the 1950’s: an increasing focus on a few ‘model species’ at the cost of reduced breadth in the field. The comparative psychologists were hunting a Snark called “Animal Behavior”, but this Snark too, turned out to be a Boojum. Instead of finding many animals on which to test their hypotheses, they settled on one: the albino rat. It was there that “the comparative psychologist suddenly and softly vanished away”.
Even in the mid-1900’s Beach recognized the funneling of biological and psychological research efforts towards a single or few ‘model species’. He even went as far as to suggest that the premier journal in the field be renamed The Journal of Rat Learning as its focus had almost entirely shifted to the rat. This trend has culminated in a true bottleneck, where the vast majority of research now focuses on phenomena occurring in a small amount of ‘model organisms’ like the laboratory mouse (Mus musculus), Norway rat (Rattus norvegicus), nematode worm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster), or zebrafish (Danio rerio). Indeed, a 2008 analysis found that “75% of our research efforts are directed to the rat, mouse and human brain, or 0.0001% of the nervous systems on the planet”. Focusing on such a small fraction of the biological diversity available to us may be skewing or vastly restricting our conclusions.
The Genetics Revolution
In the last quarter of a century, the incredible advancement in genetic technology has pushed a few model organisms further towards the top. For example, the mouse was among the first mammals to have its genome sequenced, the results being published in 2002. Because of the presence of readily available sequence information, subsequent tools (primers, shRNA, oligonucleotides, etc…) and genetic techniques (conditional knockout/overexpression models) were developed specifically for use in the mouse. This further discouraged the use of other organisms in research as most of the ‘cutting edge’ tools were being developed almost exclusively in the mouse. It also promoted ‘shoe-horning’ of research that may not be appropriate for this model organism to take advantage of the genetic tools available. Indeed, this may be the case with research regarding the visual system, or many mental disorders in mouse models. The lab mouse primarily interprets environmental stimuli via olfactory (smell) cues, rather than sight (as it is nocturnal), making it a suboptimal organism in which to study visual function. Also, as mental disorders are poorly understood, developing a robust animal model in which to test treatments remains a significant obstacle. Trying to force the mouse to become the bastion of modern psychiatry research is potentially hampering progress in a field that could benefit from the comparative approach. For example, wild white-footed mice (Peromyscus leucopus), which are genetically distinct from their laboratory mouse relatives, show seasonal variations in many interesting behaviors. For instance, in response to the short days of winter, they enhance their fear responses and alter the cellular structure of their amygdala, a key brain region in the regulation of fear. Because these changes are reversible and controlled by a discrete environmental signal (day length), these wild mice contribute to the development of current translational models that involve amygdala dysfunction, such as post-traumatic stress disorder (PTSD).
What are the Benefits to the Comparative Approach?
Emphasis on a few model organisms became prevalent primarily due to their ease of use, rapid embryonic development, low cost, and accessible nervous systems. In the last number of decades, access to an organism’s genetic code provided another incentive to use it for research purposes. While these advantages are useful, they encourage researchers to become short-sighted and neglect previous contributions of diverse species to the advancement of science. As Brenowitz and Zakon write, “this myopia affects choice of research topic and funding decisions, and might cause biologists to miss out on novel discoveries”. Some examples of breakthroughs that were made possible through the use of the comparative approach include the understanding of the ionic basis of the action potential (squid), the discovery of adult neurogenesis (canary), conditioned reflexes (dog), dendritic spines (chicken), and the cellular basis of learning and memory (sea slug). More recently, incredible advancements in temporal control of neuronal function have been made (optogenetics) thanks to the characterization of channel rhodopsins in algae.
The revolution in genetics ushered in new tools that were only available to be used in the few organisms that have had their genomes sequenced. The comparative approach, however, is now gaining the tools necessary to become part of the 21st century genetic revolution. New gene-editing techniques, such as TALENS, TILLING, or CRISPR/Cas9 allow for fast, easy, and efficient genome manipulation in a wide variety of species. Indeed, this has already been accomplished in Atlantic salmon, tilapia, goats, sea squirts, and silkworms. Also, as the price to sequence an entire genome rapidly decreases, new tools will be developed for use in a wider variety of species than ever before. It is unlikely that many of the groundbreaking discoveries that stemmed from research on diverse and specialized organisms would be funded in the current ‘model species’ climate. We should not put all of our research ‘eggs’ in one model organism ‘basket’, and instead invest in a broad range of organisms that are fit for each question at hand. The time to revive the comparative approach has arrived. In the words of Brenowitz and Zakon, “Grad students, dust off your field boots!”
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Love your introductory story and the poem!