Repost: What a little caterpillar tells us about grant review.

This was originally posted June 4, 2007.

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This is a picture of Eloria noyesi eating a coca leaf from Chen et al 2006, Gene, 366 (1): 152-160, Molecular cloning and functional characterization of the dopamine transporter from Eloria noyesi, a caterpillar pest of cocaine-rich coca plants

The interesting thing is that the little buggers fail to die from cocaine poisoning, unlike other caterpillers. The authors cloned the dopamine transporter (DAT) from these guys and the silkworm (Bombyx mori) under the hypothesis that this primary target of cocaine might be responsible for the insensitivity of E. noyesi to coca poisoning. It turns out that the DATs were pretty similar and highly homologous to DAT from other invertebrate and vertebrate species. It also turns out they have a kickin’ esterase which chews up cocaine pretty rapidly.
This work led to another paper Chen et al 2006, in which a DAT insensitive to cocaine was knocked into a DAT knockout mouse. The knockin was insensitive to locomotor stimulant and conditioned place preference effects of cocaine but similar to wildtype in response to the closely related stimulant amphetamine. In vivo microdialysis, voltammetry and patch clamp data were supportive. The takeaway here is that the group was able to selectively narrow down on the cocaine-DAT interaction making a nice little model to dissociate DAT-mediated from serotonin and norepinephrine transporter mediated effects of cocaine. Selectivity being good in pharmacology, of course. It tends to cut down on “side effects” of eventual medications and the like.
What does this have to do with grant review? Well, it points out that first, research ideas are based on observation. Sometimes weird ones, sometimes unique ones. The supposed “hypothesis” may not be that rigorous. But there is value in “hey, how come that caterpiller can feed on coca and not die?” and the like. Two, it shows us that one can be completely wrong in one’s initial hypothesis, said hypothesis might even be a bit dubious at the outset and it can still lead to some pretty interesting science. For example, I can imagine where the grant application on that topic would have been met with a critique like “uhh, but why are you cloning the DAT when the most obvious thing to look at is drug metabolism and excretion, fella?”. And I can also imagine if they said in advance that they were going to clone the E. noyesi transporter and then do some knockin with DAT KO mice…well, let’s just say it would’ve been triaged. This is one example where efforts to step back and look at the big picture during grant review would possibly pay off.