To the Editor:
We are writing in response to Dr. Forman’s1 editorial “The Expanding Genetic Toolkit for Exploring Mechanisms of General Anesthesia” in the April issue of Anesthesiology. Dr. Forman covers many excellent points about the use of genetics in understanding anesthetic mechanisms. However, we think that he has overlooked, and perhaps unintentionally discounted, the key ability of an unbiased forward genetic screen to study anesthetic action. A forward screen generates mutations randomly and then looks for those mutations that affect a particular trait. Its unique beauty or power is that it can discover novel mechanisms that would not be found if one presupposed to know an anesthetic target. Forward genetic screens have identified plausible possible targets of volatile anesthetics. They have included leak channels,2 neurotransmitter release machinery,3 and mitochondria.4 All three possibilities have been shown to be directly affected by volatile anesthetics and have been shown to affect anesthetic sensitivity in multiple organisms.5–7 By dismissing mitochondrial complex I as a possible anesthetic target, it seems that Dr. Forman does not appreciate the full power of a genetic approach to solve difficult problems.
Because to date no single target has been identified as both necessary and sufficient to produce the anesthetic state for most drugs and because more than one pathway contributes to the anesthesia state even for the same drug, other relevant targets clearly exist. The search for the mechanism of action of volatile anesthetics started many decades ago, and yet new targets are occasionally discovered and validated—why should we believe that we have discovered them all? Unbiased approaches such as forward genetics seem well suited to help discover these elusive remaining targets.