To the Editor:
Dr. Tinker  comments that "one Nobel prize winner has fallen victim to the lure of this subject (quest for a mechanism of anesthetic action). Linus Pauling postulated that anesthesia was due to hydrate microcrystals or clathrates." Tinker asserts that the notion of the formation of ice crystals around anesthetic molecules is wrong.
Clathrate formation around anesthetic molecules was not in error. Clathrates do form around all hydrophobic molecules in water. It is now well established that the formation of clathrates is the main mechanism of solvation of all hydrophobic molecules into water [2-5]. The formation of "ice" around hydrophobic molecules is clearly demonstrated by the increase of heat capacities of the hydrophobic molecules when dissolved in water [2-5]. The increase of the heat capacities is caused by the melting of the "ice" covering the hydrophobic molecules when heated.
The clathrate formation can also be visualized by the decrease of the volume (partial molar volume) of anesthetics when dissolved in water. Mori et al.  have shown that the volumes of volatile anesthetics decrease in water compared with the liquid states or in the nonpolar solvent, n-decane. (See Table 1 of this letter.) The reduction in volume occurs mainly because the clathrate contains guest molecules in the cage-like structure. The total volume is smaller than the free anesthetic molecules floating in solvents.
There appears to be a misconception on "ice" structure. The solid ice formed at 0 degrees C is in a steady state. The microcrystals in the bulk water at higher temperatures are short-lived. They are formed and destroyed with a time scale of 10-11-10-12 s  and are designated as flickering clusters . These flickering structures are stabilized when interfaced with hydrophobic surface, and the lifetime is prolonged to about 10-5 s. What Eger et al.  demonstrated was that the anesthetics did not form stable ice at 0 degrees C. They did not refute the presence of structured water at higher temperatures.
Clathrate formation is now considered to be the most important factor for the stability of macromolecules, including proteins and lipid membranes, in water. It is also important in anesthesia mechanisms because the initial event of hydrophobic molecules interacting with macromolecules is the destruction of clathrate structures both at the anesthetic molecules and at the hydrophobic binding sites on proteins and membranes . The destruction of clathrates means that the hydrophobic surface is dehydrated.
The colloid theory of Claude Bernard is in accord with the modern theory on the structural stability of proteins, since he proposed that diethylether dehydrates protein molecules.
The comment that bacterial luciferase emits light by reacting with adenosine triphosphate is misinformed. Adenosine triphosphate is not involved in bacterial luminescence.
The attitude that the mechanism of anesthesia is an arcane subject to clinical anesthesiologists is disappointing. It shows a tendency that medicine is becoming more service-oriented and geared toward vocational training.
Supported by the Department of Veterans Administration Medical Research Funds.
Issaku Ueda, MD
Anesthesia Service, Department of Veterans Administration Medical Center, Salt Lake City, UT 84148
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