Paradise engineering

Anesthesia grew from humble beginnings. Inca shamans performing trephinations (drilling holes in patients' skulls to let out evil humors) chewed coca leaves and spat into the wound, effecting local anesthesia. The systemic effects of cocaine were studied by Sigmund Freud, but cocaine's use as a local anesthetic in surgery is credited to Austrian ophthalmologist Karl Koller who in 1884 used liquid cocaine to temporarily numb the eye. Since then dozens of local anesthetic compounds have been developed and utilized in liquid solution to temporarily block nerve conduction from peripheral nerves and/or spinal cord. The local anesthetic molecules bind specifically on sodium channel proteins in axonal membranes of neurons near the injection site, with essentially no effects on the brain.

On the other hand general anesthetic molecules are gases which do act on the brain in a remarkable fashion — the phenomenon of consciousness is erased completely while other brain activities continue.

General anesthesia by inhalation developed in the 1840's, involving two gases used previously as intoxicants. Soporific effects of diethyl ether ("sweet vitriol") had been known since the 14th century, and nitrous oxide ("laughing gas") was synthesized by Joseph Priestley in 1772. In 1842 Crawford Long, a Georgia physician with apparent personal knowledge of "ether frolics" successfully administered diethyl ether to James W. Venable for removal of a neck tumor. However Long's success was not widely recognized, and it fell to dentist Horace Wells to publicly demonstrate the use of inhaled nitrous oxide for tooth extraction at the Massachusetts General Hospital in 1844. Although Wells had apparently used the technique previously with complete success, during the public demonstration the gas-containing bag was removed too soon and the patient cried out in pain. Wells was denounced as a fake, however two years later in 1846 another dentist William T.G. Morton returned to the "Mass General" and successfully used diethyl ether on patient William Abbott. Morton used the term "letheon" for his then-secret gas, but was persuaded by Boston physician/anatomist Oliver Wendell Holmes (father of the Supreme Court Justice) to use the term anesthesia.

Although its use became increasingly popular, general anesthesia remained an inexact art with frequent deaths due to overdose and effects on breathing until after World War II. Hard lessons were learned following the attack on Pearl Harbor — anesthetic doses easily tolerated by healthy patients had tragic consequences on those in shock due to blood loss. Advent of the endotracheal tube (allowing easy inhalation/exhalation and protection of the lungs from stomach contents), anesthesia gas machines, safer anesthetic drugs and direct monitoring of heart, lungs, kidneys and other organ systems have made modern anesthesia extremely safe. However one mystery remains. Exactly how do anesthetic gases work? The answer may well illuminate the grand mystery of consciousness.

Inhaled anesthetic gas molecules travel through the lungs and blood to the brain. Barely soluble in water/blood, anesthetics are highly soluble in a particular lipid-like environment akin to olive oil. It turns out the brain is loaded with such stuff, both in lipid membranes and tiny water-free ("hydrophobic") lipid-like pockets within certain brain proteins. To make a long story short, Nicholas Franks and William Lieb at Imperial College in London showed in a series of articles in the 1980's that anesthetics act primarily in these tiny hydrophobic pockets in several types of brain proteins. The anesthetic binding is extremely weak and the pockets are only 1 /50 of each protein's volume, so it's unclear why such seemingly minimal interactions should have significant effects. Franks and Lieb suggested the mere presence of one anesthetic molecule per pocket per protein prevents the protein from changing shape to do its job. However subsequent evidence showed that certain other gas molecules could occupy the same pockets and not cause anesthesia (and in fact cause excitation or convulsions). Anesthetic molecules just "being there" can't account for anesthesia. Some natural process critical to consciousness and perturbed by anesthetics must be happening in the pockets. What could that be?

Anesthetic gases dissolve in hydrophobic pockets by extremely weak quantum mechanical forces known as London dispersion forces. The weak binding accounts for easy reversibility - as the anesthetic gas flow is turned off, concentrations drop in the breathing circuit and blood, anesthetic molecules are gently sucked out of the pockets and the patient wakes up. Weak but influential quantum London forces also occur in the hydrophobic pockets in the absence of anesthetics and govern normal protein movement and shape. A logical conclusion is that anesthetics perturb normally occurring quantum effects in hydrophobic pockets of brain proteins.