[Part 5 of 5]
Following the discrediting of Meyer and Overton and the less than stellar debut of Pauling’s theory, anesthesiologists were again left without a central working theory of anesthesia. While Pauling still supported his own work, his fellow scientists remained uninterested and he gradually disappeared from the scene altogether.
Fortunately, the problem was not forgotten for long. Beginning in the mid 1970s, Nicholas P. Franks and William R. Lieb, researchers at the Imperial College in London, began work on a new theory of anesthesia. They suggested that anesthetics are, in fact, similar to conventional pharmaceuticals. They theorized that anesthetic molecules are able to bond to protein receptors in the brain and, in doing so, manipulate specific ion channels. Like the hydrate theory, the protein theory suggests that, by affecting the brain’s ion channels, the anesthetics would have the ability to disrupt brain functions and result in unconsciousness.
Franks and Lieb spent several years testing the effects of various liquid anesthetics on isolated, lab-grown proteins. In 1984, they published “Seeing the Light: Protein Theories of General Anesthesia.” The paper introduced the protein theory to a wider audience and suggested that, through extensive testing, scientists might be able to identify the correlations between specific anesthetics and binding sites. This, in turn, would allow researchers to predict the effects of a given anesthetic and eventually develop improved synthetic chemicals.
In order to positively demonstrate the relationship between anesthetics and protein receptors, researchers in the
United States and Switzerland began developing genetically modified mice. These test subjects, known as knockin mice, lacked specific proteins thought to be affected by a given anesthetic. By using the anesthetic on the supposedly immune mice, the researchers were able to pinpoint correlations between anesthetics and proteins. With improved technology, the researchers were eventually able to minimize the necessary genetic changes by altering amino acids within the proteins. This allowed the researchers to avoid eliminating any macromolecules within the knockin mice, creating a more authentic testing process.
The results from the knockin mice experiment proved monumental. Through extensive testing, researchers were able to locate and identify specific interactions between anesthetics and protein receptors. For the first time in over a century of studying anesthesia, scientists were finally able support theoretical claims with conclusive experimental data.
Unfortunately, this breakthrough did not solve the mystery completely. Anesthetics in gaseous form, which are commonly used to induce general anesthesia, do not necessarily adhere to the same principles as injected anesthetics. Inhaled anesthetics do not seem to bind as tightly as their injected counterparts, and instead pass over a huge number of receptors rather than triggering a single one. Though a great deal of disagreement exists among scientists, it is widely believed that gaseous anesthetics affect anywhere from three or four types of receptors to over one hundred. To further complicate this issue, there is disagreement whether every receptor affected by the gas contributes to the anesthetic effect.
Currently, several teams around the world are engaged in determining receptors for inhaled anesthetics. The process, however, will be long and tedious. Each knockin mouse must be genetically altered so that its significant receptors are modified to match a given anesthetic. This process is one of trial and error and provides an amazing challenge for scientists.
From Ernst von Bibra to Pauling to Franks and Lieb, the theory of anesthesia has had a bumpy ride. But, with each researcher and each breakthrough, we have moved a little closer to a better understanding of our biological selves. With a little luck and a lot of hard work, the next decade will yield even more progress and, undoubtedly, more questions.
Click here to view our previous posts on Linus Pauling and the theory of anesthesia. For more information on Pauling’s life and work, visit the Linus Pauling Online Portal or the OSU Special Collections homepage.