As to Dr Ringach’s request that I explain how animal models inform us about anesthesia in humans, I will comply, provided he tells me how they work at all. I will save him the effort. We still do not know. There are hypotheses that are being tested but we do not understand the mechanism or mechanisms at present. (See (1-8) for more on this.) Until we do understand the mechanisms, no one can assign credit to this animal model or that human observation. A finding from animals, or humans, that looks good today might be proven wrong tomorrow. This is the nature of science. I (along with two coauthors) currently have under review a paper on the evolution of receptors that appear to be involved in the anesthesia response. In our paper we assume the receptor hypothesis will be, in part or in whole, the reason humans and other animals respond to certain chemicals by experiencing amnesia, analgesia, unconsciousness, and so forth. We might be wrong. Receptors might turn out to be unimportant or less important than membrane stabilization.
What cannot be denied however is that anesthetics seem to have the same effects across species and even phyla. Such a response is fascinating and I grant that many hypotheses about how anesthetics work have come from the study of animals and other life forms. In Animal Models in Light of Evolution we state very emphatically that animals can be used as heuristic devices and to generate hypotheses. This is a good example of that phenomenon. But that is not the same as using them to predict human response to drugs and disease. Medications, anesthetics or otherwise, can have very different effects among species. For example, consider the effects of the following drugs, safely used in the administration of anesthesia for humans:
Administration of ketamine and anticholinergics such as atropine and glycopyrrolate have been associated with myocardial infarction in young cats (9). In dogs, the use of anticholinergics increases the incidence of gastroesophageal reflux, esophagitis (10), and post-op gastrointestinal complications in horses (11). Rabbits, cats, and rats have atropine esterase that rapidly metabolizes atropine (12). Benzodiazepines when used in cats and young dogs do not reliable result in sedation and doses vary greatly among species (13). Diazepam (Valium) does not reliably work in dogs or horses possibly causing ataxia, dysphoria, and excitement in dogs (14) and produces aggression and dysphoria in cats (15). Midazolam does not reliably sedate dogs or cats either (13). Opioid response varies greatly among species. Depression of the central nervous system is usually seen in dogs and monkeys while stimulation is seen in swine, cats, sheep, goats, horses, pigs and cows. These effects are particularly frequent when morphine is used. Responses such as emesis, panting, temperature changes also vary among species however humans are more likely to experience respiratory depression secondary to opioids than are most other species (16).
According to Branson (17), in animals, unlike humans, opioids alone cannot produce a state of general anesthesia. Propofol is commonly used in animals but causes a prolonged recovery in greyhounds (as do thiobarbiturates) possibly due to decreased fat content of greyhounds and or variability of the cytochrome P-450 enzyme system among dogs (18-20). Repeated doses in certain cats can lead to heinz body anemia presumably due to the cats compromised ability to conjugate phenol (21).
Furthermore, the only reason animals have given us the data and hypotheses they have in answering the question of how anesthetic work is that the response is the same across species, meaning an evolutionarily shared or conserved process (see (22) for more on this). As the above indicates, the response to the drugs used in anesthesia is not conserved as anyone who has experience anesthetizing humans and other animals can tell you. Dr Shanks and I maintain that animals can be used to learn about conserved processes, e.g. the homeobox, but not to predict human response. (I realize I am repeating myself but apparently the message is not getting through.)
In some ways Dr Ringach’s desire to discuss the role of animals in studying anesthetic mechanisms is an example a claim typically made by those promoting the use of animals in research. They point to the increase in knowledge that has come from using animals in a particular area of research and then attempt to equate that with advances in treating human disease. Such conflation is inappropriate. If increasing knowledge about a disease or condition in general were the equivalent to finding cures, we would have cured cancers in humans a hundred times over. In fact, scientists have cured cancer in rodents but those cures have not been effective in humans. Thomas E Wagner, upon retiring from his position as Senior scientist at Ohio University's Edison Biotechnology Institute said: “God knows we've cured mice of all sorts of tumors. But that isn't medical research” (23). Richard Klausner, then-director of the National Cancer Institute: “The history of cancer research has been a history of curing cancer in the mouse. We have cured mice of cancer for decades--and it simply didn't work in humans” (24). (Go to http://articles.latimes.com/1998/may/06/news/mn-46795 to make sure I am not quoting this out of context.)
Again, Dr Shanks and I are not opposed to basic research or comparative research. We are opposed to saying animals are predictive and selling their use to society on that basis then, when they turn out not to be predictive, backtracking and claiming you were never using them in that fashion as you were only doing basic research.
As for Dr Ringach’s assertion that it is my explanations of science that have provided the intellectual basis for the home demos conducted at Dr Ringach’s dwelling, I can only say that in fact it is the animal rights philosophy that is responsible for people opposing his research or his views in such a fashion. While the protesters might yell slogans that reflect the science I explain they would be there regardless of whether research on animals was predictive or not. That is not their point. But I am flattered that Dr Ringach attributes such power to me.
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