Scientists at the Medical College of Georgia, together with researchers at Caltech, are trying to decipher the mechanisms of action of inhalational anesthetics by studying genetics and physiology of a tiny soil nematode, Caenorhabditis elegans. In fact, it seems they have the best genetic model, to study the physiology of general anesthetics, to date:
Critical pieces have come together to make the studies possible including the relatively recent finding that volatile anesthetics interact with proteins. Now that they know they need to look at proteins, sophisticated RNA interference technology enables researchers to do so by stopping the usual process in which information encoded by a singular gene is transformed into a cellular protein.
Tiny C. elegans, free-living soil nematodes that share 50 percent to 60 percent of their genes with humans and are the first study animals to have their genome decoded and sequenced, have given the scientists a manageable model for knocking out select genes, giving anesthetics and measuring the results.
The researchers started their work with the 637 genes known to be expressed in the nervous system of the C. elegans. They designed a tiny gas chamber to deliver Isofluran to the worms. Not unlike earlier days in anesthesiology – before sophisticated monitoring such as the bispectral index system that measures brainwave activity to determine a patient’s level of consciousness during surgery – the researchers assessed the anesthetic effect from just watching their subjects. They compared the movement of anesthetized worms to controls.
“This is the best genetic model system,” says Dr. Nazir. “The worms we study are about the same age and carry the same genes. If there is a difference between the control and the knock-down mutant, we know that particular gene has something to do with the anesthetic, he says. Using this method, they initially identified 37 candidate genes.
Next, they applied a sophisticated quantification system, developed in conjunction with the California Institute of Technology, that allows 144 precise, objective measures of how far anesthetized worms and the controls travel, including speed, top speed, roaming range, track patterns and other complex behaviors.
That systematic analysis narrowed the field to 10 genes – nine that are hypersensitive and one that is resistant – that are biological modifiers of the anesthetic effects of drugs, Dr. Nazir says.
“These are modifier genes that influence the effect, the degree, the extent of the anesthetic effect,” says Dr. Meiler. “We cannot yet say these are direct targets of volatile anesthetics. That is to be tested in another series of studies.”
Rather, these first steps have shown the researchers their approach works, so they are moving toward a genome screen in these tiny worms that includes genes whose function is unknown.
The press release by Medical College of Georgia…