Oct 23 2005
Ten genes that may make patients more or less susceptible to a common anesthetic agent have been identified by researchers using tiny worms and sophisticated technology that eliminates the activity of individual genes.
"We are anesthetizing 25 million patients a year in the United States alone; we put them to sleep and wake them up and we still don't know a lot about why it happens," said Dr. Steffen E. Meiler, vice chair of research for the Medical College of Georgia Department of Anesthesiology and Perioperative Medicine and a study author. "A lot of research has been done but the main mechanisms of how these volatile anesthetics (volatility means the anesthetics move easily from liquid to gaseous form) work have really alluded us."
Drs. Meiler, Aamir Nazir and their colleagues are taking advantage of advances in genomics and technology to begin to identify those mechanisms with the ultimate goal of better drugs.
"Eventually what we would like to do is design more specific drugs," says Dr. Meiler of the work being presented during the American Society of Anesthesiologists annual meeting Oct. 22-26 in Atlanta. "The principal question is how can we design anesthetic drugs that have the desired effect of rendering a patient unconscious during surgery without affecting other brain functions that lead to adverse effects," he says.
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.
Drs. Zhong Chen, research associate, and C. Alvin Head, chair of the MCG Department of Anesthesiology, are co-authors on the study.
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