With the help of fruit flies and jellyfish, Johns Hopkins scientists have proved they can quiet firing nerve cells -- at least temporarily -- by inserting the genetic version of an off switch.

The feat has possibilities as a gene therapy for conditions marked by nerve excitability or excessive firing, including epilepsy, severe pain, spastic muscles or the heartbeat arrhythmias that are still leading killers in Western society, says molecular cardiologist Eduardo Marbn, M.D., Ph.D., the research team leader.

In a study reported in the March Journal of Neuroscience, the researchers took "silencing genes" cloned from electrically quiet human heart tissue and ferried them into cultures of rat spinal tissue using non-harmful viruses that readily infect nerve cells.

Once turned on inside the spinal nerve cells, the genes generated fine channels in the cells' outer membranes. Potassium ions then flowed through the channels into cells, changing their electrical state to the equivalent of dead batteries. Within one to three days, the spinal cells, which normally fire rhythmically to the beat of an internal pacemaker, became still, says Marbn.

Taking the work a step further, the team also fitted the silencing genes with a control switch. That "switch" was a set of genes that insects such as flies rely upon to start or stop their various molting stages. A common insect hormone called ecdysone activates these genes whenever the insect grows too big for its exoskeleton. "Insects don't want to molt all the time," says Marbn, "so they've evolved this extremely effective and efficient switch as a way of controlling gene action."

In the Hopkins study, the genetic switch originally was recruited from fruit flies and its use marks the first time, the researchers say, such a system has been used in the context of gene therapy. To activate it, the researchers applied muristerone, a lab version of the insect h
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Contact: Marjorie Centofanti
mcentofanti@jhmi.edu
410-955-8725
Johns Hopkins Medical Institutions
19-Feb-1999