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February 19, 1999

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Human/Insect/Jellyfish Genes Team To Quiet "Hyper" Nerve Cells

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 Marbán, 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 Marbán.

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 Marbán, "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 hormone, to the nerve cell culture. The muristerone turned on the insect switch, which in turn activated the silencing genes. "The effect is not permanent. If muristerone is withheld, the nerve cells go back to their normal electrical activity in less than two days," says David Johns, Ph.D., who ran the study.

Hopes for clinical use, though well down the road, are positive, Marbán adds. "You might put silencing genes into pain nerve fibers," says Marbán, "and wait a few weeks, then try successively higher doses of muristerone until you get relief. If there's a bad effect, you can stop activating the system. We'd never be so bold to think about doing gene therapy for problems like this if we couldn't fine-tune what we were doing and reverse it."

The Hopkins group also developed a novel way to tell if the genes in their system are working, with a fluorescent green pigment that oceanic jellyfish use to signal each other. The researchers added a gene for this pigment, called GFP (for green fluorescent protein) in the middle of the switch-silencer gene system. When the system is active, the silenced nerve cells turn a bright green. "It's a quick, colorful way to see how fast and how intensely we're turning on gene expression," says Marbán.

The research was funded by grants from the National Institutes of Health and by the Tanabe Seiyaku Company in Japan. A patent for the gene system has been applied for.

Also on the research team were Ruth Marx, Ph.D., Richard Mains, Ph.D., and Brian O'Rourke, Ph.D.

Related Web Sites:

Invitrogen Web Resource -- http://www.invitrogen.com

Dana BrainWeb -- http://www.dana.org/brainweb (see epilepsy)


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