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Resisting Ricin

9 August 2004 (All day)
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Safer solution By removing a few stretches--marked yellow and blue in this image--from the ricin protein, researchers made it more soluble and less toxic.

On a late-summer day in 1978, a Bulgarian dissident named Georgi Markov was stabbed in the thigh at a London bus stop by an assailant who had fashioned an umbrella tip into a weapon. Markov developed a high fever and died 4 days later from a potent toxin called ricin, presumably delivered by the KGB or Bulgarian secret police. Now, researchers say they have developed a vaccine that can neutralize ricin, which today ranks as one of the most feared weapons in the biowarfare arsenal.

Ricin is derived from the castor bean, grown worldwide for its oil, which is used in paints and polymers. Because castor plants are so readily available and inhaling a drop of ricin can kill, biodefense experts worry about the toxin's getting into the wrong hands, particularly because there's no good treatment and no vaccine.

To create a vaccine, Mark Olson and colleagues at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland, first separated the ricin toxin into the two small proteins that constitute it. One of these, called ricin A-chain, kills the cell by blocking it from making new proteins. Researchers knew that the ricin A-chain can trigger an immune response that protects mice from the whole toxin, but they worried about side effects. What's more, the protein slowly clumped and precipitated out of solution, so it wouldn't have the shelf life needed for an effective vaccine.To get around both problems, Olson and his colleagues compared detailed computer models of ricin A-chain with those of a related protein from pokeweed. They genetically altered the ricin A-chain to delete two stretches absent from the pokeweed protein, creating a safe and soluble variant. When they vaccinated 10 mice with the engineered ricin A-chain, it protected all of them from a ricin dose five times higher than one lethal to unvaccinated mice, the team reports in the current issue of Protein Engineering, Design & Selection. Next, the team will test the vaccine in African green monkeys, says co-author Leonard Smith."It's a nice piece of work," says immunologist Ellen Vitetta of the University of Texas Southwestern Medical Center in Dallas, who is working on an alternative ricin vaccine. Eventually, the goal is to stockpile enough vaccine to protect soldiers, who may be at the highest risk of exposure to ricin, she says.

Related sites
Facts about ricin from the Centers for Disease Control and Prevention
Background on ricin from the U.S. Department of Labor's Occupational Health and Safety Administration.
USAMRID

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