Ricin: the most potent -- and readily available -- bioterrorism weapon

The search for agents that could protect cells, and ultimately people, against the deadly ricin poison has turned up two contenders. These compounds also render cells immune to the effects of Shiga-like toxins produced by infectious strains of E. coli bacteria among other pathogens, suggesting they may be useful against other threats to public health.

Ivanhoe Newswire reports that according to Daniel Gillet of Commissariat a l’Energie Atomique et aux Energies Alternatives (and coauthor of the Stechmann et al. article; see below), the discovery was made as part of a larger effort in France to address potential bioterror weapons following the 9/11 attacks in the United States. “There is a real need for countermeasures against ricin,” one of the most toxic chemicals known to man, Gillet was quoted as saying. Of particular concern is that ricin is not only deadly, but it is also easy to obtain. It is a natural ingredient in the seeds of castor oil plants, which are used in the industrial production of brake fluid, varnish, soap, ink and other products. “There are many plants growing, and there is about one milligram of toxin per seed,” Gillet said. “Ricin is a byproduct of this industry.”

In an accompanying editorial, Matthew Seaman and Andrew Peden were quoted as saying that ricin first gained notoriety when it was used to assassinate the Bulgarian journalist Georgi Markov in 1978. There are currently no known antidotes to ricin or Shiga toxins.

Researchers found two compounds that allowed cells to survive assaults of ricin and Shiga-like toxins. The compounds work not by acting on the toxins themselves, but they affect the route the toxins follow as they travel through cells. Both ricin and Shiga-like toxins normally travel through cells by the so-called retrograde pathway. Ricin delivers its fatal blow after it escapes into the cytosol where it disrupts the ribosomal “factories” that produce all the proteins needed to do the work of the cell.

The compounds, which researchers call Retro-1 and Retro-2, block the toxins’ escape, study coauthor (see the Stechmann et al. article below) Ludger Johannes of Institut Curie and Centre National de la Recherche Scientifique, was quoted as saying. Importantly, the protective agents manage to block toxins without halting the flow of other cellular cargos. “These [protective] compounds block the toxin in early endosomes; the toxin gets stuck and broken down or eliminated in some other way,” Johannes said.

In mice, treatment with one of the two compounds offered clear protection from what would otherwise be lethal exposure to ricin. “In a key experiment, Stechmann and coworkers showed that Retro-2 protected mice from a lethal dose of ricin,” Seaman and Peden wrote. “To achieve this effect, however, Retro-2 had to be administered prior to ricin exposure, which may preclude the use of Retro-2 in treating individuals already exposed to ricin. Nevertheless, this result suggests that it may be possible to protect against ricin exposure or to treat Shigella infection with compounds that selectively block the transport of AB chain toxins in the endosome-to-Golgi pathway.”

Gillet remains cautious. “We’re on a good track,” he said, but it remains to be seen whether either of the compounds will eventually turn into a useful drug.

—Read more in Matthew N. J. Seaman and Andrew A. Peden, “Ricin Toxin Hits a Retrograde Roadblock,” Cell 141, no. 2 (16 April 2010): 222-24; and Bahne Stechmann et al., “Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge,” Cell 141, no. 2 (16 April 2010): 231-42