Neurotoxin Threat Impels Research
With Botulism, Early Detection Is Key


by Sandra J. Ackerman

May, 2005

In an era when new threats to public health and safety seem to spring up frequently, it may come as a surprise to realize that the world’s deadliest neurotoxin already exists throughout our environment, albeit in a dormant form.

Botulinum toxin, in minute and precisely controlled applications, can have medical or cosmetic uses—Botox, for example. But as a poison it is more powerful than any other: a single gram released as an inhalant could kill an estimated 1 million people.

It acts rather slowly, usually producing no symptoms for at least 12 hours after exposure. The toxin takes effect at the presynaptic terminals of the neuromuscular junction, blocking release of the neurotransmitter acetylcholine and thereby causing paralysis, which ultimately cuts off the victim’s breathing.

The bacterium Clostridium botulinum lives in dense soil in every part of the world. Its spores are inert as long as they remain in the soil but can grow rapidly and to fatal effect in animal or human tissue.

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The bacterium Clostridium botulinum is very common in nature, where it is dor-mant. However, it also produces nature’s strongest poison: botulinum toxin. Courtesy of CDC

Botulism, whether caused by accidental poisoning or by deliberate use as a weapon, is a familiar disease in human history. The toxin can be added to food or drink or applied directly to a wound. For use as a means of bioterrorism, the toxin might be rendered in an aerosol form for the greatest dispersion over a large area.

“If botulism is detected early— within the first 48 hours—and the physician can obtain the correct antidote, there is a good hope of recovery,” Shri Mishra, professor of neurology at the University of Southern California, says. But it must be exactly the right antidote, Mishra emphasizes, for there are at least seven distinct types of botulinum toxin, and the antidote for each type is ineffective against the others. Currently available from the Centers for Disease Control and Prevention, or CDC, is a combination derived from horse serum that treats three of the most common types.

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The quahog, a relative of the clam, offers intriguing research possibilities because it appears to be completely immune to the botulinum toxin.  Courtesy of EPA Gulf of Mexico Program Office.

A botulism attack that sickened many thousands of people at a time would call for an antidote that could be given rapidly to a whole population. At the University of Massachusetts at Dartmouth, Bal Ram Singh and his colleagues have found that botulinum toxin gains access to nerve cells by binding tightly to a protein receptor on the cell surface; the scientists are now developing a possible antidote based on a compound that binds even more tightly to the toxin itself, thereby preventing it from entering the cell.

Other promising lines of investigation include a vaccine to prevent botulinum poisoning of the mucous membranes, which could counter an airborne attack; a fluorescent sensor to detect active botulinum toxin in living cells; and an innovative approach that uses a combination of antibodies to treat or, possibly, prevent botulism. One of the newest prospects for treatment comes from the quahog, a cousin of the clam (and a key ingredient in many forms of chowder). Singh and his collaborators recently announced that the quahog appears completely immune to botulism, and they have mounted an effort to identify the substance in the animal’s blood that effectively neutralizes botulinum toxin.

Meanwhile, at the CDC, specialists are working hard to bolster what Daniel Sosin, associate director for science in the CDC’s Office of Terrorism Preparedness and Emergency Response, calls “the fundamental role of practitioners on the front lines.” A prime concern at the CDC is that a single case of botulism—or, worse, multiple cases—might not be recognized early. A positive diagnosis can come only from laboratory testing of a blood sample, but a clinician would have to suspect botulism already in order to have the test done in the first place. Hence, the CDC is focusing on the detection and reporting of botulism at the earliest possible stage “so we can identify exposures and assure that others are safe,” Sosin says.

At this moment, our country’s preparedness in general requires the same prompt attention. No one knows whether a bioterrorist attack is imminent, but when it comes to the use of botulinum toxin as a weapon, Sosin says, “We are working with a sense of urgency—a different sense historically, perhaps, from at other times.”