Brunger's team altered the protein by single amino acids, which they selected based on their crystal structure, and then tested the effect on the nerve that causes the diaphragm to contract in mice. "We found that just single mutations can lower the toxicity of BoNT/B a thousand-fold," he says. Their work suggests that a small-molecule inhibitor could be designed to interfere with the binding of botulinum toxin and avert lethal paralysis of the diaphragm.

Both researchers are energized by the broader prospects of the research. Chapman's inspiration is to see the creation of a mutant toxin that would not affect regular cells but would bind to an engineered mutant receptor for targeted use in the body. "By persuading the toxins to act only on cells that have been sensitized to them, we hope to further harness their usefulness as medicines and as research tools," he says.

Meanwhile, given the threat posed by botulinum as a biological weapon, U.S. military and security officials are very interested in the development of inhibitors or vaccines. The current state of the art is limited to two problematic options: an equine antitoxin that carries a significant risk of adverse reaction in humans, and an investigational detoxified botulism toxin that prevents botulism poisoning but also renders Botox and other botulinum treatments ineffective.

		As the first biological toxin approved for the treatment of human disease, botulinum has already addressed an impressive array of conditions. It is licensed as a therapy for involuntary neck-muscle spasms and eyelid contractions, crossed eyes, and abnormally heavy perspiration. Experimental uses—some with promising results—include treatment of migraine headaches, chronic low back pain, stroke, and cerebral palsy. National Public Radio talk show host Diane Rehm has spoken extensively about the botulinum treatment she receives for spasmodic dysphonia, a larynx-muscle disorder that nearly ended her career. Meanwhile, history suggests that the potential use of botulinum toxin as a biological weapon should be a continuing concern. The Journal of the American Medical Association published a report months before the 9/11 attacks that summarized the threat in a short history—from Japan's testing of botulinum toxins on prisoners in Manchuria in the 1930s to Iraq's 1991 revelation to United Nations inspectors that it had created enough botulinum to kill the world's population three times over. —T.T.

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