A physician named Jones has posted this message on his website: "Botulinum toxin A injections, or Botox therapy as it is more commonly known, was the top cosmetic procedure performed in 2001. Considering how safe and effective it is in treating facial wrinkles, it is no wonder that men and women are increasingly choosing Botox to combat the signs of aging."
Neurobiologist Mauricio Montal, at the University of California at San Diego, makes the point that "Botox in American society today has been popularized enormously by the cosmetic arena. But it has tremendous applications in pediatric medicine. It was discovered that Botox could be effective in the treatment of strabismus [cross-eyed squint] in kids, and has wide adult application in a variety of tissues related to muscle contractures, such as dystonia in particular, which causes painful paralysis of the muscles in the neck. And therapy for eyelids - blepharospasm," he added. "There are many clinical indications. The prescription known as Botox [owned by Allergan Inc.] has been a blossoming field in the past 10 years, and I think it will continue."
On another - life-threatening - note, Montal said, "Botulinum toxin, as we know it today, is a powerful biological weapon, because it is the most poisonous toxin known to humankind. Not even anthrax is as toxic. Like anthrax, botulinum is a spore-forming, soil-dwelling pathogen. It's carried by a widespread bacterium, Clostridium botulinum, best known as a frequent cause of botulism - food poisoning.
"Once weaponized, the botulinum toxin would probably spread through the aerosol, just like a spray," Montal related. "Spray C. botulinum and the bacterium falls into the soil. Also, it may be aspirated - inhaled. If so, it will reach back to where it can be an effective poison. That bacterium is just a factory," Montal said. "It produces the botulinum toxin and secretes it into the environment. For C. botulinum it is probably just a survival kit. (See BioWorld Today, Aug. 7, 2002, p. 1.)
"The toxins have medical applications as a paralyzing agent," Montal went on. "So the interest in botulinum toxin has been manifold for many decades, because it blocks neurotransmitter release at the synaptic motor neuron terminals."
Fast Access To Respirators Saves Lives
"As a bioweapon delivered to populations," Montal foresees that "botulinum toxin would be deadly. Respiratory paralysis is the main effect. If it gets internalized in the body, the system affected initially is the diaphragm, which is the muscle that allows us to breathe. So if that muscle is paralyzed, people will be entering very quickly into respiratory arrest. Unless they are close to an artificial respirator they will die pretty fast, depending on the dosage. Death will not come in seconds but probably in hours.
"So that's why it's very important - not just for warfare but civilian situations. Exposed people have to be transported very quickly to a hospital where there are artificial respirators. And if victims manage to get to them in time, and are given weeks of supportive care, they will recover perfectly. There is no permanent damage."
The CDC, the Centers for Disease Control and Prevention in Atlanta, maintains a supply of antitoxin against botulism. If administered early in the course of infection, it reduces the severity of symptoms.
Montal is senior author of a paper in the January 2003 issue of Nature Structural Biology, released online Dec. 2, 2002. It's title: "Translocation of botulinum neurotoxin light chain protease through the heavy chain channel."
"What we do in this paper," he recounted, "is provide direct evidence that the heavy chain [HC] channel mediates the translocation of the light chain [LC] across the membrane. And the HC operates as a chaperone - a protein-protein interaction in which one of the partners prevents inactivation of the second partner by interacting so closely. Those two molecular components - a light chain and a heavy chain - are each harmless," he told BioWorld Today. "The toxicity by itself has a proteolytic activity of the LC, which is an enzyme. But the LC cannot enter into neurons by itself. If you or I were to be injected with LC, or were exposed to the LC of the toxin, nothing would happen to us. The reason: LC doesn't have a way to enter into the cell, and act on the substrates that are critical for synaptic transmission.
"So it is a partnership between the heavy chain that's translocating the light chain into the correct compartment. That accounts for the toxicity. The counterpart is that the heavy chain by itself is not toxic either. Only when the two of them are combined are they deadly. Clostridium botulinum neurotoxins," he continued, "abort the process of neurotransmitter release at presynaptic motor nerve terminals, causing muscle paralysis. An enigmatic step in the intoxication process is the mechanism by which the neurotoxin heavy chain forms the conduit for the translocation of the light chain protease across the endosomal membrane into the cytosol - its site of action. Our findings," he went on, "also suggest that the botulinum neurotoxin [BoNT] channel may represent a potential target for intervention to attenuate BoNT neurotoxicity."
Montal's research lab at UCSD focuses on molecular membrane neurobiology. It is supported by the U.S. Army Medical Research and Materiel Command in Frederick, Md., "which is indirectly connected with the possibility of botulism attack," he observed. "But the bias is that if we understand the fundamental mechanisms of the toxin, we may design better inhibitors for it."
Cosmesis Is Fine; Inhibition Is Vital
"The university is in the process of applying to patent this work. In general it claims that we have a discovery that suggests an approach to intervene and block the toxin by using this novelty of its channel translocators." Montal is sole inventor.
"In the biotechnology area," he said, "I think that there are plenty of opportunities to contribute with biotechnological tricks to further the activity, for example, of Botox. It's an excellent toxin, but could be improved, as we have published. And on the other side of the coin," he continued, "there may be high-throughput screens to discover inhibitors of the toxin more quickly. This is significant not only for biotechnology but also for the pharmaceutical industries to get involved," Montal concluded, "not just in cosmetics."