The major source of botulinum toxin is the organism Clostridium botulinum; C. barati and C. butyricum also produce the toxin [1-3]. The toxin is synthesized in seven serotypes, designated A, B, C, D, E, F, and G. Serotypes A, B, and E account for almost all cases of human botulism. Serotype A has been approved by the Food and Drug Administration for treatment of various medical problems, and other serotypes are being evaluated in clinical trials.

Each of the seven toxin serotypes is synthesized as a single-chain polypeptide (molecular weight, 150 000) that has only minimal toxicity [4]. To become fully active, the single-chain molecule must be cleaved by proteolysis to generate a heavy chain (molecular weight, 100 000) that is linked by a disulfide bond to a light chain (molecular weight, 50 000). It is the dichain form of the molecule that causes both poisoning and therapeutic benefits.

Although humans can come into contact with botulinum toxin in several ways, two situations account for almost all outbreaks of botulism [5]. In the first, patients ingest food that is contaminated with performed toxin. The bacteria that manufacture the toxin are ubiquitous, and it is not unusual for food to contain traces of the organism. Traces alone are not usually a source of concern, but a problem arises when tainted food is stored or processed in a way that allows anaerobic organisms to grow and multiply. As part of the growth cycle, the bacteria produce and release toxin. If food is not subsequently heated to destroy toxin, clinically significant amounts of the toxin can be consumed. The toxin can then escape the gut and reach the general circulation, from which it is distributed to vulnerable sites throughout the body.

In this issue, Townes and colleagues [6] describe an example of this type of poisoning. Unsuspecting patrons of a delicatessen consumed cheese sauce that had been contaminated with C. botulinum. Eight patients met the case definition of botulism; five were hospitalized and one died. Had it not been for the diligence of the medical investigators who traced the tainted food to its source, even more persons might have been affected.

The second set of circumstances that can lead to botulism begins in a similar fashion. This sequence also involves ingestion of tainted food, but in this case it is ingestion of organisms that is important [7, 8]. Ordinarily, obligate anaerobes such as C. botulinum do not colonize the human gut [9, 10]. Infants are the exception to this general rule: The infant gut can be colonized, thus allowing growing organisms to manufacture and release toxin. As in the first scenario, toxin can escape the gut to be distributed throughout the body.

Regardless of the way in which patients come into contact with the toxin, the manifestations of poisoning are the same. Patients may have diplopia and ptosis, difficulty speaking and swallowing, autonomic dysfunction such as stasis of the bowel, and muscle weakness that can progress to flaccid paralysis. These problems may seem diverse and unrelated, but they have a common basis. Botulinum toxin binds with high affinity to peripheral cholinergic nerve endings, such as those at the neuromuscular junction and in the autonomic nervous system [11-13]. The toxin proceeds through a complex sequence of events that culminates in blockade of acetylcholine release. This means that toxin action at the neuromuscular junction can cause weakness and even complete paralysis. Similarly, patients may have many signs of parasympathetic and sympathetic dysfunction attributable to toxin action on autonomic nerves.

The past several years have been exciting for botulinum toxin research because investigators have discovered the mechanism of toxin action on cholinergic cells. After binding with high affinity to receptors on nerve endings, the toxin penetrates the cell membrane by receptor-mediated endocytosis and then crosses the endosome membrane by pH-dependent translocation [14-16]. When it reaches the cytosol, the toxin acts as a zinc-dependent endoprotease to cleave polypeptides that are essential for exocytosis [17]. In the absence of these peptides, nerve impulses can no longer trigger the release of acetylcholine.

The discoveries that culminated in an understanding of toxin action are only one reason for current excitement about the toxin. Another reason is the use of the toxin as a therapeutic agent [18, 19]. Botulinum toxin is being used to treat such disorders as strabismus, spasmodic torticollis, and loss of detrusor sphincter control. These disorders are all characterized by excessive efferent activity in cholinergic nerves. Botulinum toxin is injected near these nerves to block release of acetylcholine.

Broadly speaking, the toxin has been tested or adopted for therapeutic use in four clinical areas [20]: ophthalmology (for treating blepharospasm and strabismus); neurology (primarily for treating focal dystonias but also for treating some segmental dystonias); otolaryngology (for treating spasmodic dysphonia); and areas of medicine, such as gastroenterology, that focus on smooth muscle and sphincter control (for treating achalasia). Although a single clinical assessment that applies to all situations cannot be offered, in general botulinum toxin has emerged as the therapy of choice for conditions characterized by excessive cholinergic activity.

Several factors explain why botulinum toxin has proved to be such a valuable drug. First, the toxin is highly selective in acting on cholinergic cells, a characteristic that diminishes the chances of adverse side effects. Adverse effects that do occur are usually caused by toxin diffusion and action on nearby cells. Second, the toxin has a long duration of action. Clinically significant responses can last from several months to more than a year, after which time the toxin must be readministered. Finally, the dose of toxin can be individually titrated for each patient to ensure maximal benefits. No other form of therapy can match the combination of these three qualities and the toxin's impressive clinical efficacy.

The recent advances in our understanding of botulinum toxin indicate not only the triumph of scholarly research but also the emergence of a supreme irony. In probing the biology of this molecule, investigators have discovered the toxin's mechanism of action and grasped the significance of that action. As a result, they have found that the molecule has the characteristics of not only a poison but also a powerful therapeutic agent. It is ironic that botulinum toxin, which is generally considered the most poisonous of all poisons, may have more desirable than undesirable qualities.