Perspectives in Biology and Medicine

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 40 ¦ Number 4 ¦ Spring 1997 BOTULINUM TOXIN: THE STORY OFITS DEVELOPMENT FOR THE TREATMENT OF HUMAN DISEASE EDWARD f. SCHANTZ and ERIC A. JOHNSON* In 1885 the eminent physiologist Claude Bernard wrote in his classic work Experimental Sciences "Poisons can be employed as a means for the destruction of life or as an agent for the treatment of the sick" [1] . In line with his prediction for medical uses of natural poisons and toxins, over a century later, in 1989, the Food and Drug Administration (FDA) licensed botulinum toxin type A as an orphan drug for the treatment of persons who suffer from the involuntary muscle disorders strabismus, blepharospasm , and hemifacial spasm. The successful use of the toxin for these conditions soon led to its use for the treatment of many other diseases caused by involuntary muscle contractions, particularlyfocal and segmental muscle movements. Diseases treated have included spasmodic torticollis, limb dystonias , vocal disorders, tremors, cerebral palsy in children, gastrointestinal disorders, spasticity in adults, and various pain syndromes [2] . The nerve impulses causing these involuntary muscle contractions originate in the brain or basal ganglia ofpersons affected with these diseases, the cause ofwhich is unknown. Many of these diseases are defined as dystonias, disorders characterized by involuntary movements of muscle groups. In 1911, Oppenheim introduced the term "dystonia musculorum deformans" to describe children who had involuntary movement disorders [3] . In many diseases in adults such as spasmodic torticollis and hemifacial spasm, the contractions cause severe pain and bodily distortions, particularly in the *Department of Food Microbiology and Toxicology, Food Research Institute, University of Wisconsin, Madison, WI 53706.© 1997 by The University of Chicago. All rights reserved. 0031-5982/97/4002-1OOOfOl.OO Perspectives in Biology and Medicine, 40, 3 ¦ Spring 1997 | 317 head and neck regions. Although the impulses from the brain or other sources may continue in these maladies, the action of the toxin blocks the release of acetylcholine produced at the nerve ending from reaching the muscle and prevents the involuntary contractions, with great relief to the patients. Fortunately, voluntary muscle contractions appear to be carried on in a normal manner. Many thousands of people throughout the world are afflicted with these painful dystonic and other involuntary muscle contractions. In the United States alone, over 100,000 individuals suffer from some form of involuntary muscle contraction. The injection of one to 10 nanograms (10~9 grams) or less of type A botulinum toxin directly into or near the affected myoneural junction is the most effective means of treatment known at this time and has greatly improved the lives of patients suffering from these diseases. The pain described by some spasmodic torticollis patients brings on a suicidal desire and loss of one's objective in life. The relief obtained with a few nanograms of the toxin has meant the salvation of an enjoyable life and a productive occupation for many patients. The first use of botulinum toxin for these disorders came about more than 25 years ago, beginning in about 1968, through the collaboration ofAlan B. Scott and E.J. Schantz and later (1985) EricJohnson. Our work has opened a new field of investigation on the application of botulinum toxin type A to nerve tissue and involuntary muscle activity in the human body. The following is the story of how botulinum toxin, one of our most dangerous foodborne toxins and the cause of botulism, became one of the most preferred drugs for the treatment of certain human diseases. Botulism resulting from the consumption of foods contaminated with botulinum toxin is an ancient disease associated with high fatality rates. The disease was first described in Germany by Müller (1735-1793) and by the poet and noted physician Justinius Kerner (1786-1862) [4]. The disease became known as Kerner's disease and was associated in Germany with eating insufficiently cooked "blood sausages." Symptoms of botulism included muscle paralysis, suffocation, and frequently death. Although numerous theories were proposed for the cause of botulism, its nature remained obscure until the Belgian microbiologist Emile Pierre van Ermengem successfully isolated an anaerobic bacterium, Bacillus botulinus, which he showed produced a toxin lethal to various animals including monkeys [5]. Kempner in...