History of Botulinum Toxin

In the late 1700s in Europe an outbreak of a deadly illness from contaminated foods swept across the continent, fuelled partly by the poverty from the Napoleonic War that resulted in unsanitary food production. The main cause of food-borne illness at the time was from smoked blood sausages. Dr.Justinus “Wurst” Kerner (1786-1862), began a lifelong quest to uncover the mysteries of the poison. He was later considered to be the godfather of botulinum toxin Kerner’s intense research between 1817 and 1820, who identified and described the first accurate descriptions of botulism (a term coined in 1871 from the Latin botulus, meaning “sausage”). In 1822, he compared contaminated sausage ingredients and concluded that the toxin must occur in the fat, leading him to call the suspicious substance “sausage poison”, “fat poison’, or “fatty acid,” and published the first complete monograph of the “fatty toxin” from blood sausages. Kerner described the symptoms of botulism as follows: vomiting, intestinal spasms, mydriasis, ptosis, dysphagia, and respiratory failure. He recommended methods for the treatment and prevention of food poisoning. During animal and selfexperimentation, Kerner observed that the toxin developed under anaerobic conditions and was lethal in small doses. Since the effects of this blood poison were similar to atropine, scopolamine, nicotine and snake venom, Kerner surmised that sausage poison was likely biological in nature which considering microscopic pathogens had not yet been discovered at the time was considerably remarkable. Kerner interrupted signal transmissions within the peripheral and autonomic nervous system. Kerner suggested that small amounts of this sausage poison could be used to lower nervous system activity associated with movement disorders.

Biological Weapon of Warfare

During the first world war Germany unsuccessfully attempted to produce chemical and biological weapons. As World War II approached, the American government learned that the multiple countries were engaged in bio-warfare programs. President Franklin Roosevelt then ordered the US National Academy of Sciences to learn to use it as offensive and defensive biological weapon.

In 1946, Carl Lamanna and James Duff developed concentration and crystallization techniques for the toxin which were subsequently used by Dr Edward J. Schantz to produce the first BoNTA for human use (the basis of the later clinical product). The US Office of Strategic Services (OSS) developed a plan using Chinese prostitutes to assassinate high ranking Japanese officials via gelatine capsules containing the newly purified BoNTA. The government abandoned the plan when test donkeys that received the capsules survived. Ironically, though BoNT today is considered one of the deadliest poisons in the world, with just 1 gram it has the potential to kill 1 million people, however the toxin is not an ideal biological weapon, since large amounts need to be ingested and mortality rates vary.

In 1972, President Richard Nixon signed the Biological and Toxic Weapons Convention, effectively putting an end to all investigations on biological agents for use in war. Schantz took his research to the University of Wisconsin, where he produced a large amount of BoNTA that remained in clinical use until December of 1997.

Human Experimentation

Clinical use of the toxin began in the late 1960s and early 1970s, when Dr. Alan Scott began experimenting with BoNTA, supplied by Dr. Schantz, and other chemical agents in monkeys, with the hope that one of the compounds could be used for the nonsurgical treatment of strabismus in humans. Scott publishes his first studies proving that BoNTA could weaken extraocular muscles in 1973 and postulated that the toxin could be potentially used for a wide variety of musculoskeletal disorders and spasticity, even before human studies were conducted. Scott received approval from the Food and Drug Association (FDA) in 1978 to begin testing small amounts of the toxin (then called Oculinum) in human volunteers; his landmark paper, published in 1980, showed that intramuscular injections of BoNTA could correct gaze misalignment in humans. In 1989, one year after manufacturer Allergan Inc acquired the rights to distribute Scotts Oculinum in the United States, BoNTA was approved for the nonsurgical correction of strabismus, blepharospasm, hemifacial spasm, and Meige’s syndrome in adults, and clinical use expanded to include the treatment of cervical dystonia and spasmodic torticollis. Shortly thereafter, Allergan bought Scott’s company and renamed the toxin, Botox.

Cosmetic Use

In the mid-1980s, Dr. Jean Carruthers, an opthalmologist in Vancouver, Canada, noticed that her patients injected with BoNTA for blepharospasm experienced a reduction in glabella rhytides, and discussed her findings with both Scott and her dermatologist spouse, Dr. Alastair Carruthers, who was attempting to soften the forehead wrinkles of his patients using soft-tissue augmenting agents available at the time. Intrigued by the possibilities, the Carruthers used the toxin experimentally in their receptionist’s forehead and subsequently published the first report of BoNTA for the treatment of glabellar frown lines in 1992. Other reports soon followed, including the first double-blind, placebo-controlled study for the treatment of hyperkinetic facial lines.