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 (1795-1815) that resulted in unsanitary food production.
- The main cause of food-borne illness at the time was from smoked blood sausages.
- The largest outbreak occurred in 1973 in Wildebrad, Southern Germany; by 1811, the Department of Internal Affairs of the Kingdom of Württemberg named “prussic acid” as the culprit in sausage poisoning.
- The district medical officer officer 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 (BoNT). Kerners intense research between 1817 and 1820, 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.
- In his monograph, Kerner described the symptoms of botulism – including vomiting, intestinal spasms, mydriasis, ptosis, dysphagia, and respiratory failure – and recommended methods for the treatment and prevention of food poisoning.
- During animal and self-experimentation, 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 sympathetic nervous system activity associated with movement disorders (i.e. treat St. Vitus’ dance or Sydenham’s chorea, a disorder characterised by jerky, uncontrollable movements, either or the face or of the arms and legs) and hypersecretion of body bodily fluid, as well as to treat ulcers, delusions, rabies, plague, tuberculosis, and yellow fever.
- Professor Emile Pierre van Ermengem (1851-1922) was a microbiologist who trained under Robert Koch, who discovered anthrax, tuberculosis, and cholera and was the first researcher to prove that microorganisms could cause disease in animals.
- Ermengem identified the bacterium Clostridium botulinum (originally called Bacillus botulinus) in 1897, as the causative agent of botulism after examining post-mortem tissue of patients in Belgium who had contracted gastroenteritis and died from having eaten raw, salted pork.
- Over the next 20 years, different strains of the bacterium that produced serologically distinct types of toxins were recognised; these were eventually classified alphabetically into seven stereotypes (A, B, C1, D, E, F and G).
- Dr. Herman Sommer (University of California, San Francisco) isolated the most potent stereotype in 1928 – BoNT type A (NoNTA) – in purified form as a stable acid precipitate, paving the way for future studies.
- 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 biowarfare programs.
- President Franklin Roosevelt in response, ordered the US National Academy of Sciences and Fred Ira Baldwin, chairman of the bacteriology department of the University of Wisconsin, gathered bacteriologists and physicians in a laboratory named Fort Detrick: the investigation of dangerous infectious bacteria and toxins to use as offensive and defensive biological weapons.
- In 1946, Carl Lamanna and James Duff developed concentration and crystallization techniques for the toxin that were subsequently used by Dr Edward J. Schantz, a young US army officer stationed at Fort Detrick 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.
- 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 primate 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 andspasmodic torticollis.
- Shortly thereafter, Allergan bought Scott’s company and renamed the toxin, Botox.
- 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.