It can be easily assumed that almost all of us have heard of Botox- the “enhancement” that celebrities are getting so rapidly as if it were from a grocery store. Well, it does not come from a grocery store but rather from the toxins of a bacteria called Clostridium botulinum, and its history is quite interesting.
Figure I: Clostridium botulinum, the bacteria responsible for botulism [5].
Foodborne Botulism Throughout the History
During the late 1700s in Europe, human botulism caused many deaths. Triggered by the Napoleonic War, economic poverty led to the neglect of sanitary measures in food production, especially in rural areas. The main source of botulism at the time was smoked blood sausages–which eventually led to the term ‘botulus’, from the Latin word for ‘sausage’ to be attached to the disease by German physician Muller [4]. By the earlier 1800s, the Department of Internal Affairs of the Kingdom of Württemberg ascribed ‘sausage poisoning’ to a substance named ‘prussic acid’. Studies of botulism started after an outbreak in Germany in 1793 associated with ‘blood sausage’. Clostridium botulinum was first isolated by van Ermengemin 1897 from raw salted ham implicated in an outbreak in Belgium that involved 23 people, leading to the death of three. Since then, botulism has been shown to occur in many animals and birds. The disease results from the production of a powerful neurotoxin by the bacteria of C. botulinum. Two prominent researchers, Dr. Justinus Kerner and Dr. Emile van Ermengem, were the key names leading to the isolation of C. botulinum [4].
Justinus Kerner, also known as Würst (German term for ‘sausage’) Kerner because of his work with the mysterious ‘sausage poison’, was a German physician and poet. He was the first to publish case studies on botulinum intoxication between 1817 and 1820. In 1822, he wrote the first article on the ‘fatty toxin’ that came from the sour sausages [4, 6]. As any dedicated scientist would do, he conducted experiments upon himself and laboratory animals, leading to several major observations about the toxin:
Kerner also correctly described all the neurological symptoms of botulism recognized in modern medicine: intestinal spasms, vomiting, mydriasis, ptosis, dysphagia, and respiratory failure. Moreover, he proposed that the toxin be used for therapeutic purposes such as lowering sympathetic nervous system activity associated with movement disorders and hypersecretion of body fluids (sweat, mucus), ulcers from malignant diseases, rabies, delusions, and consumption from lung tuberculosis and yellow fever. In spite of the fact thatmany attempts at artificially reproducing the toxin had failed, Dr. Kerner suggested that the poison was of zoonic origin, an audacious statement at a time in history when microscopic pathogens had not yet been discovered [4].
Figure II: Justinus Kerner [7].
Emile van Ermengem was a microbiologist who trained in Berlin under Robert Koch (1843–1910) and was the initial researcher to demonstrate that certain microorganisms could cause disease in animals. Koch’s prominent discoveries included anthrax (1880), tuberculosis (1882), and cholera (1883). In 1895, a botulism outbreak occurred after a funeral in the Belgian village of Elezelles, and van Ermengem was the first to correlate botulism with a bacterium found in raw, salted pork and the postmortem tissue of victims who had consumed the contaminated meat. After successfully isolating this bacterium, Dr. Ermengem named it Bacillus botulinus, which was renamed as Clostridium botulinum in later years [4, 6].
Botulinum Neurotoxin as a Biological Weapon
Botulinum neurotoxin was among the first biological agents to be regarded as a potential weapon during a time when neither the composition of the toxin formed by C. botulinum nor its action mechanism was completely understood. It has been developed as a biological weapon by state-led programs in several countries such as Germany, Iraq, Japan, Russia, and the United States [4]. The toxin was initially used as a weapon in the 1930s by the Japanese when General Shiro Ishii, a military medical commander, directed that prisoners be fed lethal doses of C. botulinum [3]. With the strike of World War II, the United States government began to research biological weapons thoroughly. The US conducted a biological weapons program in 1943. At that time, initial botulinum neurotoxin research efforts were to isolate and purify the toxin and to determine its pathogenicity mechanism. Botulinum neurotoxin was given the US code name “agent X,” and its potential as an effective biological weapon was examined when the United States Office of Strategic Services conceived a plan to use Chinese sex workers to assassinate high-ranking Japanese officers by slipping a small gelatin capsule containing a lethal dose of botulinum neurotoxin into drinks or food [3, 4]. A large batch of capsules was composed and sent to the US Navy detachment for testing. The capsules were tested on stray donkeys. Unexpectedly, the animals survived, causing the project to be abandoned. Later projects were also conducted, such as the Fort Detrick – a research facility for biological weapons and botulinum toxin, founded during World War II, stationed many bacteriologists and physicians. In 1946, at Fort Detrick, researchers acquired a crystalline form of botulinum toxin type A, and the method was later used by Dr. Schantz to produce the first batch of botulinum toxin for use in humans. In 1972, the Biological and Toxin Weapons Convention was signed, which terminated all research, and Fort Detrick was formally closed. However, research into the use of botulinum toxins for medical use was carried on at the University of Wisconsin under the leadership of Dr. Schantz. In 7 years, Schantz had produced a sufficiently large batch of botulinum toxin A. This original preparation preserved its toxicity and was in use until 1997. During 1980-1990, a master batch record was written for the manufacture of medical-grade botulinum toxin. In addition to these research findings, several batches of botulinum toxin type A were bought by a pharmaceutical company named Allergen Inc., and eventually the toxin was given the name Botox [3, 4, 6]
What Is Botox and What It has Brought Us
Even though botulinum toxin became the center of attention for therapeutic causes in the 1920s, it was not until the end of the 1940s that the first batch of crystalline toxin was produced [3, 6]. In 1997, the product that would reach its popularity today was introduced, transforming the ways of treatment of strabismus and other muscular disorders and creating a new approach in cosmetic rejuvenation. The colossal expansion in the integration of its use and the first regulatory approval of botulinum toxin type A (BTX-A) for the treatment of the glabella in the United States and Canada have led to a wider clinical experience [1]. Now, BTX-A has demonstrated effectiveness in several therapeutic fields and is now acknowledged as a crucial element of noninvasive facial rejuvenation. Possessing an ever-expanding formation of applications, there is no hesitation that, along the way, some may have underestimated the potential of what was once considered the most lethal toxin known to humankind.
Figure III: Botox injection on the upper face [8].
While Botox (BTX-A Allergan, Inc, Irvine, Calif) and Dysport (BTX-A; Ipsen Ltd, Maidenhead, Berkshire, UK) dominate the market, some of the major distributors of BTX-A can be listed as: Xeomin (Merz Pharmaceuticals, Germany), Azzalure (BTX-A, Ipsen Ltd, Paris, France), Jeuveau (Evolus, Inc, South Korea), and Daxxify (Revance Therapeutics, Inc) [1]. As predicted, therapeutic utilizations of BTX-A make up a long list, such as the blepharospasm and hemifacial spasm, cervical dystonia, hyperhidrosis, and migraine; cosmetic uses such as facial rejuvenation (including brow lifts, widening of the eyes, lines among the lower face and neck, and facial contouring); and surgeries such as ablative and nonablative resurfacing and soft-tissue augmentation. The working mechanism of botulinum toxin type A is constraining the presynaptic exocytosis of acetylcholine-containing vesicles into the neuromuscular junction at cholinergic nerve endings of the peripheral nervous system; as a result, it paralyzes skeletal muscles. The primary organs of interest for aesthetic interventions include the muscles responsible for facial expressions, skeletal muscles throughout the body, as well as the sweat and salivary glands, which are innervated by the autonomic or somatic nerves of the peripheral cholinergic nerve system [6]. On account ofthis working mechanism and that BTX-A is a lethal toxin, complications are possible [1, 6]. The most common complications may include transient swelling or bruising at the injection site, mild headache, and flu-like symptoms. To minimize the symptoms, patients are instructed to stay clear of aspirin, vitamin E, and nonsteroidal anti-inflammatory drugs (NSAID). Generally, smaller doses of BTX-A are less likely to cause problems than larger doses. In contrast, less concentrated doses on the upper face could lead to inaccurate placement of the injection; therefore, higher concentration on the upper face is favored. Most complications are relatively uncommon and are caused by faulty injection techniques [1].
References
[1]A. Carruthers and J. Carruthers, “Botulinum toxin type A,” J Am Acad Dermatol, vol. 53, no. 2, pp. 284–290, Aug. 2005, doi: 10.1016/j.jaad.2005.03.060.
[2]B. M. Lund and M. W. Peck, “Clostridium botulinum,” Guide to Foodborne Pathogens, pp. 91–111, Aug. 2013, doi: 10.1002/9781118684856.CH6.
[3]Z. F. Dembek, L. A. Smith, and J. M. Rusnak, “Botulism: Cause, Effects, Diagnosis, Clinical and Laboratory Identification, and Treatment Modalities,” Disaster Med Public Health Prep, vol. 1, no. 2, pp. 122–134, 2007, doi: 10.1097/DMP.0B013E318158C5FD.
[4]P. T. Ting and A. Freiman, “The story of Clostridium botulinum: from food poisoning to Botox,” Clinical Medicine, vol. 4, no. 3, p. 258, May 2004, doi: 10.7861/CLINMEDICINE.4-3-258.
[6]M. Y. Park and K. Y. Ahn, “Scientific review of the aesthetic uses of botulinum toxin type A,” Arch Craniofac Surg, vol. 22, no. 1, p. 1, 2021, doi: 10.7181/ACFS.2021.00003.
Figure References
1-[5]“Clostridium-botulinum-bacteria-Credit-EYE-OF-SCIENCE-SCIENCE-PHOTO-LIBRARY.png (850×702).” Accessed: Aug. 31, 2024. [Online]. Available: https://www.researchgate.net/profile/Cedric-Woudstra/publication/304792202/figure/fig1/AS:380429820547073@1467712945160/Clostridium-botulinum-bacteria-Credit-EYE-OF-SCIENCE-SCIENCE-PHOTO-LIBRARY.png
2-[7]“File:Justinus Kerner 1852 von Ottavio d’Albuzzi.jpg – Wikimedia Commons.” Accessed: Aug. 31, 2024. [Online]. Available: https://commons.wikimedia.org/wiki/File:Justinus_Kerner_1852_von_Ottavio_d%27Albuzzi.jpg
3-[8]“The Remarkable Story of Botox.” Accessed: Aug. 31, 2024. [Online]. Available: https://www.verywellhealth.com/how-botox-came-to-be-1124145
Referans 1- cosmetic uses ve side effects and complications bölümlerinden yararlanıldı.
Referans 2- 6.2, 6.3.1, 6.3.2, bölümlerinden yararlanıldı.
Referans 3- Botulinum toxin as a biological weapon, clostridia microbiology bölümlerindenyararlanıldı.
Referans 4- sayfa 258, 259 dan yararlanıldı.
Referans 6- Introduction, Botulinum Neurotoxin: a miracle poison bölümlerinden yararlanıldı.
