Tropical medicine rounds Botulinum toxin historical aspects: from food poisoning to pharmaceutical Daisy Kopera, MD Department of Dermatology, Medical University Graz, Auenbruggerplatz, Graz, Austria Correspondence Daisy Kopera, MD Department of Dermatology Medical University Graz Auenbruggerplatz 8 A-8036 Graz Austria E-mail: daisy.kopera@medunigraz.at Abstract Background In the history of medicine, unexpected coincidences indicated the development of new treatment options. Objective One of the most peculiar ones concerns the finding of botulinum toxin, and this should be familiar to physicians using the drug. Methods A survey through the history of the ‘‘fat-poison’’ has been performed. Result A poison turned to one of the most popular drugs in aesthetic medicine. Conclusion Depending on the dose, a substance may be poisonous or not. Conflicts of interest: None. all ding’ sind gift und nichts ohn’ gift; alein die dosis macht das ein ding kein gift ist all substances are poisons; there is none which is not a poison. Only the dose makes a remedy poisonous Philippus Theophrastus Bombastus von Hohenheim, known as Paracelsus Swiss-Austrian physician and philosopher (1493 Zurich–1541 Salzburg) 976 Food-borne intoxications have probably accompanied mankind from the very beginning. Efforts to preserve and store food by smoking, drying, and salting created ‘‘perfect’’ environments for microorganisms to ferment and digest the goods and gave them the opportunity to produce residues of potential harm to the human body. Some examples are: ham used to be stored in barrels of brine in northern parts of France, not yet dried fish were stored in baskets for fermentation in the Baltic, in Scandinavia, poorly smoked sausages, and bacon hung from the rafters of Austrian huts.1 However, in ancient times the connection between food consumption and poisoning symptoms or death was not perceived. History does not give much information on this subject; however, some dietary laws and taboos reflect at least some knowledge about it. One proof may be the fact that Emperor Leo VI of Byzantium (886–911) prohibited the production of blood sausages.2 In the history of medicine, unexpected coincidences indicated the development of treatment options. In my opinion, one of the most peculiar ones concerns the finding of botulinum toxin. International Journal of Dermatology 2011, 50, 976–980 Southern Germany in the late eighteenth century During the Napoleonic Wars 1792–1815 devastating warfare by the French led to general economic poverty in rural areas of central Europe. Hygiene declined in all parts of everyday life, including food production. In southern Germany ‘‘Blunz’n’’ or ‘‘Saumagen’’ – a pigs stomach, stuffed with mixtures of meat, grease, blood, herbs, bread, cereals, and sometimes also the pig’s inwards – smoked and then boiled – was a common dish. In the early years of the nineteenth century, the medical administration of the Dukedom – later Kingdom – of Württemberg registered an increasing number of lethal food poisoning cases in their population. In July 1802, the government in Stuttgart published a notice on the ‘‘harmful consumption of smoked blood sausages’’ to alert their people. Almost 10 years later, in 1811, the medical section of their Internal Affairs Department suspected that the disastrous ‘‘sausage poisoning’’ was probably caused by prussic acid (hydrogen cyanide HCN, which may be found in small quantities in certain plants such as sorghums and closely related species). When the medical faculty of the University of Tübingen became involved in this problem, the Dean [Professor Wilhelm Gottfried von Ploucqet (1744–1814)] stated that prussic acid could be a zoonic, probably organic poison. Johann Heinrich Ferdinand Authenrieth (1772–1835), a medical professor at this university, initiated that further outbreaks of food poisoning should be very well recorded, and systematic studies on this ª 2011 The International Society of Dermatology Kopera issue were prompted by the government of Württemberg. Aside from this, Authenrieth blamed local housewives in charge of food preparation that they might not be boiling the sausages long enough in order to prevent them from bursting, and therefore they probably become rotten inside. In 1815, a health officer in Herrenberg, a small town south of Stuttgart, J.G. Steinbuch3 (1770–1818), reported seven cases of intoxication after ingestion of liver sausage and peas, and he described his autopsy findings in three victims of this incident. In the same year, the ambitious 29-year-old physician Justinus Kerner (1786–1862) (Table 1, Fig. 1, http://guenther-emig.de/kerner/bio01.html) also reported on food poisoning in the small town of Welzheim. These reports revealed various kinds of sausages as the probable cause of the poisoning. Professor Authenrieth was attracted by the authenticity of these reports and decided to publish them in 1817.4 Subsequently, Kerner5 observed 76 cases, which he published in his first monograph, entitled ‘‘Neue Beobachtungen über die in Württemberg so häufig vorfallenden tödlichen Vergiftungen durch den Genuss geräucherter Würste’’ (‘‘New observations on lethal poisoning occurring so frequently in Württemberg through the consumption of smoked sausages’’). He stated that the toxin interrupts chemical processes of nervous transmission in the same way that rust does not conduct electricity. Kerner received a 100-Taler grant from the government in Stuttgart and intensified his research by starting animal experiments in 1821. In the laboratory of a local pharmacist, he extracted the poisonous substance from sour sausages and similar products, calling it ‘‘sausage poison’’ History of botulinum toxin Tropical medicine rounds Figure 1 Justinus Kerner (1786–1862) as an old man around 1860 (from: http://www.google.at/imgres?imgurl=http://de. academic.ru/pictures/dewiki/74/Justinus_Kerner_Altersbild. jpg&imgrefurl=http://de.academic.ru/dic.nsf/dewiki/724406 &usg=__rMnFlKaTRtTGi5OJ-Gh55s3R6qc=&h=1339&w= 1065&sz=382&hl=de&start=0&zoom=1&tbnid=Z6lQn_ 1yQJ6L2M:&tbnh=166&tbnw=132&prev=/images%3Fq% 3Djustinus%2Bkerner%26hl%3Dde%26biw%3D1276% 26bih%3D819%26gbv%3D2%26tbs%3Disch:1&itbs=1& iact=hc&vpx=143&vpy=62&dur=1760&hovh=252&hovw= 200&tx=132&ty=191&ei=03QYTaGlJsWCswaY_P3uAQ& oei=03QYTaGlJsWCswaY_P3uAQ&esq=1&page=1&ndsp= 24&ved=1t:429,r:0,s:0)) Table 1 Justinus Kerner’s short biografy (see also http:// guenther-emig.de/kerner/bio01.html;german) Justinus Andreas Christian Kerner (1786–1862) Kerner was born in 1786 in Ludwigsburg in a well established family of governmental officials. After his father’s death in 1799, he had to work as a trainee in the local cloth factory. He disliked this dull work and started to write poems, which he recited to patients of a nearby madhouse playing the jew’s harp to them. Interestingly he became one of the most famous German poets of the romantic period. His former teacher and pastor convinced his mother, that the boy was gifted enough to study at the University of Tübingen. In 1808, he attained degrees in Natural Sciences and Medicine. After 2 years of traveling he started to work as a medical officer in Dürmenz; in 1811 he was physician at the spa of Wildbad, and later general practitioner in Welzheim. Kerner married his fiancee, Friederike Ehrmann (1786– 1854), in 1813. They had three children (Marie 1813–1886, Theobald 1817–1907, and Emma 1822–1895). He was appointed head of the local public health officers in Gaildorf in 1815 and spent the years 1818–1851 in Weinsberg. As a poet he met Ludwig Uhland (1787– 1862), Gustav Schwab (1792–1850), Nikolaus Lenau (1802–1850), and Alexander von Württemberg (1801–1844), all well known German writers, who he regularly invited to his house (Fig. 2). As a consequence of his cataracts he spent the last years of his life in almost total blindness. ª 2011 The International Society of Dermatology Figure 2 Kerner’s house in Weinsberg (from: http://de. academic.ru/pictures/dewiki/75/Kernerhaus_in_Weinsberg. jpg) International Journal of Dermatology 2011, 50, 976–980 977 978 Tropical medicine rounds History of botulinum toxin or ‘‘fatty acid.’’ He mixed the poison with honey and fed it to various animals, including cats, rabbits, birds, frogs, snails, and insects, such as locusts and flies. In particular, the clinical symptoms observed in cats were similar to those occurring in humans. He described all muscular and autonomic symptoms and pointed out that the intoxication did not affect the brain, as no disturbances of consciousness occurred. The toxin’s action was represented by an interruption of the signal transmission in the peripheral sympathetic and parasympathetic nerves without sensory disturbances. Autopsies showed that secondary respiratory and cardiac failure were responsible for lethal outcomes of the poisoning. Kerner also conducted heroic experiments on himself: he ingested few drops of the poison – exploiting it’s sour taste – and feeling mild symptoms of ‘‘sausage poisoning,’’ as his tongue, palate, and pharynx dried out rather quickly. As a last step in his experiments, Kerner wanted to synthesize artificial ‘‘sausage poison,’’ but he did not succeed. Still, in 1822 he published his second monograph entitled Das Fettgift oder die Fettsäure und ihre Wirkungen auf den thierischen Organismus, ein Beytrag zur Untersuchung des in verdorbenen Würsten giftig wirkenden Stoffes (Fat poison or fatty acid and its effects on the animal organism: A contribution to the examination of poisonous substances from bad sausages), reporting the clinical evaluation of no less than 155 cases, including human autopsies, animal experiments, and all knowledge he had gathered so far. He mentioned very interesting clinical details: ... the tear fluid disappears, the gullet becomes a dead and motionless tube; in all mucous cavities of the human machine the secretions of the normal mucus stands still, from the biggest, the stomach, towards the tear canal and the excretory ducts of the lingual glands. No saliva is secreted. No drop of wetness is felt in the mouth, no tear is secreted any more …. The main clinical symptoms he described were: vomiting, intestinal spasms, mydriasis, ptosis, dysphagia, and finally, respiratory failure.6 Kerner compared many different recipes for sausages and found that the only common ingredients were fat and salt. As salt was known as being ‘‘innocent’’, the toxic change must take place in the fatty parts, what implicated a second denomination for the toxin: ‘‘fat poison.’’ He compared the mode of action with those of already known poisonous substances, such as atropine, scopolamine, and snake venom. He concluded that the ‘‘new poison’’ was probably of zoonic origin, as it develops in rotten sausages under anaerobic conditions, acts on the nervous system, and is lethal in smallest doses. In order to prevent further incidents of poisoning, Kerner pointed out again that sausages should be stored International Journal of Dermatology 2011, 50, 976–980 Kopera in dry conditions, they should be boiled properly, and conspicuous parts should not be eaten. He invented an elastic tube to avoid aspiration in case of prodromal symptoms of poisoning. In the final statements of his second monograph, Kerner discussed the toxin as a possible remedy for a variety of diseases, favoring a condition known as ‘‘Veitstanz’’ (St. Vitus dance, comparable with chorea Huntington and chorea minor) or the hypersecretion of body fluids. More than 180 years ago, Kerner presumed that his statement on ‘‘fatty acid’’ as a therapeutic agent ‘‘belongs to the realm of hypothesis and may be confirmed or disproved by observations in the future.’’1,7,8 The term botulismus In Kerner’s days, the symptoms of food poisoning that occurred after ingestion of meat products of rural origin were simply called ‘‘sausage poisoning.’’ Derived from the Latin word ‘‘botulus,’’ which means ‘‘sausage,’’ the term ‘‘botulismus’’ was created more than 50 years later, in the 1870s. Belgium 1895 Eighty years after Kerner’s work, after the funeral of 87-year-old Antoine Creteur in the Belgian village of Ellezelles, 34 musicians of the local brass band ‘‘Fanfare Les Amis Réunis’’ gathered at ‘‘Le Rustic’’ for the funeral meal. They reveled in pickled and smoked ham. Shortly afterwards they all developed mydriasis, diplopia, and some of them dysphagia and muscle paralysis, and three of them died. The ham was examined and autopsies were carried out by the microbiologist Emile Pierre Van Ermengem (1851–1922), professor at the University of Ghent, formerly trained by the famous Robert Koch (1843–1910) in Berlin. Van Ermengem was the first to correlate the symptoms of ‘‘sausage poisoning’’ with a bacterium found in raw salted pork and in the tissue of victims who had died from contaminated ham. In his report on an anaerobic, spore-forming, toxin-producing bacillus, in 1897, he named it Bacillus botulinus, as the term botulismus was already known at this time.9 Subsequent investigations discovered different serological subtypes. In later years, van Ermengem’s bacillus was renamed Clostridium botulinum.10 Botulinum toxin: a biological weapon? During World War I, first attempts were made to develop biological or chemical weapons by the Germans. Luckily, they did not succeed. In the 1920s, Herman Sommer11 at the University of California had obtained a crude botuª 2011 The International Society of Dermatology Kopera linum toxin preparation from culture fluid by acidic preparation. At the beginning of World War II, the US Academy of Sciences worked on this in a secret laboratory in Fort Detrick, Maryland. Bacteriologists and physicians were stationed there to investigate bacteria and toxins that could be used for this purpose. At the same time, the United States Office of Strategic Services devised a plan to use Chinese prostitutes for the assassination of high ranking officers of the Japanese army by smuggling a lethal dose of botulinum toxin in a pin-size gelatin capsule into their food or drink. When the capsules were sent to Chunking, China, they were tested again – on stray donkeys – and the whole program was abandoned – as the donkeys survived.12 Years later scientists found out that donkeys may be one of the few species immune to botulinum toxin.13 In 1946 Edward Schantz,14 scientist at Fort Detrick, produced the first botulinum toxin for use in humans. Signing the Biological and Toxin Weapons Convention in 1972, US President Richard Nixon (1913–1994) terminated all research on biological agents used in warfare. Medical research on botulinum toxin In the 1960s, Alan Scott, ophthalmologist at the SmithKettlewell Eye Research Institute in San Francisco, started research on the treatment of strabismus by injecting various substances into hyperactive ocular muscles as an alternative to conventional surgery.15 He did not succeed with a number of different substances until he approached Edward Schantz for botulinum toxin. In 1978, Scott16 received permission from the FDA to conduct a pilot study in human volunteers for the treatment of strabismus. A year later, type A of the toxin was approved by the FDA for certain use in humans. Injected in larger muscles in different parts of the body, neurologists found out that larger quantities of botulinum toxin effectively block involuntary muscle contraction. In 1989, botulinum toxin A was approved by the FDA for this, hemifacial spasms, strabismus, and blepharospasm. Today, treatment of neurological conditions such as torticollis, various forms of dystonias, spasticity, tremors, and migraine headaches are routine procedures. Even if these applications are still for off-label use of the drug, more and more medical indications will be approved in time.17 Otolaryngologists use botulinum toxin for the treatment of phoniatric disorders.18,19 In 1987, dermatology stumbled into this matter by accident: the Canadian ophthalmologist Jean Carruthers observed that after injecting botulinum toxin for the treatment of blepharospasm frown lines disappeared. She shared this observation with her husband, Alastair Carruthers, a dermatologist. After that, the Carruthers promoted a cosmetic procedure that revolutionized aesthetic ª 2011 The International Society of Dermatology History of botulinum toxin Tropical medicine rounds enhancement treatments. They published their first report on botulinum toxin application for cosmetic purposes in 1996.20 Since then numerous clinical and experimental studies have been conducted and new indications have been found: it is used for the enhancement of frontal and periocular wrinkles, hyperhidrosis, bruxismus, and migraine, just to name a few. An orphan adopted by pharmaceutical industries In 1991, several batches of botulinum toxin A and all research findings concerning this ‘‘orphan drug’’ were bought by Allergan Inc., Irvine, CA 92623-9534, who, as new parents, gave the substance the name Botox.14 Two years later, a slightly different formulation was launched by a British company, Porton Products Ltd, under the name DYSPORT (Ipsen Inc., Rockford, IL 61125-1266.), derived from dystonia. Various subtypes of botulinum toxins have been detected in the near past: types A, B, C, D, E, F, and G. Types A, B, E, and F may be found in food.21 Today, a variety of different products containing botulinum toxin A strains are on the market, and there are over 100 indications for medical use of this drug that can almost do miracles if used by experts.22 Some of them are also approved for aesthetic purposes. Derived from food poisoning two hundred or more years ago, the toxin has made its way and, for many reasons, it is probably the most amazing substance that has been developed as a revolutionary pharmaceutical in the last decades. References 1 Erbguth FJ. Historical notes on botulism, chlostridium botulinum, botulinum toxin, and the1 idea of the therapeutic use of the toxin. Mov Disord 2004; 19(Suppl. 8): 2–6. 2 Kreyden OP, Geiges ML, Böni R, Burg G. Botulinumtoxin: Vom Gift zum Medikament. Ein historischer Rückblick. Hautarzt 2000; 51: 733–737. 3 Steinbuch JG. Vergiftung durch verdorbene Würste. Tübinger Blätter Naturwiss Arzneykunde 1817; 3: 26–52. 4 Kerner J. Vergiftung durch verdorbene Würste. Tübinger Blätter Naturwiss Arzneykunde 1817; 3: 1–25. 5 Kerner J. Neue Beobachtungen über die in Württemberg so häufig vorfallenden tödlichen Vergiftungen durch den Genuss geräucherter Würste. Tübingen: Osiander, 1820. 6 Kerner J. Das Fettgift oder die Fettsäure und ihre Wirkungen auf den thierischen Organismus, ein Beytrag zur Untersuchung des in verdorbenen Würsten giftig wirkenden Stoffes. Stuttgart: Cotta, 1822. International Journal of Dermatology 2011, 50, 976–980 979 980 Tropical medicine rounds History of botulinum toxin 7 Erbguth FJ. Botulinum toxine, a historical note. Lancet 1998; 351: 1820. 8 Erbguth FJ, Naumann M. Historical aspects of botulinum toxin. Neurology 1999; 53: 1850–1853. 9 Van Ermengem E. Classics in infectious diseases. A new anaerobic bacillus and its relation to botulism. Rev Infect Dis 1979; 1: 701–719, (Originally published as ‘‘Über einen neuen anaeroben Bacillus und seine beziehungen zum Botulismus.’’ In: Zeitschr für Hygiene und Infektionskrankheiten 1897; 26: 1–56.) 10 Collins MD, East AK. Phylogeny and taxonomy of the food-borne pathogen Clostridium botulinum and its neurotoxins. J Appl Microbiol 1998; 84: 5–17. 11 Snipe PT, Sommer H. Studies on botulinus toxin. 3. acid preparation. J Infect Dis 1928; 43: 152–160. 12 Ting PT, Freiman A. The story of Clostridium botulinum: from food poisoning to Botox. Clin Med 2004; 4: 258–261. 13 Lovell SP. Of Spies & Strategems. Englewood Cliffs. NJ: Prentice-Hall; 1963: 86–88. 14 Schantz EJ, Johnson EA. Botulinum toxin: the story of its development for the treatment of human disease. Perspect Biol Med 1997; 40: 317–327. 15 Scott AB, Rosenbaum A, Collins CC. Pharmacologic weakening of extraocular muscles. Invest Ophthalmol 1973; 12: 924–927. International Journal of Dermatology 2011, 50, 976–980 Kopera 16 Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J Pediatr Ophthalmol Strabismus 1980; 17: 21–25. 17 Jankovic J, Brin MF. Botulinum toxin: historical perspective and potential new indications. Muscle Nerve Suppl 1997; 6: S129–S145. 18 Ptok M, Schonweiler R, Nawka T. ‘‘Off-label use’’ of botulinum toxin preparations in treatment of spasmodic dysphonia. Position of the German Society of Phoniatrics and Pediatric Audiology. HNO 2004; 52: 45–49. 19 Watts C, Nye C, Whurr R. Botulinum toxin for treating spasmodic dysphonia (laryngeal dystonia): a systematic Cochrane review. Clin Rehabil 2006; 20: 112–122. 20 Carruthers A, Carruthers J. The history of the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998; 24: 1168–1170. 21 Sharma SK, Ferreira JL, Eblen BS, Whiting RC. Detection of type A, B, E, and F Clostridium botulinum neurotoxins in foods by using an amplified enzyme-linked immunosorbent assay with digoxigenin-labeled antibodies. Appl Environ Microbiol 2006; 72: 1231– 1238. 22 Heckmann M, Rzany B. Botulinumtoxin in der Dermatologie. Munich: Urban & Vogel, 2002: 13–17. ª 2011 The International Society of Dermatology