Botulinum toxin historical aspects- from food poisoning to pharmaceutical

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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: [email protected]
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
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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
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2 Kreyden OP, Geiges ML, Böni R, Burg G.
Botulinumtoxin: Vom Gift zum Medikament. Ein
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Wirkungen auf den thierischen Organismus, ein Beytrag
zur Untersuchung des in verdorbenen Würsten giftig
wirkenden Stoffes. Stuttgart: Cotta, 1822.
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ª 2011 The International Society of Dermatology
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