In the second installment of our historical series, Dr. Patrick Treacy delves into the captivating journey of botulinum toxin. Explore the first part covering HA fillers' history here!

The Long History of Botulinum

1793 was an eventful year by any standards. It started with the French King Louis XVI being guillotined in front of a cheering crowd in Paris and ended later that year with the execution of his wife, Marie Antoinette. The fact that Louis had tried to escape and was captured while trying to make a purchase at a store, where the clerk recognised his face on the coinage, only added to the drama. It was in that same year that the British Admiralty began to supply citrus juice to its navy ships to prevent scurvy and the Holy Roman Empire decided to declare war on France after it banned Roman Catholicism. Across the Rhine, in Southern Germany, a food poisoning epidemic caused by eating uncooked blood sausages was claiming the death of over the half of those patients who fell ill. The symptoms of the disease included malaise, nausea, vomiting, diarrhoea, double vision, dilated pupils, fatigue, unsteady gait, difficulty swallowing, thirst and, when fatal, unconsciousness, rigor and ultimately death. The disease and the remnants of the century passed, and the Act of Union of 1800 united the Kingdom of Great Britain with the Kingdom of Ireland. The nineteenth century started off well with the armies of new United Kingdom finally ending the Napoleonic wars and subsequently dismissing the armies of the French and the Prussians to their homes.

However, in this poverty-stricken landscape, disease and pestilence was never far away and in 1817, the dreaded uncooked sausage food poisoning returned to the town of Baden-Wurttemberg. All this mention of disease and food poisoning in the days before antibiotics would have passed idly into history except for the actions of a meticulous medical doctor called Justinus Kerner. Justinus, who later became one of Germany’s greatest romantic poets, was born in the small town of Ludwigsburg in 1786, the same year that the first British convict ships set sail to Botany Bay in Australia. During his teenage years, he was apprenticed in a cloth factory but in 1804, he entered the University of Tübingen to study medicine. In 1808, he graduated and settled as a practicing physician in Wildbad. In 1815, he obtained the official appointment of district medical officer in Gaildorf, and three years later, he was transferred to Weisberg, where he was to spend the rest of his life. The local townspeople gave him a house at the foot of the historical Schloss Weibertreu and within these walls, he dedicated all his spare time to discover the cause of the dreaded food poisoning, which was killing half of his patients.

In the space of five years, Kerner investigated 155 cases, treated 12 patients and performed autopsies on some of the patients. He also gave extracts from sausages that had been confiscated by the police to different animals and observed their reaction before dissecting the remains. In 1822, he published the first systemic description of the clinical picture of botulism, a lethal type of food poisoning known since the era of the Roman Empire. At the end of his publication, he concluded that there was no cure for sausage poisoning and recommended that ‘all blood sausage and liverwurst still on the fireplace by February should be thrown out by the chimney sweep with the other rubbish’. With great foresight, in the dying throes of his sentinel paper, the poetic doctor also noted that small amounts of the sausage poison might be useful for neurological conditions such as St Vitus’ dance. Without knowing it, Justinus Kerner laid the opening shots in the greatest contribution of biology to the world of cosmetic medicine… he was describing the neurological action of Botulinum toxin! Kerner could isolate the toxin and use it to kill other animals, but he was lacking the biggest piece of the jigsaw – what was it and how was it formed. The next part of the botulinum toxin journey takes us back across the Rhine to meet one of the greatest scientists that the world has ever known…Louis Pasteur.

The Influence of Louis Pasteur

Louis Pasteur’s sentinel work from the late 1850s proved that milk became sour because of yet unknown living organisms; by verifying the ‘germ theory’. This sentinel work would change the whole outdated post-Aristotelian pathology and surgery forever. Of course, this great thesis led to the discovery that the bacteria van Leeuwenhoek found in his microscope slides in 1668 could cause disease and illness. Pasteur died in 1895, and in that year, the dreaded disease struck again, and this time in the exalted company of the salted pork dish at the annual gathering of the Music Society in the town of Ellezelles in Belgium.

Three people eventually died from the resultant food poisoning, amongst them a close friend of one of society’s eminent members – the microbiologist, Professor Emile P. Van Ermengem.

The professor took the death of his friend personally and armed with the twin technologies of van Leeuwenhoek’s microscope and Pasteur’s closed flasks, he became the first person to isolate the microbe Clostridium Botulinum from both the food and the post-mortem tissue of victims who had died. He also knew that the disease process was caused by a toxin produced by this bacterium.

But this knowledge remained unheralded within the dusty pages of science books, because at the end of the nineteenth century, the sexy end of microbiology was tropical disease, increasingly important with the ever-expanding colonial empires, thrusting young soldiers into evermore unfamiliar climates.

In 1898, Robert Ross proved mosquitoes were the cause of malaria, and in the same year, the Spanish American War prompted new research into yellow fever. The new century came and, with it, more effective ways for the soldiers to kill their enemies. The first chemical agent to be used was chlorine gas, on 22 April 1915, near the Belgian village of Ypres. Over 5,000 Allied troops died in that first attack and a similar number in a second attack at Ypres two days later. Both attacks wounded about 15,000 men and within the following year, both the British and German forces were also using mustard gas and phosgene gas. Overall, about 113,000 tons of chemical weapons were used in World War I, killing around 92,000 soldiers and creating a total of 1.3 million casualties. But the biggest problem with chemical attacks during this time was that their effective ability could change rapidly if the winds shifted, and they often did. The use of biological agents in warfare has been known since time immemorial.

The Use of Biological Agents in Warfare

During the sixth century, the Assyrians poisoned their enemies’ wells with ergot and in 1346, the Tartars threw the bodies of their bubonic plagued soldiers over the cities’ walls to force surrender during its siege of Kaffa. Russian soldiers used the same tactic against the Swedish in 1710. And it did not end there. Pizarro is known to have given variola-contaminated blankets to South American natives in an earlier period and the British used the same tactic against the native Indians loyal to the French in the Indian War of 1754 to 1767.

The smallpox eventually caused widespread disease amongst the natives defending Fort Carillon, allowing Sir Jeffery Amherst’s plan to work with great effect. There is little reason to see why the powerful toxin from Clostridium Botulinum would remain in the dusty pages of a Belgian book whenever the armies of the Anglo-Saxons were on the march. And so, it came to pass that these scientists and others began to try and harness the power of the Botulinum bacterium in the use of warfare. In 1916, the British set up a chemical warfare complex in 7,000 acres of scrubland at Porton Down in Wiltshire and research into the ability of Botulinum toxin as an agent went underground.

In many ways, Botulinum toxin would appear to be an ideal agent for this type of warfare as it is an anaerobic organism. This means that it effectively dies after initial exposure to oxygen in the air, meaning its use is short-lived and the bombed area can clean itself within a short period, allowing friendly troops to enter the area. But this apparent benefit also made it impractical as an easy agent for British and American armies to use as aerosol disposal. It was also known that vast quantities of Botulinum bacteria would have to be produced for it to become effective.

Botulinum Toxin During World War II

In 1944, more than 1 million doses of Botulinum vaccine were made for Allied troops in preparation for D-Day as intelligence sources indicated that Germany was interested in developing Botulinum toxin as a type of cross-channel weapon.

In the United States, research into Botulinum toxin began in earnest during the same period in a place called Fort Detrick in a militaristic bid to address the threat to the American nation from biological warfare. It is now known that members of the Special Operations Division conducted more than 200 biological warfare tests, some on ordinary subjects, from 1943 until the mid-1960s.

In 1969, President Richard Nixon banned the offensive research program and instead set up adefensive biological research program under the US Army Medical Research Institute of Infectious Diseases. When the experiments with Botulinum bacterium became public knowledge in 1977, American citizens became outraged that their government had exposed them to live organisms without their consent or knowledge. It was the same year that the rock ‘n’ roll entertainer, Elvis Presley, died at his home in Memphis, Tennessee. US military authorities during World War II were interested in the use of Botulinum as a weapon, and they recruited scientists to help produce it and evaluate its potential. One of the biochemists who gained employment at Fort Detrick during this period was a scientist called Dr Edward J. Schantz who had developed an interest in a highly lethaltoxin called saxitoxin, which was found in clams and other shellfish. Schantz was born in Hartford, Wis., and grew up on his family’s dairy farm. He received his primary and postgraduate biochemistry degrees from the University of Wisconsin and Iowa State University.

In 1946, he became chief of chemistry at Fort Detrick with the specific task of producing the different types of Botulinum toxin in their pure crystalline forms.

Botulinum Toxin and Medicine

In his first year at Fort Detrick, Dr Edward J. Schantz isolated the first crystalline form of the neurotoxin serotype BTX-A. Three years later, Arnold Burgen discovered that Botulinum toxin blocked neuromuscular transmission through decreased acetylcholine release. It was 1949, the same year that Mao Tse-Tung proclaimed China a Communist Republic. Indeed, the batch (79-11) originally prepared by Schantz was still used by Allergan Inc, Irvine, Calif., until December 1997 and marketed as the miracle anti-aging drug.

During the 1960s, Schantz continued his research into BTX-A while the rest of America decried Bob Dylan for playing an electric guitar. It is known that the CIA used some of his pure batch to saturate some of Fidel Castro’s favourite cigar type and when they were tested many years later, the neurotoxin was still found to be effective. It was during these years, as the Vietnam War waxed and waned, that Schantz became more and more convinced that Botulinum toxin would probably never become an effective biological warfare weapon and instead, he convinced his military leaders to market his discovery for the purpose of scientific research within the wider community.

One of the first people to attempt to use Botulinum toxin in the treatment of human disease was a scientist called Dr Alan B. Scott, who worked at the Smith-Kettlewell Eye Research Institute in San Francisco. Scott was looking for an agent like BTX-A for some time as he was convinced that he could use it to provide a new non-surgical treatment for the disease of strabismus, commonly known as cross-eyes. During the seventies, he injected a sample of the drug into the rectus muscles of cross-eyed monkeys to find a cure for the condition. The procedure was successful and within a short period, he had progressed to trying the neurotoxin on humans with similar eye conditions, including blepharospasm or eyelid spasm. The experiments were again successful, and his work led to the FDA to approve the use of Botulinum toxin to treat two eye muscle disorders – uncontrollable blinking (blepharospasm) and misaligned eyes (strabismus). The cosmetic effect of BTX-A on wrinkles was originally documented by a plastic surgeon from Sacramento, California – Richard Clark – and published in the journal, Plastic and Reconstructive Surgery, in 1989. It was the same year that I stood on the Berlin Wall, witnessing the fall of communism.

Botulinum Toxin and Aesthetics

During the late eighties and early nineties, the Soviet Union and Iraq produced Botulinum toxin for weapons use. This was even though both nations had signed the 1972 Biological and Toxin Weapons Convention, prohibiting offensive research and manufacturing of biological weapons. In 1990, Iraq invaded Kuwait and deployed 13 specially designed missiles with a 370-mile range and 100 bombs, filled with the toxin. It admitted, after the Gulf War, that it produced 19,000 litres of concentrated Botulinum toxin, with about 10,000 litres loaded into weapons. I became a prisoner of Saddam Hussein’s regime in that same year. Two years later, with 58 people being killed in the race riots of Los Angeles, Canadian husband and wife ophthalmologist and dermatologist physicians, JD and JA Carruthers, published the first study on BTX-A for the treatment of glabellar frown lines in 1992. Similar effects were apparently being observed by several other independent groups.

From here, I would like to look at this publication a little closer. It was, after all, the decisive observation in 1987 of Jean Carruthers that frown lines disappeared following treatment of blepharospasm that ignited the explosive cosmetic application of this product today and without her, I probably would never have penned this article. Jean once told me that she had been using Botox ® for five years on eye patients, when she was struck with the idea that her patients noticed that it smoothed out their facial lines.

She shared this seminal observation with her husband, Alistair, who was a dermatologist, by saying, “My poison will get rid of your patients’ wrinkles.” Jean Carruthers was familiar with Alan Scott’s laboratory and was aware of the potential cosmetic applications for the product. When she mentioned her findings to Alan Scott, she discovered that he had apparently used the preparation for such purposes in 1985. The first person that Alistair injected was their joint receptionist, Cathy Bickerton Swann, who was only thirty at the time but had always had deep frown lines. All were pleased with the result. And the rest, as they say, is history.

After formal trials, on April 12, 2022, the FDA announced regulatory approval of Botulinum toxin type A to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). Subsequently, cosmetic use of Botulinum toxin type A has become widespread.

This article is an excerpt from Dr. Patrick Treacy’s book The Evolution of Aesthetic Medicine.