'Twas the week before Christmas 1895, and a funeral band sat down for a meal that would lead to the deaths of three of its members. A dinner of smoked and pickled ham at ‘Le Rustic’ inn in the Belgian village of Ellezelles would be the cause of their untimely deaths. Local medics suspected ‘sausage poisoning’, otherwise known as botulism.
Botulism was first systematically characterised in a paper some 75 years earlier by German physician Dr Justinus Kerner, and named by German physician Dr John Muller in around 1870.1 He identified a toxin of unknown origin, present in certain types of smoked meat that killed laboratory animals in a similar method to our doomed musicians: stomach problems, weakness, dysphagia, diplopia, paralysis and finally death.1
Dr Kerner wrote of his studies that, “The capacity of nerve conduction is interrupted by the toxin in the same way as in an electrical conductor by rust.” The underlying cause of this toxic death remained a mystery, so local officials turned to Belgian bacteriologist Dr Émile van Ermengem, a proponent of the germ theory of illness that was rapidly gaining traction in the mid to late 19th century, and contemporary of Dr Robert Koch.
Microbial samples from the bodies and the ham produced an anaerobic, rod-shaped bacteria now known as clostridium botulinum that produced the deadly toxin. Dr Koch published his findings in 1897.2 During World War II, the weaponisation of this potent neurotoxin was investigated, and the crystallisation techniques used to produce the first clinical product were perfected. This ease of manufacture lead directly to the elucidation of its acetylcholine blocking mechanism of action in 1949.3
Early clinical use
During Dr Kerner’s first investigations into botulism, he concluded that whatever this toxin was, it may have therapeutic uses in hyperactivity and hyperexcitability of the motor and autonomic nervous systems if applied in minimal doses.
In the 1970s, ophthalmologist Dr Alan Scott picked up this challenge and ran with it. The development of a Teflon-coated electromyography needle allowed for the accurate placement of substances into ocular muscles. Dr Scott used this to test various chemical agents in his search for an alternative to invasive surgery in the treatment of strabismus. One of these agents was botulinum toxin type A, which early studies on monkeys published in 1973 showed to be precise, effective and side-effect-free.4
After spending four years working out the techniques for obtaining pure, sterile, consistent and stable toxin, Dr Scott was ready to begin human trials. The first human strabismus patients were injected in 1977, with the study being published in 1980.5 There were 67 injections of botulinum toxin were undertaken, with good results and minimal if any side effects.5 A large multi-centre trial began recruiting in 1982; one of the co-investigators was Canadian ophthalmologist and practitioner Dr Jean Carruthers.5
The journey to cosmetic use
The journey from strabismus and blepharospasm treatment to the cosmetic interventions we know today started with a simple observation by one of Dr Carruthers’ patients. In 1987, a patient noted that after being treated by Dr Carruthers for her blepharospasm, she developed a smooth, relaxed appearance to her glabellar region. At the time in the 1980s, cosmetic treatments for the softening of lines and wrinkles included collagen, silicone and autologous fat.
Dr Carruthers’ husband, dermatologist Dr Alistair Carruthers, was using these to attempt to treat forehead lines in his patients. None of these treatments worked particularly well or with minimal risk, and Dr Jean Carruthers suggested the possibility that botulinum toxin (at the time under the brand name ‘Oculinum’) might be an alternative. Their subsequent discussions with Dr Scott revealed that he had indeed treated a few patients for cosmetic purposes in 1985.6,7
Following this discussion, the Carruthers went into their clinic and treated the glabellar of Patient 0 – their receptionist Cathy – who noted a dramatic difference within a few days. The results of this initial patient, together with 17 others (including Jean herself), were presented in March 1991 at the annual meeting of the American Society of Dermatological Surgery.7 The treatment was met with criticism and disbelief – why would ‘serious’ doctors be injecting the world’s most dangerous neurotoxin to get rid of cosmetic wrinkles?
Formal publication of the study in 1992 did cause some interest, though, and quickly lead to follow-up studies showing botulinum toxin’s efficacy in the treatment of hyper-dynamic facial lines.6,8,9,10 These early studies had already started to expand on botulinum toxin’s uses, with expansion into frontalis and periocular lines.
By 1989, based on the data that had been collected by 240 investigators from thousands of patients, Dr Scott had received US Food & Drug Administration (FDA) approval to market Oculinum (‘eye-aligner’) for the treatment of adult strabismus and blepharospasm. Two years later, Dr Scott made the decision to continue as a researcher rather than a pharmaceutical manufacturer, and sold the rights to Oculinum. After this, a small ocular-care pharmaceutical company called Allergan bought them for just $9 million.11
The Botox boom
Renaming its new product Botox, Allergan Aesthetics set about marketing to its niche market and racked up sales of $13 million in the first year. On January 1 1998, Allergan appointed a new CEO David Pyott, who was enthusiastic about the drug’s potential for banishing wrinkles and pushed for pharma-backed studies.
The timing for a relatively risk-free and straightforward procedure that accurately and easily banished wrinkles could not have been more perfect. The baby boomer generation (born 1946-1964) was rapidly reaching an age where they looked older than they felt and were desperate for a ‘cure’. By 2002, Allergan Aesthetics had gained FDA approval for treating the glabellar, making Botox the first drug to gain a licence for a cosmetic purpose.
From 2001 to 2013, Botox sales increased from $310 million to almost $2 billon, and 1997 to 2010 saw a 4,000% increase in botulinum toxin use.12 As other pharmaceutical companies became aware of the sales to be made using botulinum toxins, they developed their own proprietary formulations.
The current toxin market
To date, there are six toxin products available in the UK, sold under the brand names Botox (Abbvie/Allergan Aesthetics), Azzalure (Galderma), Alluziance (Galderma), Bocouture (Merz), Nuceiva (Evolus) and Letybo (Croma Pharma), with other preparations available and under development worldwide (Table 1).
Following 30 years of experience and research, botulinum toxin can now be used to treat a wide variety of conditions both on and off licence. Most of these uses have been discovered by happy accident; in fact, the only deliberate use of botulinum toxin in medicine seems to have been its original use for treating strabismus.
Thanks to a large number of incremental studies adding further cosmetic treatment areas, toxin treatments are no longer limited to ‘dynamic facial rhytides in the glabellar, forehead and lateral canthus’. In the hands of an experienced injector it can be used to lift brows, tighten necks, slim and shape jaws, lift the mid-face, reduce marionette lines and reduce lines in the lower face. We are not limited to just aesthetic applications either, with the product able to alleviate migraines, manage temporomandibular joint (jaw) pain, reduce limb spasticity, limit excess sweating and treat anal fissures.13-16
More recent treatment avenues currently being investigated are tightening of the skin, reduction of sebum production and even treatment of depression. The use of botulinum toxin in dermatology, taking it in the direction of cosmetic treatments, helped open up whole new paradigms and pathways.17,18
The future of botulinum toxin
Botulinum toxin has come a long way over the last 200 years, from deadly poison to its current use for myriad conditions. But have we found the limit of its uses and applications? Companies are currently working on toxins that act faster and/or last longer or shorter to appeal to patients’ varying indications and preferences. There are a variety of adjuvants that could be added to toxins to increase their speed of onset and duration, or topical preparations to allow for easier treatments.
Yet, more researchers are using botulinum toxin’s ability to penetrate cells and bind with receptors, spliced with other various antagonists, to allow targeted blocking of different cell types, e.g. hormone secretion in tumours or neurotransmitters in pain disorders. This research is all currently ongoing and due to be published in the coming year, but is set to broaden the scope of what we can do with botulinum toxin.
The idea of using the world’s most dangerous neurotoxin to treat cosmetic lines and wrinkles would have seemed crazy 35 years ago. Today, it is a multi-billion dollar industry poised to take even further strides in conventional and aesthetic medicine.
