The world of ophthalmology and medicine has lost a giant. Alan B. Scott, MD, (1932-2021) passed away at the age of 89 on 16th December 2021(1). He was a lifelong innovator and the inventor of Oculinum, later named Botox(1).
Marine-doctor-Alan-Scott-Botox-pioneer-dies-at-89
The story of Botox from poison to therapeutic agent is largely from the collaboration of two extraordinary scientists, Alan Scott and Ed Schantz, who approached the toxin with completely different goals (2).
Alan Scott was a Californian ophthalmologist, who in the early 70s started researching a neurotoxin to weaken the oculomotor muscle with a simple, low-cost injection, rather than with conventional surgery under general anaesthesia in the treatment of strabismus in infants. Strabismus surgery has the undesirable side effect of scarring, which makes frequently needed follow up surgical interventions more difficult, and may generally compromise the eye’s mechanics. (3) He was a founding member of the Smith-Kettlewell Eye Research Institute in San Francisco and a senior fellow and co-director of the institute for over two decades (4).
Schantz’s focus was more military than medical; he had done work purifying botulinum toxin in the 60s in the Chemical Corps at Fort Detrick in Frederick, Md., home of the U.S. biological weapons program, before moving to the University of Wisconsin, where he perfected the process. (2) Schantz became a supplier of the toxin to Scott after a colleague put the two in touch. Back then, controls for shipping botulinum were next to non-existent. Schantz sent the “stuff”, in crystalline form, to Scott via the U.S. Postal Service in a metal tube slipped inside another metal tube. It was Scott who turned the toxin into a pharmaceutical (2).
Scott established that Botulinum toxin type A was the best candidate to paralyse temporarily the muscles. He was aware of the research of Drachman (5-6), in particular the safe use of intravenous injection of Botox in chicks, resulting in atrophy of their skeletal muscles, without significant atrophy of other organs, and found the histological appearance of muscle consistent with denervation.
To confirm his hypothesis, he started injecting various paralysing agents (see reference 5), to monkey oculomotor muscles and published the results of his first experiments in 1973 (5), which showed that varying the dosage could modulate the effect and its duration, as well as its good tolerance.
When, in 1978, Scott first injected botulinum toxin into the eye muscles of a patient who had undergone retinal detachment surgery that left his eye deviated to one side, Scott said that he didn’t know who was more nervous, himself or the patient. But the procedure was successful. (4)
Then he published in 1980 and 1981 his series of 8 monkeys and 42 human adult patients injected with Botulinum toxin into oculomotor muscles under electromyography guidance. The results were good, the effect on horizontal strabismus was uniformly beneficial (8).
Scott- electromyographic injection needle-1981
He predicted that theses injections could apply to other indications in ophthalmology such as injection of the levator palpebrae as a temporary technique to close the lid for corneal exposure (more attractive than tarsorrhaphy techniques) or in reducing lid retraction in endocrine exophthalmos. He also said that in neurology “to treat blepharospasm, and to influence skeletal muscle groups seems entirely .feasible” (8). He opened the door to the many successful therapeutic application of the toxin in neurology
It took him 19 years to develop, test and manufacture botulinum toxin for medical use. (2) Scott perfected one of the deadliest poisons in the world, turning it into a life-changing drug that he called it Oculinum (“eye aligner”) (3). The drug was approved in 1989 for strabismus and blepharospasm, or twitchy eyelid. Allergan licensed it from Scott, then bought it outright in 1991. (The name was changed to Botox the following year). He then returned to research and the clinic. The epic clinical story of Botox started with therapeutic applications in every field of medicine (3).
Alan Scott- MH Marion Toxins 2015
He came regularly to meetings such as Toxins as a speaker or guest of honour and I had the privilege to meet him; he came across as friendly with a good sense of humour.
We all know, as toxin injectors, as well as our patients, who have seen their quality of life transformed by the botulinum toxin treatment, how much we owe to Professor Alan Scott for his discovery of one the most powerful therapeutic tools in neurology.
Marie-Helene Marion
References
I have detailed some of Scott’s observations in the references for the interest of the BNN injectors. The quotations in italic are from Scott.
1-Edward Wilson, MD. https://www.healio.com/news/ophthalmology/20211220/alan-b-scott-md-inventor-of-botox-dies
2-Bloomberg news: https://www.bloomberg.com/news/features/2017-10-26/inside-fort-botox-where-a-deadly-toxin-yields-2-8-billion-drug
4-https://worldnationnews.com/marine-doctor-alan-scott-botox-pioneer-dies-at-89/
5-Drachman DB. Atrophy of Skeletal Muscle in Chick Embryos Treated with Botulinum Toxin”. Science 1964.145; 719-721 • doi: 10.112/science.145.3633.719 https://www.jstor.org/stable/1713788
6-Drachman DB: Botulinum toxin as a tool for research on the nervous system. In LLSimpson (ed): Neuropoisons: Their Pathophysiological Actions. New York, Plenum Press, 1971, pp 325-347.
7-Scott AB, Rosenbaum AL, Collins CC. Pharmacologic weakening of extra-ocular muscles. Invest Ophthalmol- 1973. 12:924-927 https://iovs.arvojournals.org/article.aspx?articleid=2203304
From poison to treatment: The following drugs were injected into oculomotor muscles of monkeys: (1) di-isopropyl-fluoro-phosphate (DFP); (2) a-bungarotoxin isolated from the venom of Bungarus multicinctus (cobra neurotoxin); (3) botulinum neurotoxin, Type A; and (4) alcohol.
Scott and colleagues developed EMG guided injections, which monitor muscle activity to guide needle placement, putting an electrode at the tip of the injection needle to guide drug placement.
He also observed that ketamine would give surgical levels of sedation in the monkey with preservation of an active EMG signal.
8- Scott AB. Botulinum toxin injection of eye muscles to correct strabismus., Transactions American Ophthalmological Society. 1981; vol. LXXIX. https://www.ski.org/sites/default/files/publications/taos00020-0758.pdf
Duration of effect: We were able to produce both transient weakness of individual horizontal muscles, varying between two weeks and eight months. In small doses, onset was often delayed 2 to 3 days, with peak effect not seen until 5 to 6 days after injection. He showed the increased duration of effect when increasing the dose injected.
From electron microscopy of muscles of monkeys after injections: toxin effects are reversible, and that function is regained.
Safety: The material rapidly reduces in potency when left in the open or spilled; thus the drug “self destructs.”
Diffusion: He detailed the parameters limiting the diffusion (such as a carefully planned thrust of the needle into the intended muscle without probing about, and a small volume keeping in mind that using very small volumes is the uncertainty of a small air bubble existing in the injection needle itself).
He considered ultrasonography and roentgen ray elaborations (fluoroscopy, CAT scan) as techniques to guide needle placement, but concluded that these cumbersome techniques would add greatly to the cost and time of a procedure that typically lasts about five minutes.
He recognised the variation of response from one patient to another, so he tends to make the initial injection at a moderate level for the condition existing, with the recognition that the majority of patients will require a second injection at a later time.
Conclusion: No systemic effect or local complications were encountered, except for effect on adjacent muscles. The drug appears to be a safe and useful therapy for strabismus.
