Botulinum Toxin and Botox®
Where does Botox® come from?
The neurotoxins produced by the bacterium clostridium botulinum1, categorized as types A through E, are the most potent acute toxins known (more toxic than snake or spider venom) and are the cause of the paralytic disease botulism. C. botulinum, first isolated in 1895, is most often associated with the consumption of contaminated food. However, it was not until 1946 that botulinum toxins were isolated and purified. Botulinum toxins, if prepared as an aerosol, have the potential to be potent biological weapons. One gram of an aerosolized botulism toxin is enough to kill about a million people, and a human toxic dose is on the order of a billionth of a gram. However, botulinum toxin A is also the first biological toxin which is licensed as a drug for treatment of human diseases. This drug is commonly known as Botox®. While C. botulinum is ubiquitous in nature, found in soils from around the world and consequently likely to be found in house dust, the bacterial spores are inactive; they can only grow (germinate) by fermentation in specific environments that lack oxygen and have a source of protein. Botulinum toxins are not present in spores and are only produced during germination. Improperly canned food, with its protein-rich and low-oxygen environment, presents a growth opportunity for C. botulinum.
How do the botulinum toxins work?
Proper nerve function requires the neurotransmitter acetylcholine. An electrical signal travels along the nerve cell. When the signal reaches the end of the cell it triggers the release of acetylcholine which diffuses across the gap between the nerve cells and attaches to a receptor which re-initiates signal transmission along the receiving cell. Acetylcholine is also a neurotransmitter between nerve and muscle cells, and is necessary for nerve signals to initiate muscle contractions. Botulinum toxins block the release of acetylcholine, resulting in flaccid paralysis – limp muscles that are unable to contract. With a sufficient dose, this acute muscle weakness can result in difficulty speaking, swallowing, and blurred vision. Death usually results from flaccid paralysis of lung muscles.
Why isn’t botulism food poisoning common?
As C. botulinum spores are everywhere, there is ample opportunity to contaminate food. So why isn’t botulism food poisoning common? We constantly ingest small amounts of C. botulinum spores, but our digestive systems can move the spores through the body before they cause any harm. However, infants up to a year old are susceptible to botulism poisoning as ingested spores are able to colonize and grow in the large intestine and produce the toxin. While uncommon, contamination of honey and corn syrup with C. botulinum spores has been associated with infant botulism. For processed foods, safety techniques are well known – processing with high heat or acids that kill C. botulinum. In addition, heating contaminated foods to 80-90 degrees Celsius for 10 minutes will break down the toxins, rendering them harmless.
How can a poison be used as a medicine?
The same properties that make botulinum toxins harmful to the nervous system can also be used to treat a number of physical disorders involving the neuromuscular system. As botulinum toxin biological activity (mode of action) is relatively well understood, treatments have been developed for administering the right amount (proper dose) in just the right location of the body to treat various medical conditions, with minimal side effects. Following the successful completion of U.S. Food and Drug Administration (FDA) requirements for new drug development, Allergan now markets Botox® for cosmetic purposes and the treatment of more serious medical conditions.
What is Botox®?
The active ingredient in Botox®, manufactured in the United States by Allergan, is botulinum toxin type A. It is a neurotoxin complex produced from the fermentation of C. botulinum type A (Hall strain) purified from the culture solution as an approximately 900 kD molecular weight complex consisting of the neurotoxin and several accessory proteins. Botox® is administered according the recommended dose expressed in units. One unit of Botox® is a measure of biological activity that corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice, performed in a mouse potency assay. Due to method specific conditions, such as the vehicle, dilution scheme and laboratory protocols for the mouse LD50 assays, units of biological activity are drug product specific and cannot be compared to or converted into units of any other botulinum toxin activity2. What is the actual amount of botulinum toxin type A in a unit? – on the order of 0.00000000005 or 5.0 x 10-11 grams! For comparison, this is about 10 million times less than the weight of a grain of table salt, which averages around 5 x 10-4 grams.
1 Clostridium botulinum is an obligate anaerobic, gram positive, endospore-forming, rod-shaped bacterium.
- These websites and other links do a good job of detailing how botulism occurs and the harmful effects of overexposure to botulinum toxin:
Basic and informative video about causes of botulism and how to reduce the risk of getting foodborne botulism (with American Sign Language Narration, 4:42)http://hubpages.com/hub/Botulism-Treatment
U.S. Centers for Disease Control and Prevention website that discusses more about botulism, including symptoms, diagnosis, treatment, and prevention: http://www.cdc.gov/nczved/divisions/dfbmd/diseases/botulism/
U.S. Food and Drug Administration website three types of botulism: Infant, food borne, and wound-related: http://www.mayoclinic.org/diseases-conditions/botulism/basics/definition/con-20025875
More good information specifically about foodborne sources, symptoms, prevention of botulism, and other helpful related links (NIH, CDC, FDA, USDA): http://www.foodsafety.gov/poisoning/causes/bacteriaviruses/botulism/
- These web links are excellent for learning about neuron anatomy and function.Video explaining how neurons—the targets cell of botulinum toxin—communicate with each other (sparticl): http://learn.genetics.utah.edu/content/addiction/crossingdivide/
More details about the function of neurons and their synapses (Khan academy, intermediate):
- With a good understanding now of how neurons are supposed to work, these videos specifically explain mode (or mechanism) of action; that is, how botulinum toxin and Botox (botulinum toxin A) disrupt the function of neurons. (Level: Intermediate to Highly Technical.)Short video illustrating the mode of action of botulinum toxin (1:01): https://www.youtube.com/watch?v=NZZ9fI3U4k0)
Explanation of eventual regeneration of nerve function (reversibility) and why repeated exposures (i.e., Botox treatments) to the small amounts administered for cosmetic purposes are need to sustain effects (2:14). https://www.youtube.com/watch?v=_Eo54f6Lc4c
- Botox® uses and cautions: We encourage anyone using, or considering the use of, Botox® to educate themselves as fully as possible about this product. The following resources are a good start.Botox® is a biological product containing purified botulinum toxin type A neurotoxin. Many people know Botox® mainly as a US FDA (Food and Drug Administration)-approved drug with dermatologic applications. Fewer seem to be aware that in 1989, the FDA approved Botox® to treat strabismus (crossed eyes) and blepharospasm (involuntary eyelid muscle contraction). In 2000 and 2004, approval was given to treat cervical dystonia (involuntary neck muscle contraction) and primary axillary hyperhidrosis (excessive underarm sweating). Most recently it was approved to treat overactive bladder. Other off-label uses have been proposed, and no doubt others will surface as experience with Botox® increases. Some cautions are advised, however. Uses of valuable pharmaceutical products can be abused, and no drug is without any side effects.
Interested viewers are encouraged to seek more information on these topics at the U.S. Food and Drug Adminstration (FDA) website: http://www.fda.gov/
Video detailing how Botox® works (mode of action) that also includes some indications and side effects of use (produced by MedAnim, 5:54).
Details in this video are presented at a fairly advanced level, and provides more Botox®-specific information about its mode of action than discussed in the shorter videos about botulinum toxin noted above.