Pique the Geek 20091206: Botulinum Toxin (Botox)

Botox is in the news all of the time because of its use as wrinkle reducer, but it has many more uses than that, and a very long history.  The proper name is botulinum toxin, and is a neurotoxin produced by the common soil bacterium Clostridium botulinum.  This bacterium is an obligate anaerobe, meaning that it is poisoned by oxygen.

As a matter of fact, many bacteria of this genus are obligate anaerobes, and more than one are causes of human and animal disease.  In addition, they are also spore formers, which is the mechanism that they use to survive times when they are exposed to oxygen.

C. botulinum occurs naturally in the soil and contaminates almost all food products.  In spore form, it is hard to kill.  Boiling water will not kill the spores, so canned food has to be processed at 240 degrees F to kill them.  This is reliable method, and only one outbreak of poisoning from commercially canned food has been recorded in the United States in the last 50 or more years.

The botulinum toxin is an extremely potent neural toxin, and acts by degrading a protein that is required for the release of the neurotransmitter acetylcholine.  The effects are extremely long lasting, and there is no treatment for nerves that have been affected, although if one lives long enough they finally repair themselves (that is why Botox injections are needed on a regular basis).

The most severe form of food poisoning is called botulism, is caused by botulinum toxin.  The name comes from the Latin word for sausage, botulus, and sausage has been known for centuries as a cause of this condition.  In old fashioned, fermented sausages, “good” bacteria ferment some of the proteins and fatty acids to smaller acids, such as propionic and lactic, lowering the pH of the sausage enough that C. botulinum can not grow.  If that ferment is insufficient, it does grow and produces the toxin in the anaerobic environment in the sausage.

The spores themselves, and the growing bacteria, are not harmful to humans because of the extremely acidic stomach contents that deactivate them.  Not so for the toxin itself, and it readily is absorbed by the gut.  The exceptions are infants, whose digestive systems are not yet developed enough and people who suffer from lack of acid production in the stomach.  For that reason, infants should never be given honey, because it is often contaminated with spores.  By the way, the toxin is extremely sensitive to heat, so thorough cooking of home canned, low acid food renders them safe.  The general rule of thumb is 10 to 15 minutes at the boil for safety.

The symptoms of poisoning are those of general muscle flaccidity.  Eyes droop, speech is slurred, general weakness is experienced, and death results from paralysis of the respiratory muscles.  Until recently, around two thirds of people poisoned died, but recent developments have reduced that to around 10%.  The treatment is two pronged:  first, a anti toxin is given to the patient, and, if breathing is compromised, ventilation is provided.  The anti toxin can not reverse the effects in neurons already affected, but does bind with toxin not yet assimilated, rendering it inert.

The anti toxin is manufactured by injecting horses with minute doses of the toxin and then collecting the antibodies that the horse produces to it.  Complicating the process is that there are at least seven distinct toxins, so for a complete anti toxin all seven toxins have to be used.  In North America the most common types are A, B, and E, so the most common anti toxin are just for those.  It is widely available, but requests have to go through CDC (Centers for Disease Control and Prevention) because of the possibility of an outbreak and the severe consequences involved with one.  Considering the amount of canned food sold, the possibility for mass casualties is real, but almost all poisoning is from home canned food these days.

There is an anti toxin for all seven types, available from the U.S. Army.  Hmmmmm, this might get interesting.  Well, it is.  It turns out that botulinum toxin is a prime candidate for a weapon of mass death (destruction is not a proper term, since it only kills animals and does not blow thing up).  The Army studied it for a long time, and knows all about it.  Since it is relatively easy to grow and the spores available essentially everywhere, there is concern that it might be used by asymmetric forces as well as rouge governments.

One of the assets that the material has as a candidate for a weapon is its extraordinary toxicity.  Some state that it is the most toxic material known, with a lethal dose around 1 to 3 ng per kg in humans.  A nanogram is not much.  That is one thousand millionth of a gram, so a single gram (about 1/28th of an ounce) can kill millions if completely dosed evenly.  That means that one kilogram could kill every human on the planet.  That is not even as much as a bag of sugar, and it is effective by ingestion, inhalation, and injection.  In addition, symptoms typically do not appear for many hours or more after exposure, so lots of folks could be dosed before anyone noticed.  This why the Army has an interest in it.

Apart from the vanity uses of the pharmaceutical product, it also has some very important other medical applications.  I once worked for a man who suffered from blepharospasm, a nasty condition often described as excessive blinking.  It is NOT excessive blinking.  It the involuntary closure of the eyes.  That might sound like a big deal, but he had to take a medical retirement because he could not drive to work.  Try driving when your eyes keep closing and you have to use one hand to see the road.  It is big deal.  FDA has approved the toxin for this condition, and while not a panacea, makes those folks lives much better.  The trick is to find the dosage where they can close their eyes when needed and to blink somewhat normally, because without blinking the eye dries out very rapidly.

There are several other conditions that treatment with the toxin have FDA approval, including cervical dystonia, a muscle spasm of the neck that causes the head to be held in an unnatural and painful angle, strabmismus, a condition where the eyes do not track in sync (Marty Feldman is the poster child for this condition), and severe primary axillary hyperhydrosis, wherein one sweats from the underarms so much that it interferes with normal life functions.  This might sound trivial, but my mum suffered from this condition and was so greatly embarrassed by it that she went to great lengths to deal with it.  She used pharmaceutical anti antiperspirants and dress shields (does anyone reading remember what those were?), and still had problems going out more than necessary.

So, let us not dismiss Botox as just a vanity material, since it has some really important other uses.  It is also being used off-label for other conditions, such as vocal chord dysfunction (there was a Mystery Diagnosis episode on the TeeVee this weekend about that), spastic muscle conditions resulting from injury or stroke, and other conditions.

Whilst talking about this material, we should examine the bacterial family that produces it in a bit more detail.  The Clostridium genus is widespread, and causes several other pathogenic conditions.

The most common one is C. tetani, the organism that causes tetanus.  I had a great uncle who almost died of tetanus, and it is not a laughing matter.  Everyone in the US, pretty much, gets a DPT (diptheria/pertussis/tetanus) vaccine unless their parents are kooks, so not many folks get tetanus these days.  This disease was known from antiquity, and most often occurs in deep puncture wounds.  Remember, the Clostridium clan are obligate anaerobes, so a shallow wound, where air can infiltrate, will not be a problem.  Stepping on a rusty nail in a board, on the other hand, is a good way to get it.  Uncle Guy was working in his barn and got a very large, deep wood splinter that inoculated him with the spores.  He was fine for a couple of days, then got sore and stiff.  He was the kind that did not go to the doctor, but when he could not speak, he made an exception.  He had the weirdest smiley look on his face.  That is why tetanus used to be called lockjaw.  Hospitalization and treatment with antibiotics and tetanus anti toxin saved him.  This anti toxin is also produced with the cooperation of horses.  Oddly, where botulinum toxin causes muscles to relax you to death, tetanus toxin causes muscles to tighten you to death.  Death results, in both cases, from respiratory failure.  In the case of botulinum, the muscles become to flaccid to operate.  In the case of tetanus, they become too rigid to operate.

Another nasty little bugger is C. perfringens, the cause of gas gangrene.  This condition is an immediate medical emergency, but is controllable with antibiotics.  The term gangrene is generic, meaning that tissue dies.  For example, frostbite causes gangrene by mechanical damage, and some medical conditions cause “dry” gangrene by shutting off the blood supply to the extremities.   Gas gangrene is quite different, rapidly developing and immensely destructive.  It is in infectious disease, not a chronic medical condition.  The reason that it is so fast acting is that another toxin is expressed by the bacteria that kills healthy tissue, allowing rapid and deep penetration of more bacteria.  During World War I, many casualties were the result of gas gangrene, because there were not any very good treatments for it, and shell fragments and bullets penetrated deeply.  Add to that trench warfare (remember, these Clostridium fellows like the earth) and it was no wonder.  Oddly, this very bacterium is used in cooking to act as the leavening agent in salt rising bread.  I have not been able to find definitive data about the nature of the gas, but the entry on Wikipedia does not seem to be consistent with the anaerobic nature of the bacteria, since a lot of oxygen (poisonous to them) was reported.

Related to gas gangrene is black leg disease in cattle.  I have personal experience with this, because my dad used to dabble in cattle, and one died of black leg.  It is caused by C. chauvoei infection, and there is a vaccine for it.  Interestingly, the species name seems to be from the French for horse, so I guess that not only cattle are susceptible.  Actually, that is not correct, because it was named for Auguste Chauveu, so that is a lesson to look up the origins of scientific names for species.  Like gas gangrene, there is pressure in the lesions, likely caused by gas production.

One final Clostridium infection should be mentioned, as it is becoming more common and can be debilitating and also life threatening.  That is C. difficile, a common intestinal infection.  The cause for most cases is antibiotic treatment for other conditions.  C. difficile is a normal resident of our large intestine (around 3% of all intestinal bacteria, give or take, in normal folks) but is not very susceptible to several antibiotics commonly used for other infections.  Those antibiotics kill off lots of other normal bacterial residents, and then C. difficile can take over the gut.  The most often used term for the condition is “c-diff” and it is extremely common in hospitals, especially with people who have been there for a while.  Since it is a spore former, it is extremely difficult to eliminate from settings where people are infected, so it spreads.  Although it is distasteful to imagine, fecal control in debilitated patients is very problematic, and infected patients shed enormous amounts of bacteria daily.  Controlling this condition is hard to do, and only a few antibiotics are effective against it.  One is metronidazole, the drug of first choice.  This is a very harsh drug, and is a known carcinogen.  It also has a similar effect to disulfuram (Antabuse) in that alcohol consumption concomitant with it causes extremely uncomfortable physical symptoms.  The next drug is vancomycin, but since it is one of the last antibiotics available for most antibiotic resistant bacteria there is an ethical question involved.  I fear that there is no good answer to this conundrum.

C. difficile cause diarrhea, cramping, extreme discomfort, and a condition known as pseudomembranous colitis, an extremely nasty condition where false membranes, not regular colon membranes form around pockets of infection.  There are pictures available, but they are too gruesome to post here.  Like many of the Clostridium clan, C. difficile expresses toxins that assault cells in the intestional lining, killing them and causing the intense pain and diarrhea.  I have a close former relative that had a very bad case of this disorder, but she seems better now.  Unfortunately, the relapse rate can approach 40%.

It is interesting that I have had personal experience with several medical conditions caused by this clan of bacteria.  If I have, then the chances are great that you have, too.  I make these recommendations:

1)  Get a tetanus shot every five years.  It also protects you from pertussis, a very debilitating disease that is under reported by 90% as far as I can tell from my research.

2)  Be extremely careful when you home can low acid foods.  I have home canned since I could lift the canner, but have always taken care.  Even though the most recent Ball canning book does not mention open boiling of low acid, home canned foods for 10 minutes, I still advocate it.

3)  Take antibiotics only if you really need them, and finish your course of them.

4)  Never give honey to a baby.

Well, you have done it again.  Another perfectly good batch of photons are wasted into your retinae by reading this poor concoction of an essay.  And even though Senator Joseph (Joementum) Lieberman promises to vote with the Democratic majority when he reads me say it, I sincerely say that I always learn much more than I could ever hope to teach by writing this series.  Thus, please keep questions, comments, corrections, suggestions for future installments, and other topics coming.  Remember, no scientific or technology comment is off topic here.

On a personal note, Pique the Geek will be on hiatus next week.  The Geek is traveling to Arkansas this week to attend the wedding of Eldest Son and the very intelligent, industrious, and lovely Future Eldest Son’s Spouse next Saturday afternoon.  If all goes as expected, The Geek will return 20 December 2009.

Warmest regards,

Doc

Crossposted at Dailykos.com