Wednesday, March 27, 2013

Hang A Question Mark On It

Biology concepts – toxicofera hypothesis, evolution, venom, toxin, reptile

Bertrand Russell lived in England in from 1872 to
1970. He was a pacificist who spent time in jail for
his views during WWI. Amazingly, his Nobel
Prize came in literature, not peace or the sciences.
His philosophy was based in suing mathematics
to ground logic, as well as in metaphysics. None
of this means much to mean, I just like his quote.
The philosopher Bertrand Russell said, “In all affairs it's a healthy thing now and then to hang a question mark on the things you have long taken for granted.” The study of biology is such a good example of this idea. We should always be questioning the ideas that we have come to accept, and science should welcome efforts to overturn longstanding concepts.

This is why I don’t mind efforts to disprove evolution - IF they are carried out in a scientific manner – it’s the only way science can truly work. Unfortunately, many efforts are not carried out scientifically. They're similar to that old cartoon, where one scientist is charting the mechanism of a process on the board, and one of his steps is, “and then a miracle happens.”

On the other hand, when a radical change comes to us in a scientific manner, then we should accept it is another possible explanation; now we have multiple explanations to try and disprove. We're never be done testing a hypothesis.

And that brings us to the reptiles; the testudinata (turtles and tortoises, from Latin = movable armored shed), the squamata (snakes and lizards, from Latin = having scales), and the crocodilians (from Greek = lizard). Of these, the turtles and tortoises seem to be the oldest, appearing first more than 220 million years ago. Lizards were next, and snakes were said to have developed from lizards, about 100-120 million years ago. This is harder to follow in the fossil record because snake skeletons are delicate and do not fossilize well.

The snakes get all the publicity; I think it's the big fangs and the fact that they can swallow things bigger than their heads! Children can list the most venomous snakes, boys especially like to taunt young girls with writhing snakes; they even make movies about snakes on airliners!

But did you know that only about 20-30% of all known snake species are known to be venomous? Of the non-venomous majority, only the boas and the anacondas seem to get any attention. Their immediate ancestors, the lizards seem to get even less.

Gila monsters are black with pink, orange, or yellow
patterns. As such, it is one of the few animals with
pink pigmentation. Their tails are plump, and can store
fat for times when food is rare and over the winter.
There is a type II diabetes drug made from a protein
isolated from gila monster saliva. It is sometimes
called “lizard spit.”
Until recently only two lizards were known to be venomous, both calling North America home. The gila monster (Helderma suspectum) has a bite that, though usually not fatal to humans, can cause paralysis, convulsions, and difficulty breathing. It doesn’t have fangs that inject the venom into the flesh, but its saliva contains the toxin and he will literally chew on you, driving the poison into the wound. Toxic slobber, that’s all we need.

His cousin, the Mexican bearded lizard (Heloderma horridum) lives a little south of the gila, and he is considerably bigger, reaching up to a meter in length. The bearded lizard’s venom delivery is similar to the gila’s, with modified salivary glands in the lower jaw producing venom that flows with the saliva.

I said that recent events have changed our ideas about venomous lizards. Brian Fry at the University of Melbourne has published a series of papers since the early 2000’s that have expanded our understanding of venom evolution. Dr. Fry reported in early 2006 that beyond the heloderma lizards, the monitors and the iguanas also use venom in defense or food acquisition. One of the monitor lizards is the Komodo dragon (Varanus komodoensis), the largest living lizard on Earth.

Well, that’s all anyone remembered - the Komodo is venomous?! This really caught the public’s attention. It had been assumed that it was the vile state of the Komodo’s bacteria-infested mouth that was toxic to its prey, the bite transferred horrible organisms to the wound, which replicated, let loose with some bizarre toxin, and eventually killed the prey. Whole documentaries were made about how patient the Komodo was, following the prey around for days until it succumbed to one infection or another.

This is a computer rendition of the MRI of a Komodo
head. The dragon has six venom glands on each side of
the lower jaw, shown here as alternating red and pink.
The yellow glands produce the mucus that
gives the Komodo its famous drool.
Entire research programs were set up to discern how the Komodo could live with such terrible microorganisms in its saliva. Why didn’t the Komodos die too? Teams searched for new antibiotics in the saliva and blood of the Komodo. Now it turns out that the Komodo had a different strategy all along! Its venom is strong enough on its own to kill the prey animals. Fry’s follow-up 2009 paper showed the venom was the principal killing weapon of the Komodo; it's an anticoagulant and induces shock, so the victim bleeds out and its organs fail.

Two items were lost from Fry’s 2006 paper. One, the iguanas have venomous members as well. Iguanas live in North America as well as in Madagascar, Fiji, and Tonga. They have many representative species, several of which are common household pets. It turns out that many of them have venom of a mild potency, but strong enough to hold some predators at bay. The monitors and the iguanas have something else in common, the way the produce and deliver venom.

In both groups, the venom glands are located in both the upper and lower jaws, and the ducts that deliver the venom to the saliva are located between the teeth and at several locations in the mouth. This is different from the snakes that have venom glands only in the upper jaw and deliver venom through a single duct, and the gila monster and bearded lizard that have venom glands only in the lower jaw.

The differences between gila/bearded lizard venom delivery and that of snakes had led to the idea that these two systems developed independently of one another. But following the trail backwards through evolution, Fry showed that venom production started in the lizards, about 200 million years ago. The snakes that evolved from some lizards already had the mechanisms on board to produce venom – it came from a single common ancestor that was around before even T. rex!

The pink iguana is native to the Galapagos Islands.
It isn’t known whether it is a venomous iguana.
They were only discovered a few years ago and
were thought to be a variant of the common land
iguana, but genetic tests showed it was a
novel species on its own.
The two-jawed venom glands of the monitors and iguanas are ancestors to the single-jaw venom glands of the heloderma and the snakes, some evolved to house it only in the upper (snakes) and some evolved to house the glands only in the lower (gila monster and bearded lizard).

This was a radical change for those who studied the evolution of the reptiles. Like I said, one should never consider a theory to be absolutely proven. The questions then is - if lizards started the reptile venom idea, why are so few venomous now? Well, maybe they are venomous. We only seem to care if humans are threatened by them, so we haven’t even looked for venom or venom glands in most lizards. Fry estimates that perhaps more than 100 lizard species are venomous, and that perhaps all of them still contain the genes to produce venom.

Two of Fry’s co-authors jumped on the idea of all lizards being venomous, and expanded it to the idea that perhaps all snakes might have been venomous at one time. As such, they suggested a new categorization of all these animals into one clade (evolutionary group with a single common ancestor), called the Toxicofera clade. This idea became know as the Toxicofera Hypothesis… makes sense, I guess.

This is a cladogram that shows the hypothetical Toxicofera, or
venom clade. The emergence of venom glands occurred
about 200 million years ago, so all descendents of this animal
have the potential to be venomous. This includes ALL the
snakes (serpentes), the gila and Mexican (heloderms), the
Komodo and monitors (Varanid), and the iguanas. The one
in the middle that looks like a snake is actually the group of
worm lizards, their ancestor diverged before the
emergence of venom glands.
The Toxicofera (“those who bear toxins”) hypothesis is universally accepted, but it is gaining influence and has started discussions about the relative ages of venomous animals and who evolved from whom. It has also sparked investigations into seemingly non-venomous snakes and lizards, looking for remnants of venom glands and venoms. It is completely possible that some snakes and lizards are completely non-venomous, but they may still harbor the genes for venoms or some vestigial (regressed and unused) venom glands.

But don’t misunderstand the hypothesis. It applies only to reptiles, the Toxicofera family would not include venomous mollusks, like the blue-ringed octopus, or biting ants, like the fire ant, or the stinging bees and wasps. There are certainly instances where venom and venom delivery systems evolved independently. The toxicofera hypothesis applies only to the reptiles.

How about the turtles and tortoises? They are reptiles too; could they be venomous? Well…. no, at least not yet. These reptiles diverged from a common ancestor more than 200 million years ago, before the computer programs estimate the first reptile venom appeared. However, there is one sort of exception. The three-toed box turtle of North America isn’t venomous, but it can be poisonous.

In the wild, three-toed box turtles eat just about anything – insects, small dead animals, vegetation, worms, and fungi; it's the fungi that make the difference. They have a taste for the Death Cap Mushroom (Amanita phalloides). This fungus is related to the toadstools that some people use for their hallucinogenic properties, but the Death Angel is aptly named.

On the left is the three-toed box turtle, native to North
America. It is an exceptional in that it is the only turtle
that can completely close itself in it’s shell. You can
see the hard flap under its chest that will close the opening
when it ducks its head inside. On the right is the
Amanita phalloides death cap. It is very common and
very deadly. Its toxin is alpha-amantin, an RNA
polymerase II inhibitor, that causes complete
liver breakdown.
If the box turtle has eaten some of these mushrooms, the toxin will be in its tissues for some time. If you happen to like turtle stew, you could end up meeting the Angel of Death. Grilling up a wild box turtle was supposed to have made several boys very sick in the 1950’s, but I haven’t found another instance in the literature of this occurring any more recently. The question is - why don’t the mushrooms kill the turtle?

This is something we can investigate next week, along with the difference between just having a poison in your tissues because of something you ate or actively storing it for your own use. Along the way, we will meet a salamander with a lethal rib cage. Yeah- you read correctly, ribs that can kill.

Fry, B., Vidal, N., Norman, J., Vonk, F., Scheib, H., Ramjan, S., Kuruppu, S., Fung, K., Blair Hedges, S., Richardson, M., Hodgson, W., Ignjatovic, V., Summerhayes, R., & Kochva, E. (2005). Early evolution of the venom system in lizards and snakes Nature, 439 (7076), 584-588 DOI: 10.1038/nature04328  

Fry, B., Wroe, S., Teeuwisse, W., van Osch, M., Moreno, K., Ingle, J., McHenry, C., Ferrara, T., Clausen, P., Scheib, H., Winter, K., Greisman, L., Roelants, K., van der Weerd, L., Clemente, C., Giannakis, E., Hodgson, W., Luz, S., Martelli, P., Krishnasamy, K., Kochva, E., Kwok, H., Scanlon, D., Karas, J., Citron, D., Goldstein, E., Mcnaughtan, J., & Norman, J. (2009). A central role for venom in predation by Varanus komodoensis (Komodo Dragon) and the extinct giant Varanus (Megalania) priscus Proceedings of the National Academy of Sciences, 106 (22), 8969-8974 DOI: 10.1073/pnas.0810883106  

Fry, B., Winter, K., Norman, J., Roelants, K., Nabuurs, R., van Osch, M., Teeuwisse, W., van der Weerd, L., Mcnaughtan, J., Kwok, H., Scheib, H., Greisman, L., Kochva, E., Miller, L., Gao, F., Karas, J., Scanlon, D., Lin, F., Kuruppu, S., Shaw, C., Wong, L., & Hodgson, W. (2010). Functional and Structural Diversification of the Anguimorpha Lizard Venom System Molecular & Cellular Proteomics, 9 (11), 2369-2390 DOI: 10.1074/mcp.M110.001370
For more information, see:

Venomous lizards –

Toxicofera hypothesis –

Three-toed box turtle –

Wednesday, March 20, 2013

The Best Offense Is A Good Defense

Biology concepts – venom, mammalian defenses, poison, toxin, sequester, honest signals

Humans are much of a match for most large predators, we
have to rely on our wits to get us out of dangerous
situations. Or better yet, KEEP us out of dangerous situations.
Don’t worry, no humans were harmed in the making of the
photograph; it is a re-enactment for a Discovery
Channel program.
Quick- name the mammal with the poorest sense of smell. O.K., then name the mammal with the worst ability to hold their breath. How about the mammal who is the weakest for their body mass? How about one of the slowest?

The answer to all – Homo sapiens. We’re a mess when it comes to protecting ourselves physically. Most mammals have defensive behaviors and some have built in protective anatomy, but not us. If we had to survive by fighting off a tiger, our species would be nothing but a footnote in history. We need some camouflage - or maybe a superpower.

Some mammals have super sight. Most prey animals have their eyes on the sides of their heads to scan 180˚ or more of the environment, but ours are on the front of our faces in order to allow for binocular vision and good depth perception. Don’t get cocky; even though we may be considered a predator, think of all the animals you wouldn’t want to run into in a dark alley.

Sense of smell in some mammals is quite developed.
Here a tule elk raises it nose to catch chemicals in the
breeze – always on guard for bears, and for good
reason. Bears are the champion smellers. Their brain
is 1/3 the size of humans, but 5x as much volume
is devoted to smell.
Most mammals can instinctively identify predators by shape, size and color - if it registers as a predator, prepare for fight or flight. Even behavior can be visually sensed; a sleeping lion is much less of a worry than a stalking lion. If a prey animal responded every time they merely saw a predator, they would need to eat five times as much everyday just to match the energy output. Truly, visual systems are very important to keeping mammals alive for another day.

But most mammals use other senses as well. Noses can be even more important than eyes. Chemicals from skin lipids or urine can identify predators before they are seen. Changing concentrations from spot to spot can provide evidence of time and direction; merely sensing a predator's odor alone would cause too many false alarms and wasted energy.

Added to the wealth of information prey mammals may pick up is sound. Again, differences in timing and loudness can give clues as to direction and distance, as we discussed with owls. Hearing is especially important for nocturnal mammals, as sight is of less value in the dark… duh!

Many animals have a way of avoiding predators even if you come into their range. Things like camouflage can help; predators may not attack if they can’t see you, even if they know you are there somewhere. But if they do spot you – it becomes decision time. Fight or flight are the two basic choices, although there are variations on these themes.

Some animals will freeze, based on the idea that predators are looking for grazing or some other motion. When motionless, camouflage has a better chance of working. Others choose speed to survive. Rabbits, gazelles look to outrun the predator, and turning on a dime is maneuver that a chaser may not be able to follow.

Pronking (stotting) is a defensive behavior meant to
display fitness. I am not aware of a study that shows
that he who pronks highest is least apt to be attacked,
but that is the idea. See the video for a good example.
In the fight plan, some mammals will display intimidation behaviors. Gorillas will stand up straight and become as big as possible. They show their teeth and shake nearby limbs to make them appear even bigger. They beat their chests in a show of bravado. However, if that doesn’t work, they are fully prepared to rip your arm off and beat you to death with it.

Likewise, elephants and rhinos will charge you with loud noises and clouds of dust. Same with bulls. These are called honest displays. They are true representations of fitness and/or aggressiveness. Honest displays can be used defensively as well. Stotting (also called pronking or pronging) is used by many species of gazelles, springboks and deer ostensibly to impress predators with their fitness. They bounce as high as they can using all four legs at once.

If they can expend this kind of energy when a predator is near, it must mean that they are the most fit; predators shouldn’t waste time trying to catch them. Many studies have been carried out to see if this type of behavior is stable in a species. My explanation is – if it didn’t work, they would all be dead or wouldn’t do it anymore. But other researchers want to be a little more specific.

A late 2012 study used game theory to predict the stability of signaling in prey animals. Their model showed that variable intensity signals would be stable; those where greater energy is expended in signaling the nearer the predator is to the prey. They also predict that fake signals (dishonest signals) would not be as stable because of wasted energy, as would on/off signals where an intense response would be elicited no matter the relative danger.

Sometimes signaling is not enough; pragmatic defenses are needed. Gorillas are strong, elephants are huge, porcupines have quills. These are all brilliant adaptations that serve their purposes, but I stand in awe of the mammalian biochemists.

Here is an example of a dishonest signal. The squirrel
chews up old rattlesnake skin and spreads it over its
fur. Now he smells like a rattlesnake; predators are
much more likely to leave him alone. Dishonest ---
but smart.
Opposums use thanatosis (playing dead), but that isn’t all. They have glands near their anus which release chemicals that smell like a rotting corpse. This is enough to ward off most predators – it isn’t smart to eat something you didn’t kill (unless you are a vulture and have the toughest stomach acid known to nature).

Skunks are very confident in their chemical defense, as well they should be. However, they may be a little over confident. It is hypothesized that many skunks are hit by cars because they see oncoming cars as just another predator that will cringe and run when faced with their backside and raised tail – oops.

Some mammalian chemical engineers are true exceptions. Did you know that there are venomous mammals? For one, there is the solenodon (solen = slotted, and don = tooth), a mammal that we were sure was extinct. Two species are now known to still exist, the Cuban solenodon, and the Hispaniola solendon, but they are exceedingly rare and are usually spotted only years apart.

The solenodons are very old species and have retained their ancient traits, this makes them interesting as example of what mammals were like during the dinosaur age. They have poisonous saliva that they grind into their prey with their slotted teeth, but this does not save them from their own predators. They have a tendency to stop and hide their heads if attacked; this is a less than optimal defense. Therefore, it's a good thing that they are nocturnal.

There is also the male platypus. We met the platypus when we discussed genomic imprinting, but being egg layers with the potential for parthenogenesis are just some of their exceptions. On each hind leg they have a talon or spur that is connected by a duct to the crural gland in their thigh. The venom, which is actually a mixture of many toxins, seeps out onto the spur and is transferred into the wound when the platypus kicks at a target.

But only the males have the spurs and toxin in adulthood. Females are born with the spurs, but they soon fall off. This is related to the notion that the venom is not fatal, it just hurts very badly, and that the venom is made mostly in the mating season. Put these three clues together, and the answer says that the venom is used in mate selection. The platypus has few predators, and they don’t need to subdue the worms and tiny shrimp they eat. But they do have rivals for females. A 2009 study speculates that the non-lethal venom probably developed as a mating selection device. The male who isn’t cringing in pain wins the girl. This is the only instance known of a temporal cue for venom production.

Here is a slow loris that is more than willing to show
you his toxin glands. They are not covered with fur
and are located halfway between his armpits and his
elbows.  I’m not sure I would be handling him
without gloves.
Finally, there are the slow loris primates. They seem to be both poisonous and venomous. A brachial gland between their art pit and elbow exudes a toxin that they lick and then transfer to their fur and saliva. The toxin is only mildly disconcerting for predators, but when mixed with saliva, it is something predators will back away from.

The slow lorises (all 9 species, living in southern Asia) will lick their young before stashing them away to go find food, protecting them from potential predators in a poisonous kind of way. They will also bite strongly and hold on, passing the toxin into the wound, which makes it a kind of venom.

To add to our mammalian exceptions, we should spend a minute talking about the mammals that are strictly poisonous. Two examples are known, both being toxin sequesterers. They don’t make their toxin, they gather it from another natural source and then use it for their defense.

One example is the southern vole (Microtus levis). They eat grass, and sometimes the grass is infected by a poisonous fungus. For most voles, the fungus is lethal, helping the fungus protect its grass habitat, but the southern vole is immune to the poison. In fact, the fungus toxin protects the voles from their main predator, the least weasel. One study has investigated why, with mixed results.

On the left is the Acokanthera tree. It looks harmless but is deadly.
However, the fruit is said to he edible and is used as medicine –
not for me it isn’t. In the middle is the crested rat. He has adopted
black and white colors, much like the skunk. Bright colors don’t work
so well when you are a crepuscular animal. On the right is one of the
hollow flank hairs of the crested rat that holds the oubain toxin.
Southern voles don’t poison potential predators, and the weasel can’t distinguish urine of a fungus eater from a non-fungus eater. In fact, the voles seem to freeze more, not run away better when they have been eating the fungi. And this may be the key; they seem to freeze more often. This may inadvertently protect them by fooling the weasels into thinking they aren’t there. Sometimes you’re lucky to be poisoned.

Lastly, there is the African crested rat (Lophiomys imhausi). A recent study has shown that this small mammal likes to moon its potential predators. It spends a lot of its time gnawing on the bark of the Acokanthera tree, which contains oubain, a curare-like toxin. It spreads this chewed up mess on its flanks, which contain specialized, hollow hairs (see pictures above). The hairs soak up the toxin, and then when threatened, the rat turns its flanks to the predator. This, along with its coloring and thick fur and skin in that area, is enough to keep the crested rat alive until the predator learns its lesson – it dies from the toxin.

Next week, how about discussing more exceptional animals - venomous amphibians and lizards?

Broom, M., & Ruxton, G. (2012). Perceptual advertisement by the prey of stalking or ambushing predators Journal of Theoretical Biology, 315, 9-16 DOI: 10.1016/j.jtbi.2012.08.026

Kingdon, J., Agwanda, B., Kinnaird, M., O'Brien, T., Holland, C., Gheysens, T., Boulet-Audet, M., & Vollrath, F. (2011). A poisonous surprise under the coat of the African crested rat Proceedings of the Royal Society B: Biological Sciences, 279 (1729), 675-680 DOI: 10.1098/rspb.2011.1169

Whittington, C., Koh, J., Warren, W., Papenfuss, A., Torres, A., Kuchel, P., & Belov, K. (2009). Understanding and utilising mammalian venom via a platypus venom transcriptome Journal of Proteomics, 72 (2), 155-164 DOI: 10.1016/j.jprot.2008.12.004

For more information, see:

Mammalian defenses –

Signaling theory –

Wednesday, March 13, 2013

One Man’s Poison Is Another Man’s Cure

Biology concepts – toxin, poison, venom, LD50, ED50, therapeutic index

The skull and crossbones is the most recognized symbol
for poison. It originated at the entrances of Spanish
cemeteries, so it has always been associated with death.
With advent of pirate toys and play acting, the United
States proposed moving to the Mr. Yuk symbol, shown
above, a registered trademark of the Children’s
Hospital of Pittsburgh, so they are going to want to get
paid. The design was by a fourth grader from West
Virginia in 1971.
There is a dangerous chemical that is all too common in the developed and developing worlds. Colorless and odorless, this poison is responsible for thousands of deaths and millions of injuries each year. Inhaling even a small amount can be harmful and more is certainly lethal. Likewise, ingestion of too much can also be lethal. In a gaseous state, it can cause severe to lethal burns.

And yet, there is no pending legislation to eliminate this compound or restrict its use for safety’s sake. You can find out more about this deadly substance at the only research site dedicated to its control. The molecule in question goes by many complex names in order to hide its true nature; Dihydrogen Oxide, Hydrogen Hydroxide, or simply Hydric acid.

But we know it most commonly as water…. yep, water. Look again at the list of dangers associated with water above. Are any of them untrue? Too much of even a good thing can be bad for you, like in drinking too much water. But water in your respiratory track can go bad very quickly; it’s called drowning. So next time you want to same something is harmless, think twice – just how much of something is still harmless?

This is not a new concept; one scientist was contemplating the nature of poisons and medicines 500 years ago. He called himself Paracelsus (para = as good as or better than, and celsus = the great encyclopedist named Celsus). Celsus lived just before Julius Caesar came to power. He wrote one of the first comprehensive medical encyclopedias, including books on pharmacology, pathology, anatomy, and surgery. What is more, this which was just one part of his more extensive encyclopedia of all the world’s knowledge.

Paracelsus, on the other hand, was a German-Swiss natural philosopher who lived from 1493 to 1541. He really liked himself, although I am kind of glad he adopted the pseudonym…. his real name was Philippus Aureolus Theophrastus Bombastus von Hohenheim!

Paracelsus was his own greatest fan. He traveled the
world in an effort to learn everything – he missed out
humility. Here is a quote to illustrate, “Let me tell you
this: every little hair on my neck knows more than you
and all your scribes, and my shoe buckles are more
learned than your Galen and Avicenna, and my beard
has more experience than all your high colleges.”
Paracelsus is often called the “Father of Toxicology,” although he also worked in metallurgy, botany, and astrology. He pioneered the idea of medicines; substances that could be used to treat diseases rather than just trying to adjust the systems of the body, such as that great medical technique --- bleeding.

Paracelsus believed that every chemical or substance had a good side and a bad side. His most famous quote goes like this, “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous." We usually shorten this to, “The dose makes the poison.”

You can see from the water example above, Paracelsus was right - moderation in all things. How much water kills you? Well it depends on what body system it interacts with and what organism we are talking about. For drinking water, the lethal dose is about 2x105 mg/kg. This is called the LD50.

LD50 translates to the dose that will be lethal in 50% of the organisms tested at that dose. It wouldn’t be fair to test substances out on humans (although we all know folks we would volunteer for that), so most commonly the LD50’s of known poisons and toxins are given in relation to the mouse model.

This even applies to medicines, and since rats and mice differ from humans in many ways (some more than others), LD50 in humans is most often a guess, but usually a very good guess. This is why your medicines come with a dosage – take enough to help you, but not enough to kill you.

ED50 (effective dose for 50% of patients tested) is the term used for medicines that helps determine the dosage. It is the least you can take to reasonably insure that the medicine will do what you want. The goal in pharmacological development is to minimize the ED50 and maximize the LD50, so you have a big range (called therapeutic index) in which the medicine is safe. Sometimes this is calculated as the safety margin, or LD1/ED99; the dose that kills 1% of animals divided by the dose that is effective in 99% of animals.

The ratio of the LD50 to the ED50 is a drug’s
therapeutic index. The log of the dose is used on
order to produce nice curves. Here, the therapeutic
index for digoxin, used to treat congestive heart
failure, is 1.5-2. By way of contrast, for penicillin it
is more than 100. Penicillin is a safer drug ----
unless you’re allergic.
So, your medicines are just poisons under control. Sometimes we even use things that you wouldn’t think of as medicines. Take botulinum toxin A (BoNT/A) for instance; it’s a deadly poison, but that doesn’t stop people from injecting it into their foreheads to remove wrinkles! BoNT/A has also been used to treat muscular spasms in the larynx (spasmodic dysphonia) and it may be useful for chronic pain.

A new study from Rome shows that morphine + BoNT/A works better for chronic pain than morphine alone. In addition, BoNT/A keeps mice from developing a tolerance to morphine over time. It seems that even if morphine has been used for a while, administration of BoNT/A can up-regulate the morphine opiod receptors, so that the drug regains its maximum potency in the animal.  Studies like this show us that we must be careful how we use the word ”poison.”

Do you know the difference between poison, toxin, and venom? Some definitions are in order, because they are currently being used all wrong. A poison is any substance that brings about a change in a living organism. It doesn’t say a good change or a bad change, just a change. This is why I can say that medicines are poisons, and why water can be considered a poison. You would be hard pressed to find something that isn’t a poison.

Prohibition in the United States made the production,
selling, and consumption of alcohol illegal. Many turned
to wood alcohol (methanol) for the same high. For a
good description of the practices and outcomes of this
bad idea, I recommend a book called, The Poisoner’s
Handbook: Murder and the Birth of Forensic Medicine
In Jazz Age New York, by Deborah Blum.
A toxin is a poison that is produced by a biologic process. So man-made hydrofluorosilicic acid from phosphate production is poison, but the secretions from a poison dart frog’s back contain several toxins. Here is where things are being used incorrectly. Toxic waste dumps usually contain man-made chemicals that seep into the ground water or soil. But they are not toxins, they are poisons. People commonly use toxic to refer to anything that can harm a living organism – wrong, but well accepted.

Sometimes the toxin isn’t actually the toxin. For instance, many people died from methanol toxicity during prohibition. Unscrupulous producers would concoct wood alcohol (methanol) combinations and alcoholics would consume them, because they gave the same high as ethanol; but they could also kill.  

But, the methanol wasn't directly toxic until it underwent a process called toxication. The human body metabolizes the methyl alcohol to formic acid, and this is what does damage to the cells. Formate can damage the optic nerve at very low doses and cause permanent blindness. It attacks the mitochondria to stop ATP synthesis – something not compatible with continued life.

There are more definition problems; people talk about poisonous snakes and spiders. But their poisons are made biologically, so they are better described as toxins, not poisons.

Snakes and spiders provide another level of complexity. A venom is a toxin that is delivered into the flesh (subcutaneously – below the skin) by some deliver method developed by the organism. Toxins are often absorbed through the skin or mucosal surface, but venoms often cannot be absorbed, they have to be physically placed into the tissues. Poisonous snakes and spiders are better described as venomous (we will talk about exceptions to this rule as well).  Interestingly enough, many ants inject formic acid as their venom, the same chemical formed by toxication of methanol.

The Inland Taipan snake (Oxyuranus microlepidotus) is
also called the Fierce Snake.  Despite the word’s
Chinese origin, the snake is native to Australia, as are
so many things that can kill you. They can change colors
with the season to maximize heat absorption in the
winter, and are usually very shy. The only bites on record
have been to snake handlers, and an anti-venom is
available, so no deaths have been recorded lately.
So what are the most deadly organisms on the planet? The deadliest snake is the Inland Taipan snake. One bite contains enough venom to kill about 100 people; the LD50 is about 0.03 mg/kg of body weight! LD50’s for spiders aren’t as readily available, but the funnel web spider of Australia is considered very toxic, with an LD50 of about 0.16 mg/kg.

However, these pale in comparison to the most toxic organisms – and wouldn’t you know it, they are the smallest as well. In a list posted by the University of New Mexico, the top three toxins come from bacteria, as do half of the top 16! Number one is botulinum toxin, made by an anaerobic (grows without oxygen) bacterium called Clostridium botulinum – our Beverly Hills forehead flattener. Its LD50 is 0.000001 mg/kg, so you can imagine how little the doctors must use - doesn’t stop them from charging a mint for it! The toxin of C. botulinum is especially nasty as a food contaminant, since you can sterilize the food, but the premade toxin will still be active.

A close second are the shiga toxin of Shigella dysenteriae and the tetanus toxin of Clostridium tetani, each with an LD50 of 0.000002 mg/kg. The list contains plant toxins as well as marine animal toxins and spider venoms, but once again, bacteria show us who’s in charge of this planet.

Here are the three arthropods commonly referred to as daddy
long legs. The crane fly is on the left. It is an insect with no
venom what so ever. The middle picture is a harvestman. It is
an arachnid, but it is not a spider, and it is not venomous either.
You can see that its legs are attached to its only body segment.
The cellar spider on the right is a true spider. You can see it has
a cephalothorax and a large abdomen, and the legs are attached
to the cephalothorax. Everybody got that?
One last item while we are here talking about relative strengths of toxins and venoms - the daddy long leg myth. The myth says they are the most venomous spiders in the world, but their fangs are too short to penetrate human skin. Well, the brown recluse has very short fangs, and they are deadly. And just what daddy long legs are you talking about anyway?

There are three bugs commonly called daddy long legs; the crane fly, the cellar spider, and the harvestmen. Only the cellar spider is venomous, and no one has ever assessed its LD50 (except for a short segment on Mythbusters). I think the myth started because they will catch venomous spiders in their webs, and eat them. They kill something dangerous, so they must be more dangerous -the worst kind of scientific thinking. O.K., is that settled once and for all?

Next time, mammals have defenses, but it is the rare mammal that resorts to toxins.

Vacca, V., Marinelli, S., Luvisetto, S., & Pavone, F. (2013). Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and μ opioid receptor expression in neuropathic mice Brain, Behavior, and Immunity DOI: 10.1016/j.bbi.2013.01.088

For more information and classroom activities, see:

Poisons –

Safety margin and therapeutic index –