Venom Evolution

[BWSmith]

While discussing specific envenomations cases and the apparent changes in composition we are seeing, I have a thought I would like to share.

Rattlesnake venom has, in the past, generally produced hematoxic (affecting circulatory system) symptoms in the victim. All snake venom has a combination of many dofferent protiens. So there have probably always been neurotoxins present in pit viper venom. But there seems to have been a drastic shift in the composition of venom in several species of Rattlesnake. The venom seems to be losing many of its hematoxic properties and becomeing primarily neurotoxic (affecting the nervous system).

The Mojave Rattlesnake (C. scutulatus) has been known for some time to produce a very neurotoxic bite, and was thought to be the most potent venom of any rattler. There was also a recent study of the Canebrake Rattlesnake (C horridus atricaudatus) on geographic variations in thier venom composition. They found the Canebrake to have very high concentrations of neurotoxins. In fact, specimens from Lake City, FL were found to be 24% more neurotoxic than a Mojave Rattlesnake! The Eastern Diamondback Rattlesnake (C adamanteus) has also produced symptoms in its victims that indicative of a neurotoxin. The same is true for Southern Pacific Rattlesnake (C v helleri) and of course the Neotropical Rattlesnake (C durissus).

In fact, let's look at two bites from Georgia locale snakes. I will keep it short. The first, an envenomation from a neonate Canebrake. NO hematoxic effects, not even edema (swelling) or necrosis ......... nothing. But just about every common neurotoxic symptom. The second, a 3'-4' female Eastern Diamondback envenomation during a feeding response. Severe pain at the bite site and severe edema were the only hematoxic symptoms. And again, many common neurotoxic symptoms.

These two particular snakes seem to have neurotoxins as the dominant toxin in thier venom. But this is a fairly new phenomena. That is 5 species of Rattlers that I can think of off the top of my head that are producing more neurotoxins. How many more are we going to find in the next 5 years?

My point is this. These changes seem to be occuring at an amazing rate. Typically, we think of evolution and survival of the fittest procucing such changes. Those animals most fit to survive are going to breed and new offspring carrying those advanced traits are produced. okay. The speed at which this change seems to be occuring is too rapid for simply selective breeding. I submit that the venom is not so much evolving through generations, but in the snake itself. I believe that venom is not a stationary substance, like for example a can of coke. Think of the snake as a case of coke. And the cans as doses of venom. What is commonly held at this time is that each can of coke is going to be chemically the same when opened. I believe that the chemical composition can change depending on the environment. I am not saying it sees a human and switches to Neurotoxin Mode. But I don't think that the speed of these changes and the geographic diversity lend themselves to traditional explinations.

This is pretty much rambling without having finished my first cup of coffee.

[shaggybill]

Good post.

My question is this:
The Mojave was the first rattler known to have a neurotoxic venom and was thought to be the only one in the US, but now changes in venom composition has been noted in several other species in southeastern US. Is this change the result of genes being passed on from interbreeding, or is it occuring without the help of inherent genes. If I were to guess, since the change is coming about so rapidly, it would be interbreeding. There have been successful attempts breeding a C. Scutulatus with an Atrox, but I have never heard of a C. Atrox breeding with C. Horridus. Niether have I heard of C. horridus breeding with Adamanteus. But this would have to happen if the reason is interbreeding. The big question is, why arent the northern timbers showing any sign of this change.

One theory is this:
If indeed there is any chance of the inter-breedings taking place, it would probably have gone from Mojave to Atrox, Atrox to Horridus, Horridus to Adamateus. Since all these snakes except the horridus are confined to the southern most parts of the States, the neurotoxic properties might not have had enough time to reach the northern-eastern timbers.

I dont know that much about inter-breeding, so this might be way off, but it seems like a logical theory.

[BWSmith]

Theoretically, any Crotalus can breed with each other. I have seen adamanteus/h atricaudatus crosses. But they are not crosses that this is generally occurring in. And the habitat is so expansive and diverse that environmental factors are hard to see.

I do have one pure timber that I believe to be extremely neurotoxic due to anictdotal observations in the feeder rodents.

There are several of my snakes I would love to get tested. I now have the female adamanteus that envenomated an 18 year old with primarily neurotoxic symptoms (aside from edema) and a h. atricaudatus fromt he same clutch as one that envenomated a gentleman in his late 20's last week with ALL neurotoxic symptoms (not even any swelling!). Both the EDB and the cane's parents came from South GA. Nice to know that those for sure are treated with a constrictive bandage :D

[Crotalus75]

Intersting. Could it be that we are seeing more studies being done with venom and we are now just discovering properties that were always there? Many crotalids can interbreed (I have even seen a photograph of A. contortrix X C. horridus that was produced in a display where the two were housed together), but they do not do this across a wide rang in the wild. Hybrids are only produced at lines of integration in the wild and this would rule out the genes from widely separated organisms being thrown into the same gene pool (say scutulatus X florida locale horridus, over the reasonably short amount of time like we are speaking of). I like the coke machine analogy and I agree that each dose is going to vary in compostion (within an individual, a given population of a species and interspecifically as well as intraspecifically). But if the change in composition occurs within an individual it cannot be do to darwinian forces. Evolution acts as a change in allele (gene) frequency within a population over a period of time.

I think:

Environmental factors play a role in in the snakes day to day, season to season physiology and venom is a product of the snakes physiology so it is highly possible that these changes could produce a variation in the composition of it's venom. This would not be do to differences in diet so much, because as I understand it, snake venom is a primary production and not a secondary metabolite.

Just my 2 cents.

[BWSmith]

THat was precisely my point. Darwinism works too slow. Are we seeing some kind of advanced evolution or adaptations? After all, it was not that long ago that a Diamondback bite would rot your arm off :D

I am waiting to hear Bryan's take on this ;)

[Crotalus75]

Evolution of any flavor (traditional darwinism, neo-darwinism or other) cannot take place within an individual. All adaptations are produced through evolution over many generations. Evolution through acquired characteristics (acquired by an individual and then passed to offspring) was proposed by Jean-Baptiste Lamarck (circa 1800). This theory was ultimately proven false with the rise and understanding of Mendellian genetics.

Maybe I missed the point (this often happens :) )

[BWSmith]

Perhaps it is time to redefine "evolution"

[Crotalus75]

Now that I definitely agree with. I have been reading some publications that challenge our traditional view of evolution on the biochemical level. Very interesting to say the least. Challenges to evolutionary dogma would fall under the category of "Forbidden Science" that BGF was speaking of on his forums. I am all for it! :)

[BWSmith]

Yeah, I just copied and pasted my original post from RTB. And it was before coffee when I wrote it. Terminology can be a killer. :D

[Dr. Bryan Fry]

Hi guys

its a case of more and better studies, whats there now most most likely same same range of variations that was there 100 years ago. We've done studies on the death adders showing regional variations in the well known neurotoxicity (with Ceram being the most toxic by far), myotoxicity (thought to be absent entirely but there in high amounts in some populations such as the Cairns praelongus, the Merauke rugosus as well) and variations in relative neutralisation (the Ceram not only being the most toxic but the most poorly neutralised as well). Also, we pulled out myotoxic PLA2s and antiplatelet PLA2s (PLA2s thought to be absent entirely), CRISP toxins, weird complexes that are like the potent presynaptic neurotoxins in Oxyuranus. All of this in a genus that was supposed to be only alpha-neurotoxic. Just goes to show whats there when you actually look. So, a variation in neurotoxicity is not suprising, not when extreme neurotoxicity has been shown in the full range from pitvipers (eg mojave) to true vipers (eg Berg adder, Bitis atropos). Neurotoxins have been pulled from Vipera ammodytes to Trimeresurus gramineus. So, neurotoxins go way back in vipers. They are different to the elapid/colubrid neurotoxins but still quite potent in their own right.

Cheers
B

[BWSmith]

I would be interested to see papers from 50 years ago relaying the symptoms of an envenomation from a Canebrake or Diamondback in South GA.

Ray is old enough, maybe he remembers a bite from the 40's :w

[SCReptiles]

This also address Bill’s question in the other forum about Neurotoxins developing in Agkistrodon.

I do not believe the neurotoxins are developing in Crotalus, I believe they have been there. Everyone knows I am not an evolutionist, however, I do believe in inner-species evolution or survival of the fittest. There are advantages to Hemotoxic venoms and Neurotoxic venoms. Hemo begins the digestion process. Prey begins to decompose even before it is consumed. Neurotoxic means a faster death, thus less envenomated prey will escape the snake. Take note of the locales of the neurotoxic Crotalus. All are in very warm climates. For them Neurotoxic venom would be an advantage as they have excess heat to aid digestion. To my knowledge there are no case studies of Neurotoxins in the northern Crotalus, where the Hemotoxic venom is necessary to speed the breaking down process of the prey. There is a pattern of natural in-breeding in the shared range of the Atrox and scutulatus. This is greatly advancing the Neurotoxic properties of the Atrox of that area. Also this hybrid is proving to be especially dangerous. The Mojave packs such a powerful venom that only small amounts are required and this he has a very low venom yield. The WDB on the other hand has the second highest venom yield of all Crotalus. These hybrids are packing the power of the Mojave with the yield of a Diamond. It will be interesting to see how this trend pans out. The research is just now beginning. We sold some copperhead to Auburn University this summer and the guy who picked them up was sharing this information with me. They are hoping to get a research project on this soon.

[shaggybill]

Good post, Chuck. I am not an evolutionist either, but like you, I think there can be an inner-species evolution, resulting in the fittest surviving. In fact, its only logical to believe that, evolutionist or not.

I find interesting the theory of the northern crotalus having a more hemotoxic venom due to the cold and the aid of digestion it provides. I'd like to see the results of this research.

[SCReptiles]

I find interesting the theory of the northern crotalus having a more hemotoxic venom due to the cold and the aid of digestion it provides. I'd like to see the results of this research.
If my theory is correct, then is would also tie into what Greg was saying about his venomoid being unable to digest food even though it was kept in the same conditions as the hots. To bad it died, I would have been interested to see if it would have faired better if it where offered a warmer basking spot then that of the hots.

[Crotalus75]

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[Crotalus75]

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[Dr. Bryan Fry]

I don't know if it really works that way, what with Bothrops having even more devastating venom than Crotalus and obviously flourishing throughout hot and cold, just like the elapids. We have very neurotoxic (death adder) living along side neurotoxic, neuromyotoxic, myotoxic and prothrombin-activating tiger snake venom. Similarly in the tropical North. The range of temperatures in themselves would be unlikely to correlate with an evolutionary pressure to develop a different venom.

When the vipers split off from the Colubroidea tree, just after the evolution of venom, they ended up radiating to evolve to live in some of the hottest (Sudan) or coldest (Norway) climates around. With the venom varying tremendously throughout. The elapids as a rule live in a tremendously varied climate range, having evolved many niches, particularly the peculiar evolution of the Australian elapids and then the seasnakes from within the Australian elapids.

The venom has varied tremendously but not from temperature but rather selection pressures from the environment they were in and more to the point, the prey species they were after. For example, the taipans feed on rodents as do the brown snakes. The taipans and brown snakes are actually each others closest relative. They also share a uniquely hemotoxic venom that has a particularly devastating action. As such, the taipan and brown snakes are the worlds most toxic snakes. The brown snakes range all over Australia and the venom doesn't vary in accord with temperature. However, venom can vary tremendously over a range, as shown by our death adder venom study.

An example of positive reinforcement by the environment is the mambas, lab studies have shown that the black mambas venom is more potent towards rats while the green mambas more potent towards birds. This is of course what both are feeding on in the wild. This woul aid the snake in that it wouldn't have to be as accurate or big to get enough venom into a bird to kill it. If one snake had a venom that was just a bit more potent for birds, it might get just a couple more meals which of course would give it a survival advantage. Its little things like this that are part of the driving force of evolution upon the snakes.

Sometimes the venoms have taken unusual turns. The seasnakes for example we found have a remarkably streamlined venom relative to the land snakes. The sea kraits, from within the Papuan-Melanisian area most likely, independently did the same thing. Remarkable. Even more intriguingly, the Australian sea snake antivenom made against just the venom of the beaked sea snake (and only one population at that), it actually works remarkably well against virtually all the seasnakes. A much higher level of cross protection achieved than has ever been reported for terrestrial snakes. This is well connected with the streamlined venom in contrast to the ever evolving land snake venom. Must come down to the sea snakes having one class of animal (fish and eel) while the land snakes might eat frogs, mice, birds and lizards and all variations and specialisations within. Even two sea snake species that have independently started loosing their venom and instead living off of scrapeing fish eggs out of under rocks. They do well for themselves on the reefs. Very cool.

Just a little bit on how the venom evolves and continues to evolve in snakes. ;-)
B

[SCReptiles]

Dr Fry, that is where we differ. I do not believe in evolution at that level. I believe a species can adjust to better fit its environment, but that is about it. In the case of the Crotalus horridus. Lets say a Jasper County, SC female gave birth to a litter of 8. 4 processing the Neurotoxic venom and 4 the Hemotoxic. If my thoughts are correct and the Neurotoxic venom provides an advantage to the half that have it, then they are more likely to flourish and pass on their genetics to the next generation. In a matter of just a few generations, the southern crop would be more Neurotoxic then the northern crop, as just the opposite is happening to Timbers in the north. I think that is what we are seeing here. I am not aware of any Neurotoxic Timbers from the north, but there has been some Canes collected from Jasper County that are 38% Neurotoxic and BW Smith tells me that he has heard of some research showing specimens from FL having even more Neurotoxins. Of course this is all theory at this point, but can you it really be ruled out based only on what we knot now?

[Dr. Bryan Fry]

Hi mate

Actually, we know the evolution of the snakes themselves and we have mapped the patterns of venom variation over the genetic tree and it matches. This is very compelling evidence. We've even worked out which toxins were present in the venom of the very first venomous snake. However, if you don't understand evolution then you won't be able to appreciate this.

Cheers
B

[SCReptiles]

Dr Fry, obviously I am in no position to debate you on the subject of venoms, but my question was, based on currently known data, can the scenario I put forth be ruled out? Also, there was compelling evidence that OJ killed Nichole, but is he in jail? =) Compelling evidence doesn’t necessarily make it so.

[Dr. Bryan Fry]

Hi mate

Yes the scenario you put forth can be ruled out entirely since venom changes are not spread like viruses. Certainly there will be changes in the venom of babies relative to adults but the changes would be independent and localised. This would not affect the other snakes in the area and any survival advantage would materialise over many many generations. There would not be a radical shift from hemotoxic to neurotoxic and nor can it be quantified with such simply numbers (where did you get those numbers anyway? The relative neurotoxicity of rattlesnake venoms has been poorly studied). In anycase, the neurotoxins in rattlesnakes are PLA2 toxins and are present across the board in the vipers, with high concentrations in Bitis atropos as well as of course the mojave green rattlesnake. The toxins have been further isolated from Trimeresurus species, Vipera ammodytes and even present in quite decent amounts in Atheris venoms. This is all reflective of the common origin of these snakes and that the type II PLA2s were added to the viper venoms shortly after the first viper split from the Colubroidea tree (which is why type II PLA2 toxins are present in all viper venoms). The neurotoxic action of the PLA2s was early evolved but since then it has also been modified to be antiplatelet and myotoxic as well.

Stupid juries in LA is a bad analogy since they spent about 10 minutes deciding how to screw whitey.

Cheers
B

[Mustangrde1]

Dr Fry

Do you think that possibly evolution might also be occurring do in part to Atmospheric conditions? As an example if a species that is wide spread and lives in both a warm part of its range and also a cold part. do you feel that the animals in the warmer part would produce a much less toxic venom than perhaps one in a colder region. The colder regioned snake would need a faster kill time on its prey to get to it faster without using near the energy and thus concerve energy, where as the species from a warmer temperature can afford to extend more energy.

[Dr. Bryan Fry]

Hi mate

Certainly temperature will be a strong evolutionary influence, however I would suspect that as far as the venom goes it would have a stronger correlation with prey change (which itself may certainly be influenced by temperature). So, at the end of the day temperature would be more likely to be a direct rather than indirect pressure.

Not quite sure what you mean by the energy use. Are you talking about the snake itself using less energy?

Cheers
B

[C.m.pyrrhus]

Hello, (Not a big venom guy :D)

I see the venom change myself related to prey, which in turn is why I believe it was created as a evolutionary tool for survival. As I would see it, temperature would change the scenario only if it changed the food the snake in question was survivng off of. There are week and powerful venoms in the world from snakes no matter the climate, elevation and so on IMO. What I see as a changing influance of venom is the prey, and the change of prey over time(which is related to environmental changes and the everything else thrown in that complex scenario). Now be it I have not as much study or information as everyone else, but in simple terms this makes sence.

[Mustangrde1]

Dr Fry

Yes I was reffering to the snake itself using less energy when tracking down prey after the bite.

[Dr. Bryan Fry]

Hi mate

If the snake is out, its not going to be using much more energy to track down a prey item. It comes down to a time spent. In any case, the neurotoxin/hemotoxin debate doesn't even begin to address the actual complexity that is the venom. In viper venoms there are 16 toxin types shared amongst all the vipers (and 8 of these are ancestral and shared with the elapids/'colubrids' ). These toxins can exert a wide array of effects, from hammering the blood pressure (causing it to drop precipitously), to starting the clotting cascade, to blocking the blood clotting, to acting on the nerves to destroying anything it encounters like a voracious pac-man (these are the M12B toxins which are ancestral). Rather than each toxin being a soloist, think of it as a full fledged concerto. There is no quantitative method of hemo vs neuro since where do you put the blood pressure toxins? They don't hit the nerves. In vipers, the quickest deaths are actually produced by the hemotoxic venoms, the potent prothrombin activating enzymes in saw-scaled and Russell's vipers (prothrombin activating in a manner utterly different than that done by the Australian elapids, independent evolution of the same net effect through utterly different strategies). The viper neurotoxins are much slower than the ones in elapids, the former being type II PLA2 toxins and the latter being 3FTx and also sometimes type I PLA2 (which are as slow as the viper PLA2). The difference is that the PLA2 neurotoxicity physically destroys part of the nerve while the 3FTx just block the nicotinic acetylcholine receptor. The 3FTx type of neurotoxicity found in elapid/'colubrid' venoms is very rapid while the PLA2 type is slow for both elapids and vipers. The prothrombin activating in elapids is devastatingly fast too though.

Cheers
B

Cheers
B

[reverendsterlin]

I don't think this really argues against evolution. Like with our breeding programs for morphs, smaller populations(or more isolated from other genetic materials) with usually man induced changes in environment and prey type/availability would tend to more rapidly concentrate sucessful mutation into the population. If neurotoxicity is more sucessfull to the animal that animal has the best breeding advantage and produces the better surviving offspring and can rapidly move through an area giving more animals and expanding range to intro the same genetics into other near populations potentionally rapidly increasing the survival rates of neo's getting the trait. Evolution as a trait doesn't mean it is "always" a long process, when breeding morphs we only concentrate the breeding pool to gain fast results, nature can as well.

[Dr. Bryan Fry]

Hi mate

Venom changes would take a long time to shift in a population. It would not spread like a virus and would take a long time to shift. The quickest shifts of course would occur when there is a small founder population such as in the island forms of different snakes. The tiger snakes for example are genetically quite similar but the venom differs appreciably across the different island populations. In a mainland population, it takes a larger geographic range to get significant effects but sometimes the shifts can indeed be quite pronounced.

Cheers
B

[BWSmith]

PWD (:D),
So you are saying that the composition of venom that a particular specimen produces cannot change during the lifetime of that animal?

[Dr. Bryan Fry]

Hi mate

Thats different than what is inhereted. Yes it can change and in some circumstances may change markedly between neonate and adult consistently (ie programmed to do this in each generation). However mutations that occur during the life of the adult are not inhereted unless these mutations happen in the sperm or egg, mutations inside the venom gland itself are irrelevant as far as heredity is concerned.

Cheers
B

[BWSmith]

Thank you. That was precisely my point in the original post. That venom seems to be changing without the need for selective breeding. Of course, I still hold that venom compositions are adapting and becoming more neurotoxic in populations, and, if I read correctly, you feel that the neurotoxins have probably been there all along.

[Dr. Bryan Fry]

I can certainly imagine there being signficant geographical variations in relative neurotoxicity, wouldn't suprise me in the least. I'd actually be quite shocked if it didn't occur. Those sorts of variations do take a long time to come about unless there was a bottleneck or perhaps a founder effect somewhere along the lines. How many doctors do you reckon now would be able to write the snakebite up properly? What about in the early 1900s? Think they really had a clue what was going on with the bites? Reckon that might account for the lack of precedence. We even showed that Atheris are actually quite neurotoxic (A. squamiger at least).

Cheers
B

[SCReptiles]

Dr Fry, sorry I have been away a few days.

Yes the scenario you put forth can be ruled out entirely since venom changes are not spread like viruses.
I didn’t put forth the notion that they were. I do not think a snake could change venom properties. I was saying the thriving Neurotoxic population would out breed the Hemotoxic population if there was an advantage to them.
Certainly there will be changes in the venom of babies relative to adults but the changes would be independent and localised.
But isn’t that exactly what we are seeing with the southern populations moving to Neurotoxic?
(where did you get those numbers anyway? The relative neurotoxicity of rattlesnake venoms has been poorly studied).
The number I mentioned came from an article published on the SHHS website. My theory comes from this article and others on the subject, as well as several personal conversations with Dr Gordon Schuett, author of Biology of the vipers and the world’s foremost expert in pit viper genetics.

[Dr. Bryan Fry]

Hi mate

Venom changes by and large take a long time, for an entire population to change woould take a fair number of generations, with changes being measured in thousands of years, not hundreds let alone within the last decade. This is not to say that these changes don't occur. My point is simply that I belive it is a case of more awareness rather than recent, significant changes in the venom composition. This is not to say that there isn't variations between even potentially between snakes in the same clutch. However, even if a couple key mutations occured and one snake was radically more neurotoxic. It would take a lot of breedings to swamp an area. That alone would take a long time. However, venom does not usually radically swing one way or the other because there are numerous toxins in there and they all mutate independently of each other.

All the best
B

[SCReptiles]

Dr Fry,
I would agree whole heartily with your last post. I do not feel these changes have just recently taken place, I believe they have been progressing for a very long time and we are just now becoming aware of it. I didn’t mean to suggest all southern Crotalus will be Neurotoxic within a decade, but I do think we are seeing a shift in that direction.

[BWSmith]

Have there been any studies to indicate that the composition of venom in a specimen may change over the course of that snake's life?

[Dr. Bryan Fry]

Hi mate

We are actually knee deep in exactly that study and will be submitting the paper sometime in the first part of next year. We've taken three snakes from the same clutch and milked them for five years. We're just about to do the mass spectrometry work on the venom samples to see if there were changes and if so were they consistent between all three snakes. It should be very interesting.

Cheers
B

[Dr. Bryan Fry]

G'day Chuck,

yes there very well may be a regional shift in venom composition. Wouldn't suprise me if it was. We've seen in the death adders some populations with quite myotoxic and antiplatelet venom in addition to the more normally seen neurotoxicity. This of course is what underpins regional variations in the relative efficiency of antivenoms.

Cheers
B