Chapter 4 Schlegel's Curse

4. Schlegel’s Curse

M. Reinwardt, during his residence in Java, discovered the existence of grooved teeth in several species of the ancient genus Coluber…. it has even been concluded on anatomical investigation, that we ought to consider all serpents dangerous, whose posterior teeth were long or grooved. I have arrived …at a very opposite conclusion.
Hermann Schlegel, 1837

A roadside pond in central Thailand attracted our attention because of the large number of calling puddle frogs and floating frogs of the genus Occidozyga. The males of these frogs call with a short, two-note toot and the females reply with a similar sound. To my companions and me, the presence of frogs suggested frog-eating snakes. We spread out and walked the pond’s perimeter. The beam of my flashlight exposed a familiar pattern, rust-colored bands separated by cream colored bands. It was a Puff-faced Water Snake (Homalopsis bucatta), but I could only see part of its body, the rest of the snake was below the surface. As I grabbed the snake, it immediately struck a glancing blow at my hand. Within a minute it was in the bag, and I was examining the damages. There were some superficial scratches on two fingers, blood was flowing freely, and there was a distinct burning sensation. Many writers of herpetology papers refer to this snake as non-venomous. I knew better. The bite and exposure to the venom did not mean a trip to the hospital, but it was a reminder that many snakes, if not all, carry venom― but venom that is not always life-threatening to humans.
The human mind easily deceives itself.  Despite evidence to the contrary many people are willing to accept familiar old ideas over new, unfamiliar or controversial ideas. This reluctance to accept change works against science which is continually challenging old ideas with new ideas, and testing them. Hermann Schlegel, a German born 19th century naturalist, authored the first global, scientific, survey of snakes, and became director of the Rijks Museum of Natural History in Leiden. Despite these accomplishments, Schlegel was not a man who could deal with changing ideas and technology; he opposed Darwin’s ideas about evolution to his death in 1884, and rebuffed the idea of using a microscope. He also had a problem accepting evidence discovered by his teacher, Caspar Reinwardt that snakes with enlarged, grooved teeth in the back of their mouth were indeed venomous.
Reinwardt had been collecting specimens on the island of Java for the Rijks Museum in the early part of the 19th century and discovered the snake commonly called the Asian Bockadam (Cerberus rynchops) had an open groove on the front surface of a pair of fangs located on the back end of the upper jaw bone [Figure 4–1a]. This suggested to Reinwardt that the bockadam was poisonous. In a letter Reinwardt described this tooth structure to his colleague, Heinrich Boie, in Leiden. Boie cited the letter in an 1826 publication.
Eight years later, George-Louis Duvernoy of Strasbourg published a paper on the head glands of snakes, and concluded that some species, including the Asian Bockadam, had a yellow colored gland below and behind the eye that was distinct from the white salivary glands [Figure 4–1b]. Duvernoy considered this to be a venom gland, and others accepted his conclusions. The yellow-colored glands in colubrid snakes would eventually be named Duvernoy’s gland. Today there is no clear difference between this gland and a venom gland, so the term has been abandoned. French herpetologists Constance Duméril and Gabriel Bibron published a classic 10 volume work on amphibians and reptiles between 1834 and 1854, titled Erpétologie Générale ou Historie Naturelle Complète des Reptiles, and fully accepted Duvernoy’s conclusions and established a group for snakes with grooved rear-fangs, the opisthoglyphs. The tongue tangling Opisthoglypha is derived from Greek and means “rear large tooth.” Yet, Schlegel remained un-accepting of the idea that rear-fanged snakes could be poisonous.

INSERT FIGURE 4-1.
Figure 4–1. A: The rear-fang of the Asian Bockadam, Cerberus rynchops. The deep groove with rounded edges transport venom under low pressure. An SEM photograph. Sara E. Murphy. B. The venom gland (formerly the Duvernoy’s gland) (upper arrow). Large, rear-fang (lower arrow) in a specimen of the Plumbeous Mud Snake, Enhydris plumbea. Redrawn from Duvernoy (1832 Ann. Sci. Nat. 26:113160).

Andrew Smith, author of Illustrations of the Zoology of South Africa, included the Boomslang (Dispholidus typus) a large, day-active, tree-dwelling snake in his study. Smith claimed he did not find any venom glands in this snake, despite its elongated grooved fangs [Figure 4–2a], and following Schlegel, proclaimed it harmless. Smith wrote,

As this snake, in our opinion, is not provided with a poisonous fluid to instill into wounds which these fangs may inflict, they must consequently be intended for a purpose different to those which exist in poisonous reptiles.

He continued with speculation that the fangs function to prevent the prey from escaping during swallowing― not a bad alternative hypothesis, and one that will become important later.
These differing viewpoints started an ongoing controversy in the 19th century. The controversy would have lethal consequences for several 20th century herpetologists and would add support to altering the view that venom occurs only in the front-fanged snakes.
Observations made by 19th and early 20th century herpetologists in North America, Europe, and South America suggested rear fanged snakes were indeed venomous. Mexican herpetologists Alfredo Dugès observed a Lyre Snake (Trimorphodon biscutatus) seize a whiptail lizard and chew on the lizard’s front leg; within minutes the lizard was dead. About the same time Otto E. Eiffe made similar observations on the European Cat Snake (Telescopus fallax) and its lizard prey. In Italy, Mario G. Peracca and C. Derêgibus investigated the toxic nature of the Montpellier Snake (Malpolon monspessulanus), a large, common snake from the Mediterranean area. In a letter to the Academy of Medicine at Turin in May 1883, Peracca and Derêgibus described grooved fangs, the yellow glands, and the ducts that connect them. They used two specimens and forced the snakes to bite lizards, frogs, and toads. During the forced bites, the snakes injected the prey with fluid from their venom glands by way of their rear fangs. The prey, removed from the snake's jaws, stopped breathing and lost the ability to carry out reflex actions in a few minutes. Death followed in all of their experiments.
Similar reports soon followed. John J. Quelch, director of the Georgetown Museum in British Guiana, was bitten on the finger by a large false coral snake (Erythrolamprus aesculapii). Quelch’s finger swelled and was painful. French researchers Marie Phisalix and Claude Bertrand observed secretions from the yellow gland of two species of European rear-fanged snakes were fatal to guinea pigs, and G. S. West reported observations made by others that the bite of the Green Vine Snake (Oxybelis fulgidus) was fatal to small animals. However, the study by A. Alfred Alcock and Leonard Rogers left no doubt; rear-fang snakes inject toxic molecules into their prey. Alcock and Rogers tested venom gland secretions from a variety of snakes including the rear-fanged Asian Bockadam and confirmed the toxic nature of molecules made in the yellow-colored glands described by Duvernoy.

Boomslangs, Bird Snakes, and Herpetologists
In November of 1907, South Africa’s Port Elizabeth Museum was moving its live snake collection to new quarters. Frederick W. FitzSimons was the museum’s director. His assistant, James Williams was carrying a large Boomslang (Dispholidus typus) when it bit him in the forearm just below the elbow. FitzSimons encouraged Williams to attend to the bite, but neither was concerned because Boomslangs were considered non-venomous. After all, Andrew Smith, author of the Illustrations of the Zoology of South Africa, said so. Williams continued working and within an hour he had a headache, blood oozed from his mouth, and he began to vomit. The local doctor recognized the symptoms as poisoning. The following day, he collapsed and was admitted to the hospital. Blood was now leaking from his mouth, nose, bladder, rectum, and into the spaces between the skin and muscles, forming large bluish-black patches under his skin and, making him a “dreadful sight.” He developed severe pain in his abdomen the third day after the bite, and the attending doctors did not believe he would survive the night. He remained in this state for three more days (six days after the bite), and then he started to improve.
FitzSimons documented the 1907 bite, and described experiments with boomslangs to confirm their venomous nature. Using birds he found the results to be 100% fatal; in some cases, the birds died in three minutes. FitzSimons dissected several Boomslang heads and found glands on each side connected to three fangs located under each eye [Figure 4–2a]. The previous year, another man had died after the bite from a Boomslang. The consensus, however, was that he died not from the Boomslang bite but from an infection obtained during treatment. A 1902 article by MacVicar suggested that the bite of the Boomslang might have lethal consequences for humans.
Schlegel was wrong. Rear-fanged snakes were killing their prey with molecules made and secreted by a venom gland and carried into the prey by way of an open groove on the surface of an elongated tooth toward the back of the snake’s mouth. Futhermore, at least one of these species, the Boomslang, was capable of killing humans; however, few humans are bitten by Boomslangs, and of those that are, it is the rare person injected with the toxins. FitzSimons hypothesized that this is due to the short fangs and, should venom delivery occur through clothing, the fabric would absorb some of the liquid toxins.
Another bite from a rear-fang snake had more deadly consequences. Frederick J. de R. Lock was a Game Ranger in the service of the Tanganyika Government, and an enthusiastic herpetologist. In December of 1953 he had just completed writing an identification key to Tanganyika snakes, and was preparing to write a more extensive guide to the snakes of that country. On Tuesday, December 22, at about 11 PM he returned home after attending a party, and was exhibiting his snakes to friends. He removed a Bird Snake (also known as the Savanna Vine Snake, and sometimes called a Bird Snake because it eats birds and mimics fledgling birds) from its cage and was playing with it, probably in an effort to aggravate it so that it would expand its neck and throat in a spectacular defense display. The snake bit him on the wrist, but he ignored the wound believing the snake to be harmless. Lock sucked on the bite site briefly. The next day he did not feel well. About midnight he began vomiting blood. On the morning of December 24th he was admitted to the hospital. He lapsed into a coma after a violent seizure and died at 1 AM December 25, about 50 hours after the bite. The autopsy revealed extensive hemorrhaging in the brain, lungs, liver, and kidneys. The coroner’s findings read, “Death due to Bird Snake (Thelotornis kirtlandi capensis) venom poisoning after sucking the site of the bite and swallowing contaminated mucous…” Shocked by the condition of Lock’s internal organs, the medical officer shipped the snake to Desmond C. FitzSimons, director and founder of the Durban Snake Park (and son of Frederick W. FitzSimons, of the Port Elizabeth Museum). FitzSimons swabbed the snake’s mouth, centrifuged the material with saline, and injected it into full-grown mice. The mice died from extensive hemorrhaging.

INSERT FIGURE 4-2.
Figure 4–2. Top: Rear fangs of the Boomslang (Dispholidus typus). Bottom: The rear fang of the Savanna Vine Snake (Thelotornis capensis).

Prior to this event, Raymond Cowles had been bitten by a Thelotornis while attempting to take a photograph. He wrote,

…if it did bite I would have enough time to disengage it before it could work its fangs into position to imbed them. This is a common belief among herpetologists. To my great surprise and slight consternation the snake struck with its gape so widely open that its fangs came to bear instantly, no preliminary chewing needed.

Cowles suffered only a mild reaction to the bite, and admitted that only after hearing of the Lock
incident did he suspect the snake may be dangerous to humans.
About 1:30 PM on September 25, 1957, on the ground floor of Chicago’s Field Museum Karl P. Schmidt was bitten by a snake that would result in his death 25 hours and 45 minutes later. The live snake had been brought to the museum for identification from Lincoln Park Zoo, a well-known Chicago institution a few miles north of the museum on Lake Shore Drive. The 67-year old Schmidt was Curator Emeritus of the Division of Amphibians and Reptiles. He had a long and distinguished career as a herpetologist, with one of his areas of expertise being African reptiles. Marlin Perkins, Director of Lincoln Park Zoo, had sent the 30-inch reptile to the museum because it had an undivided anal scale. Boomslangs, according to the keys used for identification, have divided anal scales. Robert Inger, then Curator of Amphibian and Reptile, was holding the serpent when Schmidt walked into the room and took the snake. The reptile promptly sunk the right fang and one other tooth into his thumb. Contrary to newspaper reports of the incident, Schmidt was aware of the kind of snake that bit him and, although he may have never seen a live Boomslang, he was undoubtedly aware that they were potentially dangerous.
A popular book on reptiles authored by Schmidt and Inger and ironically published in 1957, the same year as the bite, they wrote,

 One of these tree- or bush-dwelling snakes, the boomslang, Dispholidus typus could give a man looking for birds an unpleasant shock, as we have mentioned earlier, it is a large rear-fanged snake and is the only one considered dangerous to man.

Schmidt, a meticulous observer, recorded his symptoms in detail over the next 18 hours, symptoms that lead to his death hours later.
Thirty-nine days later, November 1, 1957, at 3:30 PM, Donald G. Broadley, an African herpetologist, was bitten on a finger by a Bird Snake, the same species that had caused Lock’s death. He sucked on the wounds, but ignored the bite; by 5 PM, the punctures from the bite were bleeding, and by 9 PM the finger was swollen; more blood was coming from the bite site, and from cuts and abrasions that were received during the capture of the snake. Broadley survived the envenomation.
Schelegel’s curse continued to kill herpetologists. Robert Mertens had been a herpetologist and director of the Senckenberg Museum in Frankfurt Germany from 1925 to 1960. Mertens had the reputation of being able to sight identify reptiles from any geographical location, had authored more than 800 publications, and had an encyclopedic knowledge of reptiles. He maintained a collection of captive reptiles, including a Savanna Vine Snake, Thelotornis capensis. At the time Mertens believed the snake to be the Forest Vine Snake, T. kirtlandi, the two species were long considered to be just one species because of their similar appearance.  Mertens had maintained this specimen in captivity for five years, when on August 5, 1975 he was bitten. He survived 18 painful days before dying. With his background and experience, it is difficult to believe that he was not aware of the FitzSimons and Smith articles; they had, after all, been published 17 years previous during Mertens’s career.  Like Schmidt, Mertens was highly disciplined in recording observations and kept a diary in the days following the bite, which he described as “a singularly appropriate end for a herpetologist.”
In general, Colubrid snakes were believed harmless to humans. The fact that few people bitten by them suffered serious consequences supported this idea. The legacies of Schlegel and Andrew Smith reinforced the idea that rear fanged species were not a threat to humans. And the overly simplistic idea that snakes fit into two categories – venomous and non-venomous all contributed to Schlegel’s curse. Even world-renowned zoologists were not savvy enough to take simple precautions from potentially deadly bites of rear fanged species, because most of the bites delivered by rear-fanged species to humans caused only minor discomfort. After all, the grooved rear-fangs were not the hypodermic needle-like structures found in vipers and elapids. Rear-fanged species had open grooves and the fangs were under the eye, or behind the eye, at the back of the mouth.  Even the coroner’s report seemed to deny the fact that it was a Bird Snake’s bite that caused his death; instead, the coroner attributes death to Locke’s ingesting contaminated snake saliva. Herman Schlegel’s narrow-minded idea that only front-fanged snakes were venomous was the curse he placed on herpetologsist.

Yamakagashi
China, Japan, Korea, and eastern Russia are home to a semi-aquatic snake considered by the locals to be harmless, the Yamakagashi (Rhabdophis tigrinus). It lives in roadside ditches, rice paddies, and other human-modified environments that are usually near water. Frogs and toads make up its diet. From all accounts, it is an abundant and commonly encountered species in a lineage of snakes generally considered harmless, the natricids. However, the Yamakagashi has a large venom gland with a duct that opens just in front of two un-grooved, solid fangs. Envenomation by this snake was reported by Sakamoto in 1932, but the report was overlooked until Myron Mittleman and Richard Goris reported on Sakamoto’s article and two other cases in 1974. All three bites were received on the hand or wrist while the snakes were being handled. All three victims exhibited delayed and sustained bleeding, with the delay time ranging from several hours to more than 10 hours, with the sustained bleeding lasting from 8 to 14 days. In one case, an 11-year-old male was bitten. Several hours later, he was spontaneously bleeding from the site of the bite as well as older abrasions and lacerations. Numerous bandages were applied before the child went to bed, but the bleeding continued throughout the night, and his sheets were soaked with blood by the morning.
In another case, 30 hours after the snakebite the patient’s blood clotting time was considered to be infinity. An earlobe puncture taken the day after the snakebite continued to bleed for 44 hours. Bleeding gums, bloody urine, and blood leaking into the spaces between the skin and muscles were also observed. Symptoms were similar to those reported for the Boomslang and the African Savanna Vine Snake, but in these three cases all of the patients survived. Mittleman and Goris latter reported the case of a professional snake catcher who was bitten twice on the left hand by a Yamakagashi he suffered symptoms similar to the other three reported cases, and showed some improvement after being placed on kidney dialysis 62 days after the bite. He died a week later from pulmonary edema, and his autopsy showed extreme kidney damage. The Southeast Asian Red-necked Keelback (Rhabdophis subminiatus), is the only other member of the 18 species in the genus Rhabdophis that has been implicated in envenomation, and the bites from this species are also considered serious threats to human health.

Loras of the Genus Philodryas and Others
South America is home to a clade of mostly rear-fanged snakes, the Xenodontinae (family Dipsadidae). While some of these are arboreal; others are terrestrial, fossorial, and aquatic snakes. Despite the hundreds of species of snakes in this group, few seem to pose a serious threat to humans, although they have a variety of fang types, venom glands, and venoms. Bites from most of these snakes results in local swelling, but a few show signs of systemic envenomation and neurotoxicity.
The genus Philodryas belongs to this clade and contains 21 species that are relatively unknown. Most are less than a meter long, have thin bodies, live on the ground and climb, and feed mostly on frogs and lizards. They are commonly called racers or loras, names frequently applied to snakes in other lineages. Philodryas eat a variety of vertebrate prey, and in a study of diet and habitat use of two species, Paulo Hartmann and Otávio Marques found the Eastern Lora (P. olfersii) in forest and forest edge habitats and was more frequently found off the ground in forests than the related species that was studied. It is this species that has been associated with the most severe rear-fanged envenomations in South America.
At least 43 bites have been reported from the Eastern Lora, and most produced minor bleeding and local swelling. However, in one case, several days after the bite, when the local symptoms had subsided, the victim had persistent severe dizziness, nausea, and vomiting. Bites from these snakes are often sustained on the hand by people working in gardens and agricultural situations and the symptoms are usually not severe, but several reports of children being bitten while they slept are in the literature. One human death is suspected of being caused by this snake, a 22 month old child who had been bitten several times on the arm. An experimental analysis of lora venom done by Alexis Rodríguez-Acosta and colleagues using mice showed proteolytic, hemorrhagic, and neurotoxic activities. The mice died within 15 minutes probably caused by respiratory paralysis suggesting this venom may be more dangerous to humans than previous studies suggest.
Maria da Graça Salomão and co-workers considered bites by dipsidid snakes (formerly part of the Colubridae) a public health problem in Brazil. In addition to P. olfersii, they listed Phalotris (a fossorial genus with about 14 species), Apostolepis (a fossorial genus with 33 species) and the False Water Cobra (Hydrodynastes gigas) as capable of delivering potential life- threatening envenomations. The aquatic snakes in the genus Helicops were reported to cause the largest number of snakebites registered in the Brazilian state of Rio Grande do Sul. Experiments with the “saliva” of Helicops were said to cause the death of a mouse in 10 minutes with spasms and distension of the hind legs. Helicops are fish-eating snakes, and when the venom was tested on fish decreased operculum movements and immobilization resulted in death in 30 minutes.

Tooth Structure Does Not Predict an Absence of Venom
During the 19th century, evidence that rear-fanged snakes were poisonous accumulated bit by bit. Not only did snakes with enlarged, grooved rear-fangs have venom glands, but some species with solid fangs also contained glands associated with their teeth. These were also venomous. So, what about snakes without fangs? Were they also poisonous? Thomas Huxley, the famous Victorian zoologist nicknamed “Darwin’s bulldog,” delivered a lecture at the London Institute in the middle of the 19th century and realized the need to suspend judgment on the issue when he said “We do not know for certain whether the ordinary teeth are poisonous or not….” 
In 1908 Albert Calmette, Director of the Pasteur Institute at Lille, wrote,

Non-poisonous as well as poisonous snakes possess parotid and upper labial glands capable of secreting venom. In the former the organs of inoculation are wanting, but we shall see later on that the toxic secretion of their glands is just as indispensable to them as to the snakes of the second category for the purpose of enabling them to digest their prey.

This was a remarkable statement for 1908 and it suggests that many herpetologists were not paying attention. Calmette attributed the discovery of these glands to Franz Leydig in 1873. Evidence that the nonvenomous-venomous dichotomy was wrong had been in the literature since 1873.
Huxley and Calmette were not the only persons suspicious that snakes lacking fangs may have been producing toxins. In 1916, W. M. Winton wrote,

The persistence of some rumors, and their confirmation in a few cases by medical men, gave him the idea that the presence or absence of the poison mechanism, grooved or tubular fangs and well developed poison sac, may not always serve as a criterion of the reptile’s potential venomousness.

As humans try to make models of nature, nature eludes us. The idea that snakes could be classified as non-venomous and venomous seems straightforward and simple enough but, like all models of nature, it is inaccurate.
Labels are important because they instantly convey a message that is quickly converted into an idea or mental image. “Harmless” is a label that has been frequently applied to colubrid snakes, and it is an accurate label, with some exceptions. In fact, some popular works written by well know herpetologists with post-1980 publication dates apply the name “harmless snakes” as the common name for the snake family Colubridae.  In a popular children’s book about snakes Hetch wrote, “There is no harm in a Hog-nosed snake.”  Now, in all fairness, it should be pointed out that hog-nosed snakes have a reputation for not biting humans; they are frequently kept as pets, and when they do strike their mouth is usually closed. Three species of hog-nosed snakes (Heterodon) occur in North America, and they have enlarged rear fangs that are solid and ungrooved. Just four years after Hetch’s snake book for children was published, University of Oklahoma herpetologist Arthur Bragg discovered there was at least a little harm and venom in the Western Hog-nosed Snake (Heterodon nasicus). Bragg had been handling spadefoot toads, and a few minutes later picked up a Western Hog-nosed Snake that bit his thumb. The snake had apparently detected the odor of its food on Bragg’s hand. Impressed with what happened, Bragg left the snake attached to his thumb and walked around the zoology building showing the event to his colleagues for 10 or 15 minutes. During this time of course the snake’s brain and sense organs are telling the reptile that it has a mouth full of food. Bragg cleaned the wound but 3.5 hours later noticed the hand was swelling. It remained swollen and sore for about a day, and he took this as evidence that hognose snakes are mildly venomous, an idea supported by later observations.
                Garter snakes (Thamnophis) compose a North American snake lineage that is common and widespread; many live in urban environments and have long been considered harmless by the general public and scientists. Even the most current field guides consider these snakes harmless; they have moderately long, solid-teeth, yet they, too, have venom glands. On May 3, 1975, Floyd E. Hayes was catching an Eastern Garter Snake (Thamnophis sirtalis) in Kent County, Delaware. The meter-long snake bit 13-year-old Hayes at the base of the right index finger. The snake did not release immediately, it stayed attached to the finger for about 10 minutes. During the next three hours the hand swelled at an alarming rate. By the following morning, the hand was cold and bluish in color and, Hayes was admitted to the hospital. Medical tests showed normal blood pressure, heart rate, temperature, and an x-ray showed the hand to be normal. The lymph nodes were slightly swollen and the right hand showed moderate edema and ecchymosis. Hayes was given cortisone, antihistamines, and antibiotics. The swelling was reduced the next day, but the inflammation of the lymph vessels showed discoloration along the entire arm. Hayes was discharged from the hospital in early afternoon. The diagnosis was listed as acute toxic or allergic reaction to garter snake saliva; there were no signs of infection. Slight swelling and discoloration were still evident five days after the bite.
There have been several poisonings from the bites of two garter snake species. These were a puzzle since children and adults throughout the continent catch garter snakes annually and many people are bitten.  If they had toxic secretions, why weren’t there more cases of envenomation?
An examination of the structure of the venom gland of the wandering garter snake revealed that it has a very small chamber for storing secretions; the cells lining this small chamber are mostly protein-producing cells which contain granules that hold the protein to be secreted, while the duct leading from the gland to the mouth contain numerous mucous cells. The study was done following reports of human envenomation by this snake and other evidence that suggested garter snakes have toxic oral secretions.
As the title of his 1996 article, Sherman Minton posed the question, “are there any nonvenomous snakes?” Minton concluded that species producing toxic molecules occur in almost all colubrid lineages and that these species are found throughout the world, use a variety of habitats, and have a variety of diets. He has a short list of snakes that he considered likely candidates for the title of “non-venomous” that included the ratsnakes, bullsnakes, and kingsnakes.  Minton included these because they are large, popular in the pet trade, and have a good record. That is, a good record of not delivering bites that result in envenomation. Many of these species bite readily when first captured and, because of their medium-to-large size, it seems probable that someone would have had a reaction and brought it to the attention of the medical community if they had toxic secretion. Furthermore, the ancient Greeks placed the open mouths of ratsnakes on human wounds that would not heal. This was a successful treatment due to the presence of molecules known as epidermal growth factors; molecules that promote growth in the tissue that form the lining in the snake’s mouth and upper digestive system. The isolation of an epidermal growth factor and its receptor in the Four-lined Snake (Elaphe quaturolineata), a widespread European rat snake, suggested injuries to humans could be healed by these molecules.

The Recovery of Toxicofera
Despite serious envenomations from some rear fanged snakes Schlegel’s idea that they were harmless persisted. The concept that two families of front-fanged snakes and a couple of lizards in the family Helodermatidae (the gila monsters and beaded lizards) were the only living venomous reptiles has been well accepted for most of the last two centuries, despite evidence to the contrary. As we have seen some snakes thought to be harmless to humans turned out not to be so harmless, even though they lacked the hypodermic needle-like fangs of the vipers, elapids, and stiletto snakes.
20th century studies of squamates described glands on the roof of the mouth, on the tongue, under the tongue, glands in the scales around the upper jaw, and glands under the scales around the lower jaw, glands around the teeth, and of course the lower jaw venom glands in the gila monster and beaded lizards, and the upper jaw venom glands of snakes. Some of these glands produce only mucus, but some produced both mucus and proteins, and some produced mostly proteins. Monitor lizards have a specialized mandibular (lower jaw) gland that has a lumen and one or more ducts and the anatomy suggested that this was a venom gland, an idea that dates to the 1960’s. Glands with chambers and ducts for carrying molecules into the mouths of iguanid, anguid and varanids lizards as well as the two species of heloderms, lizards traditionally considered venomous, were known. The glands were in the lower jaws of the lizards, as opposed to the upper jaws in snakes. And an article published in an obscure Russian journal in Turkmenistan in 1971 described injecting the product from the labial glands (upper jaws) of the Caspian monitor lizard into mice; the mice showed temporarily paralysis.
Walter Auffenberg studied the Komodo Dragon (Varanus komodoensis), locally known as the Ora, on its home island. These huge lizards inhabit just a few of the Lesser Sunda Islands in the Indonesian Archipelago, and Auffenberg’s work was the first behavioral ecology field study carried out on large reptile. Auffenberg was aware that monitor lizard bites had been reported to be poisonous, but was also aware that people bitten by oras developed sepsis and sometimes died from the infection. He observed Oras biting each other during fights, and knew that individual lizards sometimes died from these bites.  He also observed Water Buffalo with leg infections and edema from Ora bites delivered during attempts at predation.
Oras are generalist predators and, while large individuals will attempt to feed on large prey, they will take a wide range of food, including: carrion, crabs, lizards, birds and small mammals. The Ora has a mouth full of serrated teeth with the serrations on the posterior edge. When the lizard bites and pulls, the prey’s tissue is shredded, and the animal bleeds excessively. Auffenberg suggested bacteria living in the Ora’s mouth were responsible for the deaths of their larger prey, such as hogs, deer, cattle, and water buffalo. Large individuals sit and wait for prey and Auffenberg suggested that a Water Buffalo passing an Ora in ambush mode would have its leg severely bitten; the buffalo would be inoculated with the bacteria and the buffalo would wander off and die days later. However, Pleistocene fossil beds known from the islands did not contain the remains of deer, hogs, cattle, or Water Buffalo, the implication being that the larger mammals present on the islands today were recent introductions to the islands by humans. DNA studies of Sunda Island pig remains from archeological sites suggest pigs were present on Flores (also inhabited by the Ora) as recently as 7,000 YBP. This begs the question, what did Oras eat before humans and their large animals settled in Ora territory? It seems unlikely Oras evolved a large body size to be a scavenger. Auffenberg added significant interest to his story of the Ora by suggesting they once fed on miniature elephants, stegodonts, known from Pleistocene fossils in the Lesser Sunda Islands. The Ora’s scenario made for an interesting story that became popularized by the science media, but now, 40 years later, there is a new twist. 
Nicolas Vidal and S. Blair Hedges used nine nuclear genes that code for protein (a study previously mentioned in Chapter 2) and recovered a clade of squamates that consisted of the anguimorph lizards, the venomous gila monster and beaded lizards; the anguid lizards, glass lizards, alligator lizards, and relatives; the monitor lizards in the family Varanidae; the iguanian lizards (iguanids, agamids, and chameleons); and all snakes. The clade was well supported and suggested venom evolved only once in squamates. Previous authors suggested venom evolved once in the gila monsters and beaded lizards and at least once more, and probably several times, in the venomous snakes.
The idea that monitor lizards (Varanus) were toxic was further documented by observations made by Bryan Fry when he consulted on three monitor lizard bites. These were bites from three different species of captive monitor lizards (V. komodoensis, V. scalaris, and V. varius). In all cases there was rapid swelling (within minutes), dizziness, disrupted blood clotting, and shooting pains, symptoms that could not be produced by bacteria in just a few minutes.
Thus the ancestral molecules to venom evolved in lizards, including the lizard ancestor of the snakes. In a paper related to the Vidal and Hedges work, Fry and colleagues looked at the Bearded Dragon, a common Australian lizard, and a popular pet, as well other lizards in the Toxicofera clade. They found genes and toxic proteins that were shared between the Bearded Dragon and rattlesnakes. When they examined monitor lizards, they found even more genes coding for toxins and some were shared with venomous snakes.  This was surprising but not totally unexpected given that lizards were long known to be ancestral to snakes, and some lizards were long known to be venomous. Further work recovered nine toxins present in the ancestral venom. The molecules in the early toxicoferan’s oral toxic cocktail were clearly meant to disable prey by creating pain and lowering blood pressure to render the prey unconscious. The early toxins were probably not capable of killing prey outright, simply disabling it.
In order to qualify as venom, the toxins need to be actively delivered into the prey while poisons are passively delivered. Most amphibians are poisonous, but they are not usually considered venomous. And, most of the lizards and many snakes in the Toxicofera clade are not capable of actively delivering toxins to their prey. The precursors of venom in the toxicoferans may have had a purpose other than disabling prey; more on this in the next chapter.
The ancestral condition of squamate oral glands was seen in the iguanian lizards with lobed, protein-secreting glands in both the upper and lower jaws. Fry and colleagues consider the venom glands in the Iguania incipient and suggested they have little significance of the evolution or ecology of these lizards. The anguimorph lizard’s toxin-producing oral glands were mandibular (lower jaw) while the snake venom glands were maxillary (upper jaw), with most snakes showing a complete loss of the lower jaw glands. But, one snake species included in the study, the European Grass Snake (Natrix natrix), also had glands in the lower jaw. Because most snakes have an exceptionally elastic lower jaw, it seems likely that selection for enlarging the upper jaw (maxillary) venom glands was favored over a lower jaw venom gland. Swallowing large prey would have placed considerable pressure on glands in the lower jaw and the snake’s venom could have been lost, forced out of the gland when swallowing large prey.
In 2009, Fry and colleagues investigated the Ora for the presence of venom-producing glands and venoms. The research team found the Ora had a lightweight skull, with a relatively weak bite force (compared to a crocodile of similar size). The serrated teeth inflicted deep wounds. There was a large mandibular gland divided into six compartments with a duct leading from each compartment to the mouth. And they found, oral toxins that disrupted blood clotting, lowered blood pressure, induced painful intestinal cramping, and induced shock. All of this suggested that toxins were at work killing the varanid’s prey. Fry and colleagues also hypothesized that the giant (7 meter) fossil monitor lizard Varanus (Megalania) priscus was also venomous, a likely assumption.
Taking a step back to Chapter 3, to the aquatic Cretaceous lizards, the mosasaurs, and their smaller relatives, it seems likely they too possessed venom or at least toxic oral molecules. Some had elongated teeth, and some reached body lengths much greater than the 7 meter priscus. And, the morphology places mosasaurs, probably the sister to the monitor lizards, in the Toxicofera clade. Thus, mosasaurs are likely candidates for the largest venomous animals.
The fossil record of the late Triassic (about 200 MYA) revealed a reptile living in what is now Virginia (USA) that had teeth with grooves on the surface similar to those found in the venomous modern gila monster and beaded lizards (helodermatids). And, let’s not forget the venomous beak-head from Mexico discussed in Chapter 2. Unfortunately, that Triassic reptile from Virginia is known only from its teeth, and it’s not known if it was a squamate, a beak-head, or if it belonged to another group of reptiles.
Additionally, Enpu Gong and collegues report that the dromaeosaur raptor known as the Chinese-bird-lizard (Sinornithosaurus millenii) has grooved teeth, a pocket for a venom gland, and canal that leads from the pocket to the base of the grooved teeth. The authors suggest that this dinosaur was venomous and that it probably fed on birds in the Jehol forests of northeast China's Early Cretaceous.
Toxicofera is not yet resolved. Desirée Douglas and Úlfur Árnason examined squamate phylogeny by adding the entire mitochondrial genome from the blind-snake lizard Dibamus novaeguineae to the mitochondrial data set. They manipulated the data set by removing rapidly evolving sections of the genome from snakes to make the results less susceptible to artifacts from recent evolution. The result was a series of trees using different evolutionary models with a basal divergence that was not well supported. However, the trees usually did not differ significantly from each other, most showing snakes to be the sister to the Laterata clade, but one showed an Iguania-Snake clade similar to that recovered by Vidal and Hedges using nuclear genes. There will be much more to come on the status of Toxicofera.
Herman Schlegel’s narrow view of venom in reptiles created ideas that were widely accepted, but wrong, for more than 170 years. At this point, it appears that reptile venom is even older than the Toxicofera clade. And the question of a single origin for reptile venom or multiple origins remains to be answered. The fact that some lizard lineages, like the geckos and the skinks, apparently lack the glands and genes to make venom suggests the latter. But, as we will see, given the mechanisms by which venom evolved, the genes that were modified to code for venom molecules may be quite old. There is always more to learn and as evidence accumulates these views may well change.

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