What's your poison?

Snake venom has long been used to cure as well as kill. Now, scientists have found that even harmless species provide toxins of vital medicinal use

A hundred years ago, Rudyard Kipling explained to the world how the elephant got its trunk. Now, scientists in Wales and Australia believe they have written an important addition to the
Just So Stories, "How the Serpent got its Venom".

A hundred years ago, Rudyard Kipling explained to the world how the elephant got its trunk. Now, scientists in Wales and Australia believe they have written an important addition to the Just So Stories, "How the Serpent got its Venom".

Research into the origins of venom production has revealed that there are 2,200 species of poisonous snake in the world - 2,000 more than previously believed. New evolution studies by Dr Bryan Grieg Fry at the University of Melbourne show that almost all snakes share a common, venomous, ancestor, and hundreds of harmless species - previously thought only to produce "toxic saliva" - have been shown to produce true venom. It seems that even the most harmless species, such as grass snakes and rat snakes, possess a venom of similar complexity to those of their most deadly cousins, such as vipers and cobras, albeit in small quantities and without the apparatus to deliver it efficiently.

It is estimated that about five million people each year are bitten by snakes, resulting in about 125,000 deaths. A better understanding of the composition of venoms - and the way that venoms of snakes of the same species can vary - can help doctors to develop more effective antivenoms. Furthermore, venoms contain substances such as neurotoxins that can have powerful pharmaceutical effects, and can be used to create new medicines. Several treatments, including the widely used anticoagulant Arvin, have already been derived from components of snake venom. According to these findings, therefore, there are thousands more types of snake venom that can be used in medical research than previously thought.

"Snake venoms are complex mixtures of proteins. There can be as many as several hundred individual components in one venom," says Dr Wolfgang Wüster of the University of Wales at Bangor, who carried out the research with Dr Fry. "Some of the components might interfere with blood coagulation, others make blood vessels leaky, while others block the transmission of nerve signals - causing paralysis."

Scientists can use some of the components in venom to have a beneficial effect on the body. For example, some poisons reduce blood pressure so quickly that a victim dies instantly. By isolating and reproducing the relevant component in this venom, scientists can make a drug that reduces blood pressure. Moreover, drugs that imitate snake poison are fast and effective, because venom has evolved over millions of years to be fast and effective.

"We see the first recognisable snakes in the Cretaceous Period, about 100 million years ago," says Dr Wüster. "If we examine the evolutionary tree we see a series of branches that lead to the living primitive snakes." Of the 2,700 species of snake known today, about 500 are classified as primitive. "In the late Cretaceous Period, and particularly the Tertiary," continues Dr Wüster, "we see a radiation of evolution of the modern snakes, with about 2,200 new species evolving. These include all the strongly venomous species, as well as many non-dangerous ones such as rat snakes and grass snakes. In this group, venom is widespread and present in most species, whether they are dangerous to people or not. Clearly, for most snakes venom is integral to their natural history. For us, the interesting question is: when did venom evolve? Did it arise again and again in different lineages, or did it evolve only once at the base of the tree, and was retained in some species and lost in others?"

To find out whether all 2,200 species shared a common venom-producing ancestor, researchers examined the anatomy of snakes from different branches of the evolutionary tree, together with the composition of venom. "Many snakes possess a venom gland, but do not produce a lot of venom and do not have the anatomical apparatus to deliver the venom effectively," says Dr Wüster. "Some snakes produce venom but have only simple, small teeth that make only a shallow wound in their prey into which some venom might seep. The next level of sophistication is for snakes to have longer, grooved teeth at the back of the upper jaw. The venom can flow down the channels in the teeth. The most sophisticated system, which is seen in the vipers, consists of two very long tubular fangs that are hinged and can swing forwards. Venom is squeezed out of the gland by muscles and squirted into the prey."

When the researchers analysed samples of venom across a large number of species, from the marginally venomous to the highly dangerous, they found that harmless snakes of the genus Coluber, such as the grass snake, had complex venoms similar to those of the more venomous snakes.

"All the snakes seemed to have similar classes of protein in their venom," says Dr Wüster. "This strongly suggests that venom was derived from a common origin. If it had been reinvented several times throughout the evolution of different species, you would expect different families of protein in each venom."

The scientists then analysed the sequence of the amino acid chains that make up the proteins. "This is a technique called molecular phylogeny," says Dr Wüster. "We can compare the sequences against those held in databases that show the evolutionary origin of proteins. What we found was that if you look at the evolution of the venom proteins and superimpose it on the evolution of the snakes, they arrive at a common focal point in the past - the beginning of the radiation of the modern snakes. In other words, we have found strong evidence that venom evolved in the common ancestor of the modern snakes."

"This makes perfect evolutionary sense," adds Dr Fry. "There could not have been a strong selection pressure for the development of advanced pieces of architecture like fangs unless there was already a potent venom worth delivering. Therefore, venom preceded the fang just as the ability to make noise in the primates preceded the voicebox.

"The colubrids can still deliver the venom - they have teeth, after all," he continues. "Fangs were an improvement that allowed for greatly improved delivery into prey. The development of venom was therefore a key prey-capture adaptation in snake evolution and the fangs came much later."

The findings, however, have raised new questions. "What is in this venom in the colubrid snakes?" asks Dr Wüster. "There is a huge diversity of these snakes and, until now, they have been almost completely ignored from the point of view of their venom. We would like to know what is in these venoms - have they generated new families of toxins that might have potential medical applications?"

Meanwhile, the evolution of venoms continues within individual populations. "Often you find that closely related species of snake, and even snakes of the same species but in different locations, can have substantially different venoms," says Dr Wüster. In a pioneering piece of research, one of Dr Wüster's colleagues, Jennifer Daltry, collected venom from a large number of Malaysian pit vipers in the wild, together with records of the snakes' diet. Snakes in some localities fed mainly on reptiles, while those in others fed mainly on mammals; others ate both. Populations that had a similar diet had similar venom. "So the composition of the venom was being tailored genetically to the type of prey eaten," says Dr Wüster. "This strongly suggests that natural selection is at work, and would account for populations of the same species having radically different venoms."

Intriguingly, it seems that it is not only snakes that evolve to deal with their prey: there is evidence that prey evolves a resistance to venom, too. "For example, one species of amphibious snake called the sea krait feeds on moray eels," says Dr Wüster. "In areas where morays are preyed upon by kraits, the eels have developed resistance to the venom. An eel from a population that is not routinely preyed upon by the snake can be killed by a tiny amount of venom, whereas one from a population that is routinely preyed upon requires a thousand times more. In the same way that snakes must adjust the composition of their venom to best suit their prey, the prey itself can evolve resistance. What seems to be going on is an evolutionary arms race, whereby beasts of prey are evolving resistance and the snakes in turn adjust the composition of their venom to make it more effective."

Dr Fry has also made advances in analysing the genetic structure of venom. While studying the development of venom, he found that, rather that being derived from saliva, 21 of the 24 known snake-venom toxins were found to have derived originally from proteins normally expressed in other body tissues, including the brain, eye, lung, heart, liver, muscle, mammary gland, ovary and testis. He says: "By recruiting and tweaking proteins from other body tissues, snakes developed a clever mechanism for creating more specific and highly potent toxins, ones that would cause their victims' bodies to turn against themselves upon injection." This discovery, too, has implications for the medical scientists. Armed with the information that particular proteins in snake venom come from different areas of the body, they can look at that area when working out how the protein was originally produced. They have a starting point in the long process of deciding how to reproduce the beneficial component of the poisonous venom.

"There is something peculiarly fascinating in the use of a deadly toxin as a life-saving medicine," says Dr Fry. "The natural pharmacology that exists within animal venoms is a tremendous resource waiting to be tapped."

A VENOMOUS HISTORY

The use of snake venom in medicine was pioneered by Dr Alistair Reid in the 1960s and 1970s. While he was investigating the effects of snake bite in groups of people bitten by the Malayan pit viper, he found that it was extremely difficult to stop bleeding in affected patients. Dr Reid demonstrated that this was due to the effect of venom on clotting agents, fibrins, in the blood. Scientists were able to isolate the anticoagulant components in the venom, and the resulting drug, Arvin, has been used clinically since 1968.

"The benefits of snake venoms for heart patients are well-known," says Professor Sir Charles George, medical director of the British Heart Foundation. "They led to the introduction of ACE inhibitors that lower blood pressure."

New research is taking place in Oxford, Birmingham and at the Alistair Reid Venom Research Unit at the Liverpool School of Tropical Medicine intoisolating substances in snake venom that inhibit the action of platelets in the blood and prevent clotting.

Alice Fordham

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