A Viper’s Nest of Treasures

First published in the NASGP Newsletter in September 2018
Since the antihypertensive captopril went on the market in 1981 captopril has probably saved many more lives than have been lost to the venom of pit vipers from which it was derived.

I’ve watched snake charmers capitalising on our fear of snakes, and I have observed blood trickling for an hour from my leg where a leech had fastened itself, but I have only ever seen one venomous snake in the wild. Walking along a Cornish beach after a weekend on call, I came across an adder sunning itself on the sand. In Britain the only deaths from snake bite in the last 40 years have been from exotic pets. But, as makers of horror films know, snakes alarm most people, a response which may have proved evolutionarily advantageous for our forebears.

Some creatures are merely poisonous – passively producing a toxin to defend themselves, for instance, when you tread on them. A venomous beast is one which actively wounds another animal and inserts a toxin designed to achieve its aim of acquiring a meal. Apparently, we are never far from one. Most phyla in the animal kingdom have venomous members, even mammals. The slow loris is cuddly-looking, but if you are tempted to hug it when it stretches out its arms, be aware a venom gland in its elbow produces a nasty allergic reaction.

Few, if any, animals evolved their venom to attack humans; we are collateral damage in an evolutionary arms race. There are no accurate statistics, but venomous snakes probably kill more than 100,000 people every year and 400,000 undergo amputation. Deaths due to scorpions, already high, are likely to increase now that they have discovered the advantages of city living.

Few, if any, animals evolved their venom to attack humans; we are collateral damage in an evolutionary arms race.

The venomous animal overwhelmingly responsible for most deaths is the malarial mosquito. But it isn’t just blood feeders that use anticoagulants and analgesics. Venoms are a mixture of hundreds of compounds, each of which is tailored to meet the attacker’s objective. Add vasodilators and hyaluronidases and venom will more easily reach its target.

No wonder that man has used venomous animals to his own ends, from ancient tribes in Iraq who threw pots of scorpions at their enemies to radical pastors demonstrating God’s power, and their own, by handling rattlesnakes – until the rattler demonstrates its power by biting them. No wonder that most cultures have traditional remedies – ineffective and some downright dangerous. And modern snake oil salesmen still sell protection and treatment.

Inevitably rural people in poor countries suffer most, because their lifestyle exposes them to venomous animals. Health services are a long way off and an appropriate antivenom, even if available, is prohibitively expensive. Antivenoms are now on WHO’s list of essential medicines, and, in response to pressure from affected countries, envenoming has been raised to the status of a neglected tropical disease. But however sound WHO’s advice for managing the problem, for many countries implementation is unrealistic.

To produce an antivenom, you need the venom. There are well-established techniques for milking snakes, but how do you obtain venom from small sea creatures? Then, you have to analyse those hundreds of compounds. Then, making the antivenom currently involves injecting horses and collecting the immunoglobulins they produce. Testing the antivenom isn’t straightforward either, because what kills a human may not damage other animals. Add the problems of cost and the distribution of appropriate antivenoms to areas where venomous snakes abound.

Making antivenoms isn’t profitable, but venoms are a treasure trove for scientists and, as captopril shows, a potential goldmine for pharmaceutical companies. Probably more than quarter of a million species are venomous. Where to start looking? At victims’ sufferings and deaths, and at traditional communities’ use of animal toxins. These days traditional knowledge is protected, at least in theory, by biopiracy laws.

The sodium channel blocker tetrodotoxin has been invaluable in research on nerve conduction since the 1950s. One source is the pufferfish, a popular delicacy in Japan where chefs require a licence to cook it. (Even so, one professor of physiology declined to taste it.) Calcium channel blockers from spider venoms are a tool in cell membrane studies. And kraits have aided neuroscience research as the α-bungarotoxin in their venom binds to nicotinic acetyl choline receptors at the neuromuscular junction.

More generally, studying how venoms achieve their aims can help us understand the pathways involved and so design better therapies. And much might be learned from studying the ingenious devices that animals have evolved to penetrate cuticle, hide or scales to insert venom into their victims.

Even when a compound in a venom has been characterised and revealed potentially clinically useful properties, there is a long road to develop a safe and effective medication. But some drugs have made that journey. The glucagon agonist exenatide was developed from a chemical in the venom of the Gila monster, a New World lizard. Eptifibatide, derived from an anticoagulant in the venom of a rattlesnake, and tirofiban, from saw-scaled viper venom, are i.v. antiplatelet drugs. Some patients with severe chronic pain benefit from intrathecal ziconotide, developed from cone snail venom.

There is a lot of interest in exenatide’s neuroprotective effects for Parkinsons Disease, cobra venoms for multiple sclerosis, motor neurone disease and cancer, and a sea anemone neurotoxin for psoriasis. Bee venom penetrates the blood-brain barrier so could be a vehicle for therapies. So does chlorotoxin, a paralytic in the venom of the aptly named deathstalker scorpion, and it shows a preferential attachment to glioma cells. With a fluorescent marker attached, it is undergoing phase II clinical trials of its potential as a diagnostic aid and a guide for the neurosurgeon’s scalpel. And a spider venom constituent which induces priapism could lead to a treatment for erectile dysfunction.

The tiny emerald cockroach wasp has perhaps the most disturbing modus operandi. It turns its much larger cockroach victim into a zombie, alive but passive, which can be led by its aggressor to its nest and where it lays its eggs in its victim to serve as a living larder for its larvae. It’s not, I trust, the horror story scenario that fascinates scientists, but the zombie state it produces. It resembles encephalitis lethargica, so the wasps’ venom might provide shed light on dopamine and other pathways which are affected by movement disorders.

The research is expensive and challenging. Being peptides, most toxins are broken down by digestion, so they need substantial modification before they can be used orally. But, venomous animals are a source of unlimited opportunities for medical development. Like the snake charmer’s cobra they excite our awe and fear. But let us, safe in Britain, not forget those for whom venomous animals are a daily threat. They need antivenoms.

The Natural History Museum’s website has information and links about venomous animals.