Snake Venom in Medicine

(NOTE: This is a “semi-technical article”)

I have had a fascination with venomous reptiles, especially rattlesnakes, since I was a child. Kauffeld’s Snakes: The Keeper and the Kept galvanized this when I first read it at 12 years of age. What wonderful creatures they are—these amazing predators are a portrait of magnificence! However, to most people, they are the very embodiment of everything that is evil, and even among a small minority of herpetoculturists, there are those that harbor some level of disdain for these animals and the people who keep them. What possible good can come from venomous snakes? Yes, they are part of the food chain, and as such, do provide a measure of rodent control, but then so do many of their non-venomous cousins. Is there any real benefit to warrant any kind of sympathy or protection for these dangerous animals? The truth is the benefits to be gained far outweigh the dangers!

Throughout history, while most people feared these animals, there were those that revered them and some who seemed to realize that the very animal that was capable of destroying life might also be able to preserve it; in fact, the staff of Aesculapius (with the twin snakes wrapping around a staff) would end up becoming the symbol of healing and western medicine! Hippocrates, the forefather of medicine believed that fat rendered from the snake would aid in conception, this belief and others like it have followed down through the ages in the way of various medicines, charms and oils thought to cure all manners of ills. Shed skins were believed to retain some of the health benefits of the original snake.  They were used to treat a host of ailments, including backaches, sprains, and headaches. Even more bizarre was the idea in Pliny’s time that the shed skin could aid in childbirth because they represented the rebirth of the snake. Even the venom of these animals has long been considered a promising area of healing.  In China, denatured Cobra venom has been used as an analgesic for centuries (and continues today as a homeopathic remedy), and in the United States, Lederle produced a product for use in the “Control of Hemorrhagic Conditions” from the venom of the Cottonmouth. In a 1944 publication titled Snake Venom Ophthalmia, it was claimed that “Russell’s viper venom is a useful styptic for bleeding tonsils, tooth-sockets and epistaxis, but its greatest value is in haemophilia where the clotting time is reduced from days to minutes…[and that] a harmless substance capable of producing prolonged anaesthesia of the anterior segment of the eye would be of considerable value in inflammatory, conditions and after operations or other forms, of trauma, and the styptic effect of viper venom might also have its uses. Valle (1937) has treated painful ocular neuralgias, particularly in leprosy with conjunctival and retrobulbar Crotalus anavenene and claims immediate and lasting relief. Pradham and Patwardhan (1941) treated a case of recurrent vitreous haemorrhage with eight injections of 1/1,000 viper venom. Vision improved to 6/12 and the authors claim not only coagulation but absorption of clot and granulation tissue by cytolysins.” Whether these claims are true or not, it certainly informs us that throughout history, snakes and their venoms have been thought to have value for human maladies. Many of the “folk-medicines” have long since been determined to be ineffective, even though as late as the 1970s rattlesnake oil remained a popular all around curative in upstate New York and Vermont until legal protection was finally given to Timber Rattlers (Crotalus horridus). Despite the many mistaken avenues of treatment, tremendous pharmacological discoveries and medicinal breakthroughs have occurred through the study of the effects of venom on the various systems within the body, and a few of the “older” ideas, such as analgesics have been found to have merit.

In truth, the venom glands of these animals harbor one of the richest “protein biodiversity hot-spots” on the planet. Far from the idea that snake venoms fall into the two main categories of being either neurotoxic or hemotoxic, the complexity of most species’ venom is staggering! Here, in Southern California, the Pacific Rattlesnake (C.o. helleri) has a very rich diversity of venom constituents. A typical venom analysis will yield Bradykinen-precursor inhibitors, several small basic peptides, Crisps, a wide variety of Serine Proteinases, Metalloproteinases, Phospholipases A2, and L-Amonio Acid Oxidase, to name a few. Each of these has a very specific target, mode of action and effect. As I will attempt to illustrate throughout this article it is this specificity that is so important to the scientific and medical community and ultimately to humanity as a whole.

Venom in Pharmacology

Pharmacology is basically the study of how drugs affect us, and by extension, how poisons and venoms act. The study of pharmacology has also helped in the understanding of how various systems in the body work and some very important discoveries have been made as the direct result of studying the actions of venom on various systems in the body.

One such discovery was the isolation of a hypothesized nicotinic acetylcholine (nACh) receptor using alpha-bungarotoxin (from the Many-Banded Krait, Bungarus multicinctus). This was possible because of the extreme affinity of the venom to these receptors. This same property allowed researchers to determine the density of nACh receptors on the motor endplates as well as watch their synthesis in the developing skeletal muscles of fetal and neonatal rats. Another use for this wonderful toxin is its use to aid in the determination of drug interaction with these receptors! Finally, in the study of a disease that weakens the skeletal muscles, Myasthinea gravis, experiments using alpha-bungarotoxin revealed that it was an autoimmune attack that reduces the number of receptors—a very crucial insight! Another elapid neurotoxin, Dendrotoxin (from mambas), is used to characterize potassium channels which are part of the synaptic transmission process. These toxins have also helped in our understanding of the distribution of the various nACh receptors in different tissues thus, snake venom neurotoxins have a valuable role in helping us to understand the human nervous system and for this reason their value cannot be overstated.

Knowledge of the complement system, which aids in the destruction of bacterial invaders, has also benefitted from the use of snake venom. Cobra venom factor (CVF) was used to determine that there was a “third” component of the complement system (originally believed to consist of only two), and in fact, C3 is the name still employed today despite the fact that it is not actually the third part. CVF has been found to deplete the complement system, and this property has been used in various studies on the mechanisms related to activation of the system, by depleting the system the processes involved in its reactivation have been elucidated. By this method leucocytes were determined to be responsible for many immunological and inflammatory problems affecting our health, such as adult respiratory distress syndrome and immune complex disease. Though a better understanding leukocyte involvement, better treatment options can be devised.

Another class of venom constituents that have been proven valuable in pharmacology is the disintegrins, these proteins function by limiting platelet aggregation thus affecting blood clotting as well as inhibiting cell adhesion to each other in the body.  Disintegrins have been employed in the diagnosis of cardiovascular diseases due to their effect on the blood. They are also used to aid in the understanding of the interactions between cells and the extracellular matrix—in fact, the disintegrins found in the copperhead (Agkistrodon contortrix) inhibit cancer cells from adhering to the extracellular matrix and shows great promise for cancer therapies, if cancerous cells cannot adhere and form a mass they be dealt with by the body more readily!

Venom in Medicine

While at the Venom to Drugs conference in Australia, I was amazed at how few people were actually interested in snake venoms for medicine. The problem is that many of the components in snake venom are large, complex proteins (above 50 amino acids in length) that are difficult to synthesize in the lab. In contrast, cone snail (Conus sp.) venoms are made up of smaller molecules, and peptides (below 50 Amino acids in length), making their synthesis much simpler, leading to an emphasis on their use for pharmacological research. The problem with this trend is that cone snail toxins are generally fish specific peptides, and therefore, are more likely to have severe, unwanted side effects in man; however, many snake venoms are mammalian specific, which reduces potential complications. Generally speaking, the greater specificity of a protein, or peptide, leads to a reduction in secondary, unwanted side effects.

One of the greatest success stories for the usage of snake venom in medicine is Captopril. It is derived from the venom of the lance-headed viper (Bothrops jararaca) and acts as an ACE (angiotensin converting enzyme) inhibitor that prevents the conversion of angiotensin I to angiotensin II. Since angiotensin II acts as a vasoconstrictor, the reduction in the concentration of this enzyme results in vasodilatation reducing blood pressure and allowing needed blood flow.  Captopril had been used to combat hypertension, some types of congestive heart failure, and to preserve kidney function in diabetic nephropathy. This drug gained FDA approval in 1981, and is still widely used today resulting in millions of lives being saved worldwide and therefore should serve as a flagship example of the importance of preserving these animals!

Another very successful derivative of Bothrops venom is Reptilase. It is used to detect abnormalities in blood clotting, and is not affected by contamination from heparin, a common problem with other tests used. Reptilase has procoagulant activities and is used to detect abnormal fibrin formations which affect the clotting pathway. This enzyme has led to a test of clotting efficiency termed “reptilase time”, abnormalities in the clotting pathway can be diagnosed based on coagulation times. When the test is administered, if coagulation is delayed, the clinician then adds normal plasma to the sample, if the coagulation time returns to normal, it points to disturbance in fibrin polymerization in the blood

While Reptilase functions to stimulate clot formation, several drugs have been developed from venoms for the reduction of unwanted clots. Integrilin, a drug derived from the Dusky Pygmy Rattlesnake (Sistrurus miliarius barbouri), is a type of disintegrin that is prescribed to patients with unstable angina, and is often used in conjunction with other therapies such as aspirin to limit clotting. Ancrod, from the venom of the Malayan Pit Viper (Calloselasma rhodostoma), is effective in the earlier stages of stroke acting through its ability to cleave fibrinogen reducing clot formation. As a disintegrin this same chemical (from the copperhead, Agkistron contortrix) has been shown to be promising for cancer therapies because it also prevents adhesion of tumor cells to the extra cellular matrix. Cancer cells need to be able to attach to the extracelluar matrix in order to tap into the blood supply needed for tumor growth—without it, the tumors would starve!

Fibrolase, developed from the venom of the copperhead (Agkistrodon contortrix) is a metalloproteinase (a class of enzyme) that is also used to destroy blood clots. It was used successfully in the treatment of carotid blood clots in dogs, and thus shows promise for human usage. Another metalloproteinase from the Saw Scaled Viper (Echis carinatus), called Ecarin, is used in the detection of von Willbrand disease—a disease that prevents proper clotting, causing nose bleeds, abnormal menstrual bleeding, and bleeding of the gums.

Aside from the many cardio-vascular benefits to be gained through snake venoms, there are a host of favorable neurological properties as well. One of the most debilitating diseases that affect humans is Multiple Sclerosis (MS). It is widely thought that MS is the result of the person’s own immune system’s mistakenly attacking nerve cells. This autoimmunity is against the myelin sheath, the covering that aids in the transfer of electrical signals necessary for proper nerve function, and associated cells. It creates lesions in the white matter near the vesicles of the cerebellum, spinal cord, optic nerve and brain stem. With the loss of the myelin sheath, the conduction of electrical impulses is impaired and eventually lost. Over time, repeated “attacks” on the myelin sheath ( the fatty layer referred to as the myelin sheath), the oligodendrocytes (the cells that maintain and rebuild the sheath) cannot rebuild it, and scarring results after which a plaque builds up, resulting in the loss of proper nerve function. MS also destroys the oligodendrocytes themselves, further compounding the problem. Alpha-cobratoxin, modified via treatment with hydrogen peroxide (to “remove” the neurotoxic effects of the venom), has been shown to be a powerful immunosuppressive agent. It is currently in Phase II clinical trials for the treatment of this disease. Another interesting aspect of MCTX (modified cobra toxin) is that it binds to both the postsynaptic alpha-1 and presynaptic alpha-7 nACh receptors, thereby preventing apoptosis (programmed cell death), which is also a problem for MS patients, as it can occur with greater frequency then in healthy people. Because of the immunosuppressant qualities in cobra venom, it has also been used to aid with tissue transplants and cancer therapies.

There are many other venom components being tested for various diseases, even HIV! At this point, the message should be quite clear—the extinction of one of these venomous creatures could very likely become the extinction of a new, safe therapy for some debilitating disease, and it might be you or your loved ones that would have benefitted. Humans need to learn that any decrease in biodiversity results in a decrease of our own overall health and ability to find novel remedies. Venomous snakes serve their purpose in the food chain, both as food and consumers, but have proven to be even more valuable for bioprospecting!