Venom: Not Just a Poison

Decades of research into the compounds that make up snake venom has led to some startling discoveries

Cobras can be deadly, but perhaps they could save you, too.     Photo: Srinayan Puppala/Flickr

Some think venom could prove the key component in new drug therapies aimed at slowing or halting cancer’s advance without as many side effects.

Humans have worshiped snakes for thousands of years. In Ancient Egypt the Nile Cobra adorned the crown of the pharaoh. In Ancient Greece they could be found in many medical symbols, some of which we still use today, such as the Rod of Asclepius. Further East in India, snakes have their own festival; Nag Panchami is a day when snakes are venerated for their power over the rains. The snake even has its own spot on the Chinese zodiac. And in non-Eurasian cultures, snakes were welcomed in Peru and Mexico, where they were revered as mortal forms of the gods. But the snake’s image hasn’t always been so positive. In Judaism and Christianity, it often represents sin, evil, and the devil.

One of the most well-known symbols of the snake is the Ouroboros, which is an image of a snake eating its own tail. Said to represent the cycle of life, death, and rebirth, the Ouroboros may seem like an anachronistic symbol, but it’s quite fitting; the snake, if recent studies are to be believed, may soon resume its honored place in the history of medicine.

A protein called eristostatin, taken from the venom of the Asian Sand Viper, could be helpful in the fight against melanoma and other cancers, according to a study published this year by Toxicon, the journal of toxicology.

“I was drawn to the idea of using a component in venom, something most people think of as deadly, to combat cancer,” said Dr. Stefan Hailey, a student working on his Masters when he co-authored the study back in 2010. While all of the components of venom taken together are lethal, individually they can be quite beneficial.

Disintegrins, proteins found in the venom of many vipers, for example, act as binding partners to integrins, which play a large role in several different cellular processes. Hailey and his colleagues found that eristostatin, one of those disintegrins, which normally bonds to platelets in a snake’s victim and carries toxins throughout the circulatory system, also bonded to melanoma cells in mice and kept tumors from metastasizing into other parts of the body.

Hailey’s finding isn’t the result of some lucky guess, though; it is the culmination of research that began in the middle of the 20th century. Hailey’s adviser and a co-author on the Toxicon study, Dr. Mary Ann McLane, has been studying the potential benefits of snake venom since the 1980s under Dr. Stefan Niebiarowski.

“Stefan was the best example of a scientist,” McLane said. “He noticed differences that others might not, he always questioned what he didn’t understand, he was adept at creating scientific experiments out of his hypotheses, and, most of all, he was a collaborator.” Niebiarowski was interested in how different snake venoms affected victims differently. Some induced paralysis, while others induced circulatory collapse.

In the late 1980s Niebiarowski began working with Chinese researchers on breaking down the components of snake venom and their effects. Using new techniques in atomic force microscopy, he and his partners found out that venom was made of many different proteins and molecules, including the aforementioned disintegrins, neurotoxins, and hydrolases.

After McLane left his tutelage she continued studying snake venom in order to better understand the beneficial proteins that could be isolated. While McLane and others have made leaps in their working knowledge of the proteins, “We still don’t really understand how they work,” she said.

Dr. Stephen Mackessy, a biology professor at the University of Northern Colorado and a snake expert, helped explain to me what we do know. The snake uses regulatory compounds found in other body systems—many of which are also found in humans, but at lower doses that are much harder to activate and then isolate—to make its venom. When the snake injects that venom in high quantities, it is deadly, but in small doses it is a scientific goldmine.

The snake survives the toxicity of its own venom by storing it in highly acidic glands that neutralize the various compounds. These compounds remain neutral until the snake bites its prey. Since most animal bodies keep themselves at a neutral pH, the venom’s dangerous components are able to do their damage once the snake injects its poison.

Scientists have primarily focused on two types of venomous snakes: front-fanged snakes, such as cobras, and the viper family. Theses two groups are the subjects of most research because they are large enough to produce quantities of venom that scientists can easily break down into its molecular parts and study. Mackessy is also interested in looking at the production of venom in smaller snakes. He says they might have completely different proteins—but all of that remains largely unknown.

Lyre snakes present an interesting example of this. Their venom is similar to that of a cobra but very small differences make it non-toxic to humans. It is only toxic to birds and lizards and thus has not received as much attention.

There are other factors that have slowed the study of venom as well, namely money. “To produce these drugs costs many millions of dollars,” McLane said. First, she needs to get interest from pharmaceutical companies with the necessary capital. According to Mackessy, this is the hardest part. The creation of a new drug from discovery to marketing takes, on average, 10 years. It can be hard to convince anyone to invest with no hope of return for over a decade. Drugs fail all the time, but what many people don’t know is that a single drug’s failure could lead a company to bankruptcy.

Once testing is finally in progress—if the protein still shows promise, which is, of course, not guaranteed—scientists must find a way to get the human body’s immune system to accept the compounds. Snakes typically inject these proteins so quickly and at such a lethal dose that the body does not have a chance to resist it.

If doctors were to inject these compounds at lower doses into humans, however, they might produce a positive interaction—but the body would still recognize them as foreign proteins and create antibodies to destroy them. The body would build up a resistance even if the compounds were acting beneficially, and doctors would have to use higher and higher doses to overcome the reaction, which could, in turn, produce negative consequences.

McLane said the best option would be to isolate the active components and have pharmaceutical companies synthesize them artificially. Using recent advances in nanomedicine, doctors could attach the protein to a normally inactive protein in the body, which could then activate itself once it enters the bloodstream. Unfortunately, this isn’t anything like cutting and pasting on your computer. The complicated science is still in development.

Advances in medicine in the fight against bacteria have typically focused on the use of helpful bacteria or fungi to destroy invading bacteria. Unfortunately, these methods haven’t proved as promising in the fight against terminal illnesses like cancer. Traditional radiation therapies produce so many negative consequences for cancer patients that they can almost be worse than the disease itself. “Right now modern medicine is like trying to set your wristwatch with a shotgun,” Mackessy said. “It’ll do more harm than good.” But venom, some think, could prove the key component in new drug therapies aimed at slowing or halting cancer’s advance without as many side effects.

This isn’t, though, the only potential good to be found in the venom of snakes. “Because venom is slightly different from one species to the next, there are numerous components that will most likely have an important role in medical innovation as they are discovered and as therapies become more personalized,” Hailey said. According to McLane, every species of viper has its own version of disintegrins and while there is lots of similarity, the subtle differences can have huge impacts on how they operate. Rattlesnakes, part of the viper species, produce a protease called bradykinin, which acts as a vassal dilator and can cause death in high quantities. But instead of looking at the negative effects, scientists like McLane and Mackessy see the potential to do good. They believe bradykinin could help people lower their blood pressure and also act as an anti-coagulant to be used in surgeries or during recovery for patients.

And research continues to turn up potential new benefits. Hannalgesin, a neurotoxin found in the venom of the King Cobra, has morphine-like properties, but Kini Manjunatha, a professor of biology at the National University of Singapore, has shown in studies that it can be 20 to 200 times as effective as morphine without causing neurological or muscular deficits. An added bonus is that it can be taken orally, whereas morphine must be injected. Manjunatha expects to start clinical trails this year or the next.

Hailey is convinced that venom could be the no-longer-missing key to spectacular innovation in his field. As medicine becomes more and more personalized, doctors will be able to use different proteins to treat specific aspects of a disease. The amazing biodiversity of proteins found in snake venom could contribute to a larger understanding of our own bodies as well as disease itself.

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