Making Medicine from Venomous Snakes

This article was originally published on the National Institute of Health Animals in Research web site and is reproduced verbatim.

Snake-Venom-250pxWithin minutes, the bites of rattlesnakes, cobras, pit vipers, or other poisonous snakes may cause you to have severe burning pain and swelling at the bite site. This local reaction may quickly be followed by a severe drop in blood pressure or paralysis that causes you to collapse, and have extensive bleeding everywhere in your body, with major bruising spreading from the bite, and blood escaping from your nose and mouth. Without treatment, you may die.

Knowing all this, you would think medical researchers wouldn’t want to come close to these poisonous snakes, or the deadly venom they produce in their saliva and eject out of fangs. But poisonous snakes are the prized research animals for some scientists searching for better treatments for such disorders as high blood pressure, heart disease, stroke, Alzheimer’s disease and cancer. These investigators think that the very proteins that make snake venom so deadly, may, in the right amounts or with the right changes, be healing for millions of Americans. (And fortunately, researchers don’t have to wrestle with the snakes themselves, thanks to facilities, such as the NIH-funded serpentarium of the Natural Toxins Research Center. These centers send scientists the venom they “milk” from poisonous snakes they raise on site.)

Before you shake your head in disbelief, think about how snake venom works. What makes the toxic saliva of snakes so deadly is its knack for hitting on key pathways the body uses to keep its blood flowing and nervous system acting properly. These are the same pathways that many diseases also disrupt, but in the opposite way. For example, strokes and heart attacks stem from blood clots. So the same snake venom proteins that cause some people with snake bites to bleed to death by preventing or dissolving blood clots, may, in small doses, be safe and effective treatments for a stroke or heart attack.

In fact, there are already two drugs on the market that are based on snake venom proteins and are used to prevent heart attacks. One drug, called eptifibatide, is a modified rattlesnake venom protein. The other is called tirofiban and is based on a venom protein from the African saw-scaled viper. Both drugs have been used since 1998 to treat people having minor heart attacks or those with chest pain indicating they are likely to suffer a heart attack.

These people with chest pain or minor heart attacks usually have what is called coronary heart disease. This disorder stems from a buildup of a substance called plaque on the insides of the heart arteries (coronaries). The plaque makes it more likely for blood clots to form inside the arteries and block blood flow to the heart. When blood flow is severely blocked, a heart attack happens that causes some heart cells to die because they are not getting the oxygen they need from the blood. Coronary heart disease affects millions of people in the United States and is the single largest killer of Americans—about every minute someone will die from a heart attack in this country.
Another common disease caused by blood clots is stroke. Most often, stroke occurs when blood flow to the brain stops because it is blocked by a clot. The brain cells in the immediate area begin to die because they stop getting the oxygen they need. Stroke damage in the brain can affect the entire body and cause mild to severe disabilities. These include paralysis, problems thinking or speaking, and emotional problems. Each year in the United States, there are more than 700,000 strokes, which is the third leading cause of death in the country.

Jungle Medicine

Doctors can use clot-busting drugs to treat stroke patients. But these drugs have to be used within three hours of the start of the stroke to be effective. Many people don’t realize they are having a stroke at first, so they do not make it to the hospital in time to receive theseSouthern-Copperhead-200px drugs. That may soon change thanks to the work of investigators who have biochemically combed the venom of the Malayan pit viper to discover its deadly secrets. This particularly touchy, reddish snake with black triangles has long fangs that readily release its toxic saliva to victims that happen to step on it while traipsing through the jungles of Southeast Asia. The medical potential of this snake’s venom first came to the attention of physician Dr. Hugh Alistair Reid in the 1960’s, when he treated patients bit by the snake at Penang General Hospital in Malaya. Impressed by the venom’s ability to foster bleeding, he suggested it might contain something that could be used to treat troublesome blood clots.

Researchers are currently conducting a large international study to test the effectiveness of small amounts of a Malayan pit viper venom protein in treating stroke. The protein, which is called ancrod, seems able to dissolve the blood clots that cause stroke for as long as 6 hours after stroke symptoms start. Ancrod can also prevent new blood clots from forming, studies suggest. It is already used in Europe to treat patients with deep-vein blood clots or to prevent problematic blood clots from forming after certain surgeries or procedures. Investigators are also testing other snake venom compounds for their effectiveness as clot busters, including a protein from the southern copperhead snake.

The first drug derived from snake venom, and one of a widely used group of drugs for treating high blood pressure, owes its origin to the Brazilian pit viper. Workers in the banana plantations of southwestern Brazil were known to collapse suddenly after being bitten by this snake due to a drastic drop in blood pressure. Curious about what exactly this venom does to the body, Brazilian and British researchers studied its effects in animals. These scientists discovered a protein in the venom that blocked the action of a compound called angiotensin-converting enzyme (ACE), which the body uses to keep blood pressure at the right level.

American researchers then concocted a protein similar to the venom protein to create one of the first of many ACE inhibitor drugs to treat people with high blood pressure. These drugs, which debuted in the 1970’s, cause the fewest side effects of all blood pressure drugs, and have added benefits beyond lowering blood pressure—they also stem the risk of developing diabetes, stroke, heart failure, and kidney disease. High blood pressure is a common and serious problem that affects more than 50 million adults in this country. Half of all middle-aged and elderly adults need to take blood pressure medication to prevent heart and kidney disease.

Cancer-fighting Proteins

More recently, researchers have begun exploring the potential cancer-fighting properties of certain snake venoms. Most cancers do not become deadly until they spread via blood vessels to new sites in the body. That spread depends on the cancer cells’ ability to grabBlood-Elements-200px onto neighboring normal cells and prompt new blood vessels to sprout and supply them with the nutrients they need to grow. These blood vessels also provide the highways the cancer cells need to travel to new sites in the body.

While assessing how a protein in the venom of the southern copperhead snake prevented blood clots, biochemist Dr. Francis Markland of the University of Southern California in Los Angeles discovered it worked by preventing tiny blood disks called platelets from latching on to each other. This bunching together of blood platelets is needed to form a blood clot. He reasoned that if the venom protein prevented platelets from attaching to each other, it might also prevent cancer cells from spreading by attaching to adjacent cells.

Dr. Markland’s suspicion was confirmed by laboratory studies that revealed a surprising double whammy–the venom protein, called contortrostatin, not only prevented cancer cells from attaching to other cells, but it also prevented them from producing the signals that prompt new blood vessels to sprout and support the spread of the cancer. Encouraged by these findings, he and his colleagues tried the compound out on mice with implanted breast cancer tumors and it stemmed the spread of the cancer to the lungs by a remarkable 90 percent, and reduced new blood vessel formation by nearly the same percentage.

Because controtrostatin comprises less than a tenth of a percent of snake venom, Dr. Markland used genetic engineering to coax bacteria into making the protein. He then encased this bacterial protein in a fat molecule to allow for easy transport in the body to tumors, where its anti-cancer baggage will be released. With financial support from the National Cancer Institute, one of the 27 Institutes and Centers that make up the National Institutes of Health (NIH), he is currently testing this potential cancer drug in animals. If those tests go well, testing the compound on women with breast cancer will be the next step.

Scaling Brain Disorders

The paralyzing effects of the venom of African mamba snakes can be so powerful that bites from these snakes have been known to topple giraffes and lions, and can kill a person within 20 minutes. But that hasn’t stopped biochemist Dr. Krishna Baksi of the Universidad Central Del Caribe in Puerto Rico from working with the venom of these snakes. With funding from the NIH National Institute of General Medical Sciences, Dr. Baksi is trying to figure out what enables proteins in the mamba venom from latching on so tightly and specifically to certain structures called receptors, which jut out of the surface of brain and nerve cells. The brain uses certain kinds of these receptors to receive the chemical signals that let it learn, form memories, perceive pain, and do many other functions. Nerve cells use the same receptor type to pass on signals to neighboring muscles that trigger them to contract or stay at rest, and affect breathing and heart beat rates. There are five known subtypes of these receptors, each of which are thought to play a role in various diseases, including asthma, Parkinson’s disease, Alzheimer’s disease and certain pain disorders. So researchers are eager to find drugs that can alter the actions of these receptors.

But their efforts have been hampered by an inability to find compounds that act specifically on only one type of receptor–you don’t want a drug that acts on the receptor involved with Alzheimer’s disease if you have Parkinson’s disease, for example. And that’s where the mamba snake comes in. Its venom has proteins that are highly specific for which receptors they will latch on to. By studying the structure of these proteins, Dr. Baksi hopes to have results that drug makers can use to design new and more selective drugs for a wide range of neurological disorders.

Many more researchers continue to study the usefulness of snake venom in medicine. So, the next time the mere mention of a poisonous snake sends shivers down your spine, think again—the proteins in the venom of that snake may someday save your life.

References

Finn, R. (2001) Snake venom protein paralyzes cancer cells. Journal of the National Cancer Institute, 93(4), 261-62.

Minea, R., Swenson S, Costa F., Chen T.C., & Markland F.S. (2005). Development of a novel recombinant disintegrin, contortrostatin, as an effective anti-tumor and anti-angiogenic agent. Pathophysioogy of lHaemostasis and Thrombosis, 34(4-5), 177-83.

Krishna, B. (2002). Structure Function relationship of muscarinic toxin MT. Retrieved from http://crisp.cit.nih.gov/crisp/CRISP_LIB.getdoc?textkey=6436341&p_grant_num=2S06GM050695-080016&p_query=(toxin)&ticket=54141676&p_audit_session_id=285710852&p_audit_score=91&p_audit_numfound=2&p_keywords=toxin

Patlak, M. (2003). From viper’s venom to drug design: treating hypertension, FASEB Breakthroughs in Bioscience. Retrieved from http://www.fasebj.org/cgi/reprint/18/3/421e.

Rosamone, W., Flegal, K., Friday, G., Furie, K, Go, A. , Greenlund, K et al. (2007). Heart disease and stroke statistics—2007 update. Circulation, 115, 69-171.

Hawgood, B.J., & Reid, H.A. (1998) OBE MD: investigation and treatment of snake bite, Toxicon, 36(3), 431-46.
Sherman, D.G., & Ancrod, C. (2002) Current Medical Research and Opinion.. (18), 48-52.

Medscape Medical News. (2000). Ancrod shown to have favorable effect for treating acute stroke.
FDA. Integrellin consumer information. Retrieved from http://www.fda.gov/cder/consumerinfo/druginfo/INTEGRIl.HTM

Additional Sources

BBC News Online Network, Scientists target breast cancer with snake venom, August 26, 1998, accessed at http://news.bbc.co.uk/1/hi/health/159054.stm

CNN.com, FDA approves ‘super aspirin’ for certain heart patients, May 15, 1998, accessed at http://www.cnn.com/HEALTH/9805/15/super.aspirin/index.html

Lake, Stan, Pit vipers: friend or foe?, The Cold Blooded News, newsletter of the Colorado Herpetological Society, Vol. 32, No. 4; April 2005 and accessed at http://webspinners.com/coloherp/cb-news/Vol-32/cbn-0504/PitVipers.php

Natural Toxins Research Center, NTRC Kids, accessed at http://ntrc.tamuk.edu/kids.htm

Natural Toxins Research Center, NTRC Snakes, accessed at http://ntrc.tamuk.edu/download.htm

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