Sloane Boukobza

Illustrations by Sophie Sieckman

Nature’s creations can be both harmful and beneficial in unexpected ways. The ruby red berries that you see on a hike through the woods may be lethally toxic, while the leaves hanging above you could be made into a salve for burns. In the natural world, there exists a stable yet complex equilibrium of heal and harm. As humankind evolved, we learned to harness beneficial features of nature: certain animal bones became our hunting tools, flint and rock became our firestarters, and venom became a therapeutic tool [1, 2]. Despite these origins, more recently we have strayed from using nature’s remedies and instead favor relying on medication synthesized in laboratories. Scientists have spent time and resources creating new cures for pain and disease when venom’s neurotherapeutic solutions may have been already lying at their feet — or rather, between the leaves, under the sea, and flying through the air above.

In pharmacies around the country, opiates are one of the most abundant forms of pain medication [3]. However, the societal devastation caused by opiate addiction has driven a search for alternative therapies. Meanwhile, research on neurodegenerative diseases — diseases marked by the deterioration of neural functioning — has plateaued due to the focus on therapeutic over preventative measures [4]. Animal venom research may be a fruitful path in determining pain relief alternatives to opiates and finding a cure for neurodegenerative disorders. Imagine: if wielded correctly, a snake’s sharp fangs may be your friend, a bee’s sting could benefit you, and a painful sea anemone could be much more than a dangerous bundle of tentacles. The venom from our friends of the sky, earth, and water might just be the key to a host of medical advancements.

Who Will Win the Race: Morphine, Snake Venom, or Pain?

Over the past 30 years, the addictive quality of opiates and painkillers has spawned an epidemic across the United States. Considering that 98% of patients are prescribed opiates following surgery, it’s no wonder the rate of opiate dependency has skyrocketed [5]. In 2017, the U.S. Department of Health and Human Services declared opiate addiction to be a public health emergency [6]. A five-point strategy was announced in an attempt to end the epidemic: (1) prevent and treat addiction, (2) distribute overdose-reversing drugs, (3) strengthen public data collection, (4) support addiction research, and (5) advance pain management research [6]. Unfortunately, the implementation of this strategy did little to calm the crisis: the number of overdose deaths by all opioids has increased six-fold from 1999 to 2017 [6]. However, while all eyes were focused on this mostly ineffective tactical plan, a scaly friend slithered into the limelight and bared its fangs to offer a solution.

Snakes of the Elapidae family, such as Indian spitting cobras and black mambas, are known for their potent neurotoxic venom [7]. Neurotoxic venom is composed of peptides (the building blocks of proteins) that disrupt the function of cells in the nervous system by either blocking signals between the brain and body or causing neuron death [8, 9]. As soon as a cobra bites its victim, venom is injected into the bloodstream; this paralyzes the respiratory system and kills the victim through lack of oxygen [10]. Peptides in venom vary between snake species, but thanks to these molecules’ large variation in shape and size, they are remarkably similar to proteins and peptides found in the human body [10]. This molecular overlap allows the venom to target and bind to specific neurotransmitter receptors in the human body [11]. Neurotransmitters are chemical messengers used to propagate chemical signals throughout the nervous system [12]. Similarly, neuropeptides act as signaling molecules that are secreted from neurons that communicate pain, fear, and stress to the body’s response systems; certain neuropeptides play an integral role in the body’s pain response [12, 13]. When we are injured, these proteins initiate a signaling pathway to the vital organ that causes our body to experience subsequent pain: the brain [13]. When venom peptides attach to these receptors, they saturate the receptor sites and prevent the pain-related neuropeptides from binding. With nowhere to bind, the peptides can no longer stimulate the pathways that cause us to feel pain [14].

Neuropeptides and receptors specifically fit each other, and can be thought of as a square block and a square hole. The neuropeptide releases a neural signal after slotting into place, like the sound that the block makes as it falls into the hole. However, when a snake bites down and injects venom into its victim, venom peptides block these neuropeptide receptors by filling the square-shaped hole themselves. Venom peptides act like a large piece of play-doh: molding to and sticking in the receptor site, they obstruct neuropeptides from binding to the receptor [14]. Because venom peptides adapt to obstruct a wide variety of receptors — for example square, circle, or star-shaped blocks — they can overwhelm the body’s large-scale communication pathways and lead to seizures and paralysis [15]. This is why black mamba venom can kill a human in less than 20 minutes [16]. In other words, a black mamba bite will bring death in the time it takes to watch an episode of Friends, but at least you won’t feel anything [16]!

Nipping Pain in the Bud: Snake Venom as a Safer Alternative Painkiller

What if the “no pain” factor could be isolated from potent mamba venom without the typical side effects of pain medications? Snake venom works similarly to painkillers, but is perhaps even safer; painkillers block receptors in the brain, but they generate a surplus of chemicals that sit in the brain rather than binding to the receptors [12]. When the painkiller wears off, the brain still feels like it needs to process the buildup of chemicals, causing withdrawal. This problem does not occur with the venom substitute: it specifically targets receptors that only activate select pain signaling pathways, so it doesn’t induce the unwanted side effects that opiates cause, making it a safer alternative [17]. Thus, snake-venom derived painkillers are promising replacements for the opioids that have plagued our society. However, the scarcity of snake venom makes availability and treatment development challenging [18].

Milking venom from a snake is a skilled task that cannot be replaced by machine or assembly line work [19]. The snake’s head must be guided to bite down through a latex film covering a glass vial to collect the venom, and the animal poses a constant threat, regardless of the snake handler’s experience [19]. Research has shifted towards stem cell therapy to replicate venom glands in snakes and address issues of scarcity [20]. Stem cells have the ability to differentiate many kinds of cells, including neurons, liver cells, and everything in between; these cells’ diverse set of potentials makes them incredibly useful in modern research [21]. In fact, when you were a developing embryo in your mother’s uterus, your body was almost entirely made of stem cells, and now you’re you! By culturing stem cells to mimic venom-producing glands, scientists have been able to grow three-dimensional artificial venomous glands to secrete the same toxic proteins as those found in a snake’s mouth [21]. Although it is still in the early stages of research, animal venom production with stem cells introduces the possibility of a safe and nature-derived alternative to the fraught standard of synthetic painkiller use.

Sea Anemones Are Not Our Enemies: Harnessing Venom for Chronic Pain Relief

In addition to acute pain, animal venom has also succeeded in relieving chronic pain. Opiates are commonly prescribed to calm the immediate pain of traumatic accidents, such as car crashes or sports injuries; however, the long-term use of these drugs can unfortunately lead to addiction, overdose, and death [22]. Unlike acute pain, chronic pain is caused by the abnormal, constant firing of pain signals from nervous system receptors which occur for weeks, months or years on end [23]. Over 60% of adults will experience chronic back pain throughout their lives, but a non-addictive drug treatment for the condition has yet to be developed [24]. This lack of advancement has once again driven us to creatively explore the medicinal applications of nature.

Perhaps to alleviate your chronic pain, you go for a swim in the ocean, admiring the seafloor as the buoyancy of the water takes away some of the pressure in your back. Looking down, you see hundreds of sea anemone tentacles wave with the current. It may seem hard to imagine that one of these sea anemones could be used to ease the limp in your step or the pain in your neck. However, out of the sea anemone Telmatactis stephensoni’s 84 different venom peptides, one dubbed U-Tstx-1 has the ability to block pain receptors. Much like snake venom, this peptide has the ability to relieve the exhaustive perpetual activation of neurons related to pain perception [25]. It does so by interfering with receptor binding: when a cell is stimulated by something binding to its receptor, it reaches a certain voltage threshold, then sends out an electrical signal to communicate. By blocking pain receptors, U-Tstx-1 makes it so the cell can’t reach a high enough voltage to fire, preventing pain signals from being processed in the brain [13].

Weaving between the toxic tentacles of the anemone during your swim, you see a lazy marine cone snail slowly making its way across the seafloor. These slow-moving snails also have potential applications to relieve chronic pain: they possess neurotoxic peptides called conotoxins, which have developed in many organisms to target specific parts of the muscular system controlled by your brain [26, 27]. The cone snail's venom consists of thousands of different combinations of peptides; because we can isolate each peptide and mix and match them for different purposes, this feature leads to great versatility in its research applications [26]. To mimic the complex composition of the venom, scientists choose a few conotoxin peptides to target specific receptors within the nervous system. To scientists, conotoxin venom is like a box of 10,000 lego bricks. If they put the bricks together by following the instruction manual the snail used, they create a highly dangerous venom. But if scientists ignore the snail’s manual and build other things with the bricks, they can create a plethora of other things that aren’t dangerous, and may even be helpful.

Currently, there are nine conotoxins in clinical evaluation for medicinal treatment. One FDA approved conotoxin, Prialt, has been made commercially available for severe chronic pain [28]. Prialt is injected into the spinal cord, where it blocks a specific pain-transmitting receptor and pain signals to provide significant pain relief [28]. As a non-narcotic pain reliever, Prialt creates no dependence, and is especially useful for patients with a tolerance to opiates like morphine [28]. Both sea anemone and cone snail venom peptides offer a plausible alternative to narcotic pain relief for the many Americans who will experience chronic pain in their adult life [25, 29].

Reptiles, Anemones, Bees… and Alzheimer’s Disease?

The experience of chronic pain is often coupled with aging and neurodegeneration [30]. Neurological diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease all exhibit illness-specific tangles in the brain [31]. Tangles are accumulated over time, and these lumps of proteins begin to act like neurotoxic knots, decreasing neuronal signaling and function in a process known as neurodegeneration [31, 32]. They work like a knot in a hose, blocking the flow of water. When the knot prevents water from reaching the sprinklers and watering the plants, they start to wither — just like how tangles affect neurons in the brain. In 2021, Aduhelm was introduced by the FDA as the first approved Alzheimer’s drug, and it claimed to deplete levels of the protein responsible for accumulation of tangles and neurodegeneration, amyloid beta [33]. Although the FDA gave accelerated, tentative approval for human use, the drug failed to replicate the striking clinical results produced in either of its two initial trial phases, sparking immense controversy [33]. Because of Aduhelm’s inefficacy and $100,000 annual cost per patient, researchers are now trying to find more successful, affordable alternatives to treat neurodegenerative disease.

While drugs like Aduhelm work to treat existing protein buildup in the brain, a better approach may be to prevent it altogether [34]. Some diseases, including Alzheimer’s, are caused by irregular compounds binding to neuronal receptors. Animal venom peptides can selectively bind to these targeted neuronal receptor sites before these disease-causing compounds can, ultimately preventing deterioration. You can think of this as similar to how your foot should slip perfectly into a new shoe, but won’t if the shoe still has cardboard inserts inside. These venom peptides act as “inserts” to fill the bonding site, which prevents the disease (your foot) from accessing it. Venom peptides could prevent the onset of Alzheimer’s instead of just slowing its progression [34].

Slowed glucose metabolism in the brain is another strong indicator of Alzheimer’s disease, and just like with protein tangles, animal venom may provide a solution [35]. Glucose metabolism levels indicate how much energy the brain uses at a given moment; about a quarter of the body’s total glucose is consumed by brain activity [36]. Previous attempts at preventing Alzheimer’s development by maintaining these metabolic levels have been unsuccessful due to neuroinflammation, which occurs when the brain attempts to protect itself from perceived harm, but hurts itself instead. The brain’s first line of defense (white-blood cells) misrecognize the metabolic treatment as dangerous and attempt to eradicate it, causing significant harm to the brain’s own tissue in the process. This inflammatory response can be detrimental to the brain by increasing the tangled and knotted proteins that cause Alzheimer’s – speeding up the progression of the disease [37]. There has yet to be a synthetic drug created to raise lowered glucose metabolism from Alzheimer’s, but nature can again provide a preventative approach through the maintenance of brain metabolism levels using bee venom [38]. This time, scientists used a protein found in bee venom that speeds up chemical reactions called bee venom phospholipase. Mice with mutations associated with Alzheimer’s disease that were administered bee venom phospholipase demonstrated better brain glucose uptake than those given a placebo of the venom — without the adverse inflammatory responses seen in past trials [38].

Scorpions Don’t Just Sting: They Prevent Neurodegeneration, Too

Accumulated misfolded protein tangles not only block signaling between neurons, but also launch a brain-wide immune response [37]. Misfolded proteins are treated similarly to potentially harmful material, and support cells in the brain warn the immune system of possible infection [39]. However, when immune cells release toxic chemicals in an effort to protect the brain, many neurons also get caught in the crossfire. Neurons in the area die off and are not able to be replaced due to their low rates of division, causing long-term, sometimes permanent, damage [39].

The natural world offers a potential solution to neuroinflammation, which occurs in diseases like Alzheimer's. Venom from the scorpion Buthus martensii Karsch (BmK) has been able to reduce neuroinflammation after brain injuries, so the venom’s peptides could also have an anti-inflammatory effect on the brain during Alzheimer’s [40]. A peptide from BmK scorpion venom can prevent microglia from sending out the alarm signals that cause neuroinflammation during Alzheimer’s disease — without killing them [40]. Once again, nature provides, and our venomous friends present a solution.

Nature’s biochemical complexity can help drive human scientific innovation in stagnant areas of research. As we learn more about the vast ecological systems and organisms inhabiting our planet, we can better harness and re-purpose the vicious powers of nature in the pursuit of healing. It’s becoming clear that the venom of snakes, sea anemones, and cone snails can help to eradicate opiate addiction from the treatment of chronic pain. Even age and its accompanying neurodegeneration, both seemingly inevitable, can be prevented by scorpion and bee venom. Neurotherapies derived from animal venom have given us the ability to explore the curative resources that nature has to offer and treat a variety of life-altering diseases. All we have to do is learn from our slithering, buzzing, and slimy friends.

REFERENCES

Animal Venom Neurotherapy Forges the Future Using the Past

Contemporary Cyborgs: How Neuroprosthetics are Changing Lives

Exercising Neurons: How Working Out Can Improve Memory & Neurodegeneration