Petrifying Fear: Seeing Medusa

Hair of venomous snakes and a gaze that will turn you into stone. Medusa by Carlos Schwabe

A snake lurks in the grass

Some 50% of the world’s population reports being afraid of snakes. About 3% has snake phobia: An extreme, paralyzing, and persistent fear called ophidiophobia, from ophis, the Greek word for snake. It is a primal fear that is expressed in various mythologies. Medusa’s hair of living snakes in Greek mythology keeps people away from her and underscores the terrifying and repulsive monstrosity of the previously attractive girl. In ancient Egypt, the giant serpent deity Apep embodied chaos and was the sworn enemy of the sun god, Ra. In the Jewish myth of the Garden of Eden, the serpent reveals the truth about the Tree of Knowledge and seduces Eve, who does not know good from evil, to eat its fruit. God punishes the serpent, but as in the story of Medusa, its victims – the man, and especially the woman – are also punished. God says to the serpent: “And I will put enmity between thee and the woman, and between thy seed and her seed; it shall bruise thy head, and thou shalt bruise his heel” (Genesis 3:15). The curse supposedly explains humans’ fear of snakes, and perhaps the fact that this fear is even more prevalent among women.

Fear of snakes can also be seen in other primates and seems to predate the appearance of humans. Anthropologist Lynne A. Isbell of the University of California, Davis, speculates that the predisposition to fear snakes, as well as the ability to quickly and easily detect them, developed during primate evolution. Primates and their ancestors were prey for snakes; the threat they posed was one of the factors leading to the development of primates’ good vision. A primate that can quickly identify and respond to snakes has a higher chance of survival and producing offspring than a less vigilant one.

Indeed, humans and other primates specialize in detecting snakes; any snake-like shape or movement in our field of vision causes us to react rapidly. Even monkeys raised in captivity, without ever encountering a snake, recognize snakes more quickly and easily than other objects. In a 2009 study, researchers examined the ability of Japanese macaque monkeys (Macaca fuscata) to pick out the unusual image from among several images. They showed the monkeys an image of a snake among pictures of flowers and vice versa. The monkeys, who grew up in snake-less captivity, recognized the snake among the flowers faster than the flower among the snakes. A subsequent study, in which pictures of koalas replaced the flowers, yielded similar results. The macaque monkeys found the snake hiding among the koalas more quickly than the koala among the snakes.

Similar tests show that humans, including young children and infants not previously exposed to snakes, quickly and efficiently identify snakes hidden among images of other objects, such as flowers, fish, spiders, lizards, frogs, caterpillars, and birds. Humans are even better at finding camouflaged snakes and notice them more quickly than cats, fish, or birds disguised in pictures.

Very noticeable to well-hidden. Some of the snake pictures used in the Japanese macaque monkey study. (Source: PLoS One).

Learning to be afraid

Monkeys raised in captivity may excel in recognizing snakes hiding in the grass or among koalas, but they are not afraid of them. Fear itself is not innate: The monkeys have to acquire a fear of snakes, and they learn this from other monkeys. Researchers Michael Cook and Susan Mineka demonstrated this when they showed lab-raised rhesus macaque monkeys (Macaca mulatta) a video of a wild monkey, which, upon encountering a snake, behaved fearfully – screaming and lip-smacking. From then on, the observing lab monkeys also developed a fear of snakes; they learned to be afraid of snakes simply by watching a video of a monkey reacting in fear to a snake. When the researchers edited the video so that the monkey appears to be afraid of a toy snake, a toy crocodile, a toy rabbit or a flower, the observing monkeys developed a fear of snakes and alligators – but not of rabbits or flowers. It thus appears that monkeys easily learn to fear snakes (and crocodiles), but not other stimuli. The researchers concluded that while monkeys’ fear of snakes is not innate, they are naturally inclined to fear these reptiles; a fear that materializes only after they learn from their environment that they are “supposed” to respond in panic. Experiments in human adults and toddlers have shown that they easily learn to associate an aversive stimulus – an electric shock or a frightening sound – with snakes, but not with other animals or plants.

Isbell’s hypothesis is that the primate brain has a region which is linked to the ability to detect and respond to snakes. She thinks the likely candidate is an area of the thalamus called the pulvinar, which is highly developed in primates. The pulvinar is involved in processing visual information and shifting attention to threatening sights. To test this, Isbell and her colleagues inserted electrodes into the pulvinar neurons of Japanese macaque monkeys that had never previously seen a snake. The researchers then showed the monkeys images of snakes, monkeys with threatening facial expressions, hands, and geometric shapes, and measured the neurons’ response. The strongest and fastest response, and in a greater number of neurons, was measured when the monkeys saw pictures of snakes. The reaction occurred in the area of the pulvinar connected to the superior colliculus, a part of the midbrain associated with vision but also with response to threats, such as freeze or flight. The pulvinar is also connected to the amygdala, a brain structure in the temporal lobe which is involved in processing emotional responses, especially fear. Non-invasive monitoring of brain activity in humans using an electroencephalograph (EEG) device, which measures brain waves, showed a strong response in an area related to the processing of emotionally-important visual information when subjects were presented with images of snakes, in comparison with images of spiders, birds, crocodiles, turtles, slugs, lizards, worms, and others. This reaction occurred both in subjects who were afraid of snakes and those who were not.

What causes the brain to react thus to a snake? Does it identify dangerous snakes or does it respond to a general set of traits, shared by dangerous and non-dangerous snakes? The second option seems to be correct. For this reason, young monkeys tend to direct alarm calls at the sight of any snake. Only when they mature, do they learn to differentiate snakes predator species from other snakes, and avoid false alarm callings. 

Snakes’ most characteristic features, which enable us to identify them quickly, are their scales and unique shape. Wild vervet monkeys (Chlorocebus pygerythrus) were able to detect in less than a minute a snakeskin that researchers had hidden so that less than three centimeters of it were visible. After noticing the “snake,” they moved away. Even when they returned to the area after the snakeskin was removed, the monkeys remained vigilant and found the next hidden “snake” even more rapidly. In humans, snakeskin pictures, or partially obscured snake images, elicit an increased response in an area related to the processing of visual information, compared to the response elicited by pictures of lizard skin, feathers, or partially obscured lizards and birds. In addition, the brain interprets triangular and diamond-shaped patterns, as more alarming and dangerous than other forms.

Fear and admiration

In light of this, it is possible that during evolution, a set of rules developed in our brains that enables us to identify snake-related characteristics, and helps us note and avoid them. This set of rules is responsible for humans’ easily developing a fear of snakes, and is probably similarly related to our attraction to snakes, which has led to their incorporation into myths and legends from around the world. Snakes do not always appear as evil or frightening figures. In ancient Egypt, besides Apep, we also find Wadjet: A cobra goddess who is the protector of women in childbirth and of the pharaohs whose crowns she adorned. Nāga, serpentine deities, are worshipped in India and elsewhere in East Asia. The serpent is entwined around the Staff of Asclepius, the Greek god of medicine, and around the body of his daughter, Hygieia, the goddess of health and hygiene, a word derived from her name. In Judaism, during the Israelites’ journey through the desert, God sent serpents to kill them. Moses made the Nehushtan, a bronze serpent on a pole, according to God’s instructions: “Make thee a fiery serpent, and set it upon a pole; and it shall come to pass, that every one that is bitten, when he seeth it, shall live” (Numbers 21:8). Even Medusa’s hair of living snakes could help save people: All who are afraid of snakes would refrain from approaching, and be thus protected from petrification.

Despite our tendency to fear snakes, it is important to remember that no snake is trying to harm humans. These animals are beneficial to humans by hunting pests, and are also protected by law. As long as you do not surprise them or break the law and try to harm them, they do not pose a threat and should be left alone. However, if you come across a snake in your yard or at home, call a licensed catcher, who will catch the snake without hurting it, and release it in a safe place.

Those who saw Medusa

Petrification following an encounter with Medusa, the monster with the snake hair, is undoubtedly an unpleasant experience, but is at least a fast process. In reality, there are no creatures whose gaze can turn human beings into stone, but there is an extremely rare genetic disease with a much worse outcome – a slow and agonizing ossification.

A single mutation in a single gene causes patients’ skeletal muscles and connective tissues, such as tendons and ligaments, to be ossified and become bone. As in a horror movie, slowly and gradually, strips and sheets of new bones fix the joints in place. They fuse with the original skeleton and eventually form a kind of a second skeleton, which restricts patients’ ability to move. Patients can even starve to death, if their jaws lock in place, or die of suffocation or heart failure, when the extra bone growth restricts the thorax. And if that is not enough, any attempt to surgically remove the excess bones causes rapid and painful growth of new bones.

This disease is called Fibrodysplasia Ossificans Progressiva (FOP for short), a term describing the course of the disease – “soft connective tissues that turn into bone gradually.” It is estimated that FOP affects about 3,500 people worldwide, one in two million people, but only 800 verified cases are known, of which 285 are in the U.S. and 40 in the U.K. Most cases occur in families with no history of the disease: They emerged following a spontaneous mutation in a particular gene that the parents do not carry. However, FOP is also a hereditary disease: Parents who suffer from FOP can pass it on to their children, and the gene that causes it is dominant, that is, inheriting one copy of the defective gene, from the father or the mother, will lead to the disease.

The first documentation of FOP is in a letter written by the French physician Guy Patin, published in 1692, a few years after his death. Patin mentioned in his letter that “I saw a woman today who finally became hard as wood all over.” However, the first detailed description of the disease appears in a report sent to the Royal Society on April 15, 1736, by the British physician John Freke, about a unique case he encountered at St Bartholomew’s Hospital in London: “Yesterday there came a boy of a healthy look, and about fourteen years old, to ask of us at the hospital, what should be done to cure him of many large swellings on his back, which began about three years since, and have continued to grow as large on many parts as a Peny-loaf, particularly on the left side. They arise from all the vertebrae of the neck and reach down to the os sacrum; they likewise arise from every rib of his body, and joining together in all parts of his back, as the ramifications of coral do, they make as it were, a fixed bony pair of bodice.”

The disease begins with malformed toes and culminates with the formation of a second skeleton that impedes that patient’s ability to eat or breathe.  Pictures from Kaplan and Shore’s paper on FOP.

The skeleton in the glass case

The most famous FOP patient was Harry Raymond Eastlack, who died in 1973, six days before his 40th birthday, from pneumonia. Pneumonia is the most common cause of death in FOP sufferers – about 50% of them die from it. Eastlack bequeathed his body to the Mütter Museum of the College of Physicians in Philadelphia to promote the study of the disease, where his unique skeleton is displayed and constitutes a valuable asset to physicians and scientists studying the disease. In contrast to the skeletons of healthy humans, which need to be held in place with wires and glue to remain intact, the bone extensions of Eastlack’s second skeleton hold the skeleton in place. His spine vertebrae are adjoined in a bent position; bone sheets lock his jaw to his skull and his skull to the spine; bony ligaments attach some of his ribs to his arms, immobilizing them; the ribs are fixed in place and cannot expand during breathing; and the bone extensions that hold his joints in a way that prevents them from moving, have fixed his leg so that it looks like he is about to kick a ball.

Eastlack was born in 1933 and appeared to be healthy and normal. Only his big toes were malformed and crooked, a characteristic of most FOP patients, and a sign that hints of the lurking disease. At age five, while playing with his sister, he was hit by a car, and his left leg was broken. Shortly afterward, bones began to replace the muscles in his left thigh. In FOP patients, when muscles are injured, even a mild injury caused by sudden braking or a roller coaster ride, the inflammatory response at the site – normally a part of the healing process – leads to damage. Immune cells penetrate and break down the injured muscle, then other cells reach the area, and instead of repairing the damage and creating new muscle tissue, they form bone. The injured muscles are replaced by bones.

Because the disease is so rare, Eastlack’s doctors had never heard of it. Prior to FOP diagnosis, the doctors operated on him and took biopsies in an attempt to help him and find out what he is suffering from, but the surgeries only caused further bone growth, which worsened his condition. Even without injuries, patients’ muscles and connective tissues ossify, in a mostly similar way. Even before the age of ten, they suffer from flare-ups of painful lumps of inflammatory tissue, usually in the neck or upper back, which cause bone formation. This metamorphosis into a living statue continues throughout their lives, progressing slowly down the body to the feet, gradually restricting patients’ movements. By the age of 30, almost all of the patients are confined to a wheelchair and need assistance in their daily lives, and many are unable to move at all. By the age of 45, more than half of the patients will die from disease-related complications. Their average life expectancy is currently approximately 56 years. In Eastlack’s case, by age 15, his jaw had fused with his skull, and he was unable to eat solid food. Before his death, he could only move his tongue, lips, and eyes, and shuffle forward with support and a walking stick.

Eastlack’s skeleton is no longer alone in the glass case. Another FOP patient, Carol Orzel, who was inspired by his example to donate her body to science, provided it was displayed next to Eastlack’s and “Only if my jewelry can be displayed there too.” In February 2018, 58-year-old Orzel died. A year later, her skeleton was placed next to that of Eastlack, as well as a collection of her favorite jewelry.

Donated his petrified body to science. The skeleton of Harry Raymond Eastlack on display at the Mütter Museum. Source: Joh-co. Wikipedia

Skeleton Boy (Boing Boing World Premiere) from Metabook® on Vimeo.

The search for a cure

Orzel’s attending physician, Frederick Kaplan of the University of Pennsylvania, cared for her for 30 years. He met her in 1984, the first FOP patient he encountered, and she inspired him to study the disease. But the study of the causes of rare diseases, at least at the time, was considered to be professional suicide; it is far more lucrative to investigate common diseases, in terms of raising funds through donations or from drug companies, when the research leads to the development of a treatment or a drug. However, after meeting Michael Zasloff, a senior researcher at the National Institutes of Health (NIH), who could afford to study rare diseases, and Jeannie Peeper, an FOP patient and founder of the International Society for FOP (IFOPA), Kaplan decided to brave the risk and focus on the disease. IFOPA donated funds to his research and assisted him to contact many patients around the world.

Since he did not specialize in genetics, Kaplan recruited geneticist Eileen Shore to his team. They suspected that the gene involved in the disease was linked to proteins called BMP, which promote bone formation. In 2006, after 15 years of research, Kaplan, Shore, and colleagues around the world discovered the mutated gene that causes the disease: ACVR1. This gene forms a receptor – a protein located on the surface of cells which binds to various molecules, and transmits signals into the cell. The protein is associated with BMP activity and helps control bones and muscles development and regeneration. But in FOP patients, due to a single mutation, the receptor is continuously active and the signals it relays cause increased bone development. It is activated even more vigorously following an injury that causes an inflammatory response in the region.

The discovery of the gene enabled researchers to create engineered cells and animals models with the mutation, which will be used to search for a cure, and perhaps also develop therapies to grow new bones for those who need this. Several clinical trials are currently underway for FOP, with compounds that prevent the growth of new bones, including palovarotene, which was already shown to prevent the development of new bones in genetically engineered mice and is currently in tests in humans. An additional clinical trial is focused on an antibody that neutralizes an activator of the defective receptor, thus preventing bone growth.

Success in the clinical trials of these treatments could spell a brighter future for FOP patients. Petrification will be left to the tales of Medusa and other mythical creatures, and all that will remain of the disease are the extraordinary skeletons of Harry Eastlack and Carol Orzel in the glass case at the Mütter Museum.