Medicine Quest: In Search of Nature's Healing Secretsby Mark J. Plotkin
In Medicine Quest, Mark Plotkin goes beyond Tales of a Shaman's Apprentice, his critically acclaimed exploration of the Amazonian jungles that has become a classic of its genre./i>/i>
A world renowned ethnobotanist combs the far corners of the planet to unveil nature's pharmacy and detail how scientists are harvesting it to conquer devastating diseases
In Medicine Quest, Mark Plotkin goes beyond Tales of a Shaman's Apprentice, his critically acclaimed exploration of the Amazonian jungles that has become a classic of its genre. He transports readers from freezing Arctic wastes to twilit ocean depths to burning jungles, where the race is on to find new medicines for intractable diseases like AIDS, cancer, and diabetes. It is a quest powered by the desperation of the ill and the compassion of those who would cure them.
Plotkin highlights discoveries that are already producing stunning leads in the laboratory: painkillers from the skin of rain-forest frogs, anticoagulants from leech saliva, and antitumor agents from snake venom. This entertaining weave of medicine, ecology, ethnobotany, history, exploration, and adventure will thrill scientists, naturalists, adventurers, and the exploding number of Americans who spend $10 billion a year on medicine in their thirst for nature's healing secrets.
- Viking Adult
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The difference between a deadly poison and a life-saving medicine can be very small; in fact, it is sometimes merely a question of dosage.
Dr. R. E. Schultes, 1980
Time was running out, and the indefatigable frog detective Dr. John Daly decided to risk everything in one of the boldest scientific crapshoots of the twentieth century.
Daly had in his possession a tiny vial of an almost irreplaceable frog-skin extract that held the possibility of revolutionizing the way we treat pain, that might be turned into a billion-dollar-a-year medicine, and that might relieve incredible agony and human suffering. Yet he knew that analyzing the compound would destroy what little he had left of the precious substance, and he was fully aware that he might not ever be able to find it again.
For over a quarter century, Daly had been combing the most remote jungles of Central and South America, braving bandits, guerrillas, narcotraffickers, malaria, and myriad other hazards on what many would consider to be a quixotic quest: he was in search of tiny poison dart frogs and the powerful chemicals embedded in their skin. Daly knew that Indians in northwestern Colombia rubbed the skins of these frogs on their blowdarts so that even a scratch would prove lethal. He had already found a one-inch speciesthe aptly named Phyllobates terribilisa single individual of which harbored enough poison to kill ten men or twenty thousand mice. It was Daly's fervent belief that these potent poisons might one day help alleviate humansuffering.
When Daly began his investigations in the 1960s, the technology necessary to analyze the frog compounds was both slow and tedious. Unlike the Amazonian cururu frog, which can tip the scales at over seven pounds, poison arrow frogs are tiny enough to perch comfortably on the tip of your little finger. Not only was Daly sometimes unable to collect enough frogs to extract the amounts necessary to complete the study, but the chemical complexity of these compounds made it nearly impossible to synthesize them in the lab.
A 1966 article on Daly's research on Colombian frogs was published in Medical World News and caught the eye of Charles Myers, then a graduate student conducting research in Panama and now a senior scientist at the American Museum of Natural History in New York City. Unlike Daly, who was primarily trained as a chemist, Myers was a herpetologist, a biologist specializing in reptiles and amphibians, hence his background complemented that of Daly's. Myers wrote a letter to Daly proposing a collaboration that has continued to the present day.
The two Americans began their collaboration in Panama but then moved south. In 1974, they collected a brilliantly colored orange, red, and white frog known as Epipedobates tricolor near Santa Isabel in southwestern Ecuador. When Daly injected an extract of Epipedobates skin into a mouse, the rodent immediately arched its tail over its back, the so-called Straub tail reaction, which is the response usually generated by an opium-like painkiller. Believing he had found merely an amphibian equivalent of opium, the scientist then treated the mouse with naloxone, an opiate blocker, which he expected would cause the creature to lower its tail. The mouse, however, did not respond and the tail remained arched over its back. This intrigued and excited Daly because it meant that he was on the trail of one of the Holy Grails of modern medicine: a nonsedating, potentially nonaddictive, nonopioid painkiller. Not only did the new chemicalnamed "epibatidine" in honor of the frogkill pain, but it also proved two hundred times more potent than morphine and it appeared to exert its effects in a manner completely different from that of opium.
The bad news, however, was that epibatidine was too toxic and had too many negative side effects to be used on humans. Daly and his colleagues thought they might analyze the molecule to determine its exact structure, which would allow them to manipulate the epibatidine molecule in order to produce a version less toxic but still potent. Unfortunately, the laboratory technology necessary for purifying, analyzing, and synthesizing the molecule did not exist at the time. And they had used up the little bit of poison they had managed to collect. It was time to return to the jungle.
The original epibatidine had been extracted from frogs collected from two different locales in 1974. When the scientists returned to Ecuador two years later, one population of the amphibians had completely vanished; much of the surrounding forest had been felled and converted to banana plantations. Fortunately, they were able to find these frogs at the other sitebut only enough to collect less than one milligram of the poison! Then, in 1984, passage of the Convention on International Trade in Endangered Species (CITES) Treaty made it exceedingly difficult (if not impossible) to legally collect and export poison dart frogs, particularly in the large quantities necessary for chemical analysis of the toxin. And habitat destruction in western Ecuador was on the increase. Attempts to breed the frogs in the lab were successful, but the frogs contained no epibatidine! So Daly had a tiny and finite supply of epibatidine and demand for the compound for testing purposes was increasing. Daly stored his precious poison, awaiting the day when modern technology would improve to the point of being able to unlock one of Mother Nature's most closely guarded (and potentially useful) secrets.
In 1990, Daly decided it was time to roll the dice. Out of his freezer he took the tiny vial with the precious epibatidine inside. No new epibatidine had been collected in more than a decade. Meanwhile, the frogs' habitat was being decimated as the human population in southwestern Ecuador greatly expanded, causing an enormous decline in forest cover. However, analytical methods and instruments had greatly improved with tools like nuclear magnetic resonance (NMR) and gas chromatography-infrared spectroscopy, made all the more effective by the microchip revolution already well under way. Since the analysis of the chemical entailed the destruction of the tiny sample that Daly had, the decision to analyze the epibatidine was an enormous gamble.
The gamble paid off: the structure of the molecule was revealed. Within two years, scientists were able to synthesize the molecule to create a limitless supply for experimentation. Laboratories around the world eagerly began investigating the potential utility of this strange chemical from a tiny rain forest frog.
Interestingly, epibatidine bears a chemical resemblance to nicotine. Right around the time that Daly and his colleagues were determining the chemical structure of epibatidine, researchers at Abbott Laboratories were investigating nicotine-like chemicals for the treatment of Alzheimer's disease. Taking note of the similar structure of epibatidine, but aware that it was too toxic for human use, they began to create similar compounds, hoping that one might prove highly effective as a painkiller. Of the hundreds of molecules devised and tested, one stood out: ABT-594. Not only did it lack the toxicity of epibatidine, but it proved effective against several types of pain, including one caused by nerve damage against which even opiates are relatively ineffective. Unlike opiates, ABT-594 appears to be nonaddictive, enhances alertness rather than causing sedation, and has relatively little effect on the respiratory system.
Because it is so different from morphine, it appears to offer unlimited potential as a treatment for pain, provided that epibatidine makes it through the FDA approval process and enters the marketplace. Dr. Michael Williams of Abbott Labs stated, "It lacks the major side effects of morphine like constipation and addiction. ABT-594 is proving to be a very interesting molecule."
It is the fervent belief of scientists like Daly and Williams that these and other potent natural poisons will help alleviate human suffering.
A poison is any substanceman-made or found in naturethat produces disease conditions, tissue injury, or otherwise interrupts natural life processes when in contact with the body. Toxins are poisonous substances produced by living creatures, including amphibians, bacteria, insects, plants, and reptiles. Venoms are poisons of animal origin that are injected by spines (such as is the case with sea urchins), stings (such as honeybees), or teeth (rattlesnakes). Poisonous creatures have always been objects of fear and fascination. People worshiped deadly cobras in ancient India. The bite of the tarantula was believed by denizens of Europe in the Middle Ages to cause an uncontrollable urge to dance (the whirling folk dance known as the "tarantella" was inspired by this notion). And citizens of the American South still handle venomous serpents to demonstrate their devotion to the Lord.
But these days it is the major pharmaceutical companies that are most interested in these poisons, and the stakes are huge: a single blockbuster drug (like the high-blood-pressure drug Capoten, which was developed based on studies of Brazilian viper venom) can earn over 1.5 billion dollars per year
The Holy Grail of current drug study is finding a new medicament that is effective for treating a particular malady (particularly an ailment that has no other effective treatment or cure) and which meets certain criteria. The compound should ideally have a unique and (previously) unknown chemical structure (making it easier to patent); function in a unique pathway in the human body (meaning that it operates differently and, we hope, more effectively than other pharmaceuticals used to treat a given condition); be a small molecule (making it easier and less expensive to synthesize); be quick acting; and have no unwanted side effects (such as addiction, for example).
Venoms are the end result of billions of years of evolution. These molecules have been honed to generate a response in the body of the victim that is quick, dramatic, and often fatal. This response may include pain, numbness, asphyxiation, hemorrhage, clotting, shock, paralysis, or a change in blood pressure. Some venoms are composed of hundreds of various poisons, each of which does something different when injected into the body of another creature. Precisely because these poisons are so refined, their potential as medicines is enormous.
For example, eriostatin, a protein from an Asian pit viper, appears to inhibit the spread of melanoma cells, and a compound based on the venom of an Israeli scorpion binds to the cells of a type of brain cancer and seems to keep them from spreading to other parts of the body. SNX-482, from Cameroon red tarantula venom, may lead to a new class of medicines for the treatment of neurological disorders. Gila monsters from the American Southwest have a substance in their venom known as exendin, which stimulates the secretion of insulin, meaning it may one day be used to prevent the progression of diabetes. And an enzyme in the venom of the Russell's pit viper, one of the world's most beautiful and most deadly snakes, is now being employed in a diagnostic test for lupus.
Toxins produced by lethal organisms are also being employed for medical uses. Minuscule amounts of the deadly botulism bacteria are proving to be effective for the treatment of a rare condition that paralyzes the vocal cords. Under the trade name Botox, botulism toxin is being injected into facial muscles that cause wrinkles. The toxin temporarily paralyzes them, resulting in a surgeryless face-lift (though given the choice between surgery and having one of the world's most poisonous substances injected into their heads, most people still choose the knife).
Toxin molecules typically accomplish their deadly tasks through a three-stage process: first they attach to a healthy cell, then they enter the cell, and then they exert their deadly effects on the cell's machinery, causing it to malfunction and/or die. Working with a form of the deadly diphtheria bacillus, scientists are devising the means to deliver a poison into cancer cells, thereby destroying them. Similar efforts are under way with the tetanus toxin to treat diseases like Tay-Sachs.
Venoms continue to play an absolutely fundamental role in our understanding of how cells function. They have proven essential in helping us comprehend ion channels, which are pores on a cell's surface that control the flow of calcium, potassium, and sodium in and out of the cells, and which play a key role in transmission of nerve impulses (that is, how nerve cells talk to and activate each other). Because these venoms are highly specific and only interact with particular channels, they are of inestimable use in mapping these channels. In the words of the National Cancer Institute's Dr. David Newman: "Using venoms, we can turn something onor offin a particular cell which teaches you something about the function of that cell. You can block a certain response and observe what happens when you add something like a medicine. You can learn about everything from the structure and function of ion channels to how cells communicate with each other."
In the laboratory, venoms help teach us how medicines function in the human body. Drugs tend to operate in two basic ways. Many interact directly with the body's metabolism. Aspirin represents a classic example, mitigating pain by interfering with the body's production of prostaglandins, which cause the discomfort. Other drugs attack or interfere with the disease-causing organism itself. Penicillin would fall into this categoryit inhibits the ability of the invading bacteria's cells to reproduce but does not interact with human cells.
All drugs have a "target" (a site of action) in the body. Many of these targets are receptors, protein molecules on the cell's surface that interact with other molecules. (The receptor is often described as the lock into which the "key" molecule must fit.) Drugs can either fit into receptors and elicit a certain response (in which case they are termed "agonists") or they can block the receptors, eliciting no response but keeping other chemical messengers from interacting with the receptors ("antagonists").
As with the ion channels, some venom components interact only with very specific receptors, allowing us to map our nervous systems in extraordinary detail. Knowledge of these receptor sites is already helping scientists to design some drugs from scratch. In the future, when all the receptor sites on all the cells have been mapped, scientists may design all drugs that way. Until that day, however, Mother Nature will play an essential role.
Though venoms are being investigated as the source of new treatments for everything from cancer to diabetes, they are probably most promising as sources of pain relievers. Many venomous animals use poison as a means of trapping their prey rather than as a defense against enemies. How? By immobilizing it so it cannot fight or flee! The most effective way to achieve this is to interfere withor shut downthe prey's nervous system. And, for our own treatment purposes, we are learning how to use some of venom's unique properties to close down only a certain part of the nervous system, and hence block pain.
Pain represents the most common reason people visit their physicians, and chronic pain is an oft-stated reason that severely ill people give when they ask their physicians' assistance in committing suicide. Pain is usually caused by burns, cuts, pricks, excessive pressure, or other factors telling us that our body is being damaged. The very few people born with the inability to feel pain often suffer terribly for it, not realizing, until the damage is already done, that the water they stuck their hand into is too hot or that the knife they are using to slice an onion has just cut deeply into their finger.
In other cases, a problem occurs when the brain continues to receive pain messages even after the causative agent has ceased inflicting the pain. In the case of "phantom limb syndrome," the limb continues to "hurt" years after it has been amputated. This pain presumably results from crossed signals in the brain (or crossed signals in nerves near the amputated limb) rather than damage to a limb that is no longer there. Naturally, this offers little solace to the three million Americans who suffer from this malady.
The amount of such "incurable" suffering that a new natural drug might relieve is staggering in terms of both numbers and dollars. According to the New York Times, between thirty million and eighty million Americans suffer from pain ineffectively treated by common analgesics (painkillers). At least six million experience pain caused by damaged nerves; another million suffer excruciating pain due to various cancers; while still others are subjected to suffering caused by everything from AIDS to spinal cord injuries. At least one study has suggested that the annual cost of medical bills and lost wages due to pain is as high as one hundred billion dollars. The annual retail value of morphine and morphine-derived products in this country is about six hundred million dollars.
Exceedingly promising as sources of new venom-derived painkillers and other powerful potions are the aquatic masters of immobilization: the cone snails of the tropical coral reefs. Dr. Newman of the National Cancer Institute has called them "for their size, the deadliest creatures on our planet." Cone snails are the archers of the deep: they kill by shooting their prey with an arrow. The arrows are actually the snail's teeth, which are contained inside a long tube that is the "tongue" of the creature and is longer than the snail's body. Each arrow is a hollow and disposable harpoon and contains a deadly poison. The cone snails not only developed this type of hunting long before we did, they also invented the disposable syringe in the process! The case of Steve C. demonstrates the medical potential of cone snails:
Steve's medical problems began at an age when most kids have little more on their minds than whom to play with in their kindergarten class. At the age of five, several of the toes on his left foot began to ache, the result of a rare form of cancer that started there and spread throughout the rest of his body. As if cancer invading the soft tissues of his body wasn't enough of a curse, the disease caused unbearable pain that sometimes reduced him to writhing on the floor on the verge of unconsciousness. Steve said, "It [was] as if somebody stabs you and twists the knife ... it would go on sometimes for hours."
To relieve his misery, Steve relied on the best Western medicine for treating intractable pain: opium and opiate derivatives, which have been valued for their analgesic effects by humankind for thousands of years. He took morphine pills and applied synthetic morphine patches. Other narcotics were added to the mix when these powerful compounds didn't do the job. But morphine and the synthetic and semisynthetic compounds based on it cause serious side effects like addiction, constipation, and respiratory distress. Most problematic from the standpoint of someone suffering intolerable pain, the body grows accustomed to the drug so that, over time, more of it is needed to obtain relief. Some pain sufferers must take over one hundred times the lethal dose of morphine just to make it through the day.
On the other side of the planet from where Steve grew up in the American Midwest, Baldomero "Toto" Olivera enjoyed a carefree bucolic boyhood near Manila. On weekends and holidays, the entire family would travel by small seaplane to the Philippine island of Alabat, where they had a cottage that looked out over the ocean. In 1942, when the Japanese invaded and captured Manila, Toto's family fled to the island bungalow that they felt would be a safe refuge in which to wait out the war.
Disappointed that he had to leave both his friends and most of his toys behind, Toto developed a new hobby: collecting seashells. He spent long afternoons walking along the sandy beaches amidst the coconut palms, watching the waves break over the coral atolls that encircled the island. The boy would stop to pick up seashells to add to his burgeoning collection. But he never forgot the one type of shellthe most beautiful of them allthat he was told harbored a creature with a poisonous sting: the exquisitely mottled tapering shell of the cone snail.
Cone snail shells have long been an obsession of collectors around the world. Names given to each speciesthe Majestic Cone, or the Glory of the Seaonly hint at their ethereal beauty. How valuable are they? In 1796, a two-inch shell was auctioned along with a painting by the Dutch master Vermeer: the snail shell sold for seven times the purchase price of the painting.
Admiring their beauty, one has no sense of the poisons hidden within. At least two species of these tiny creatures are capable of killing a human being. Several years ago, a man snorkeling in the Philippines happened upon a cone snail slowly making its way along the coral reef. He picked it up and, not having a bag to put it into, he stuffed it down the front of his bathing suit.
This is the kind of mistake you only make once.
Cone snails are great poison producers by necessity. Inside their shells, they are essentially soft-bodied creatures. They cannot afford to get into wrestling matches or tug-of-wars with every animal they want to eatit might tear them apart. Consequently, they have evolved fast-acting poisons that can kill their prey almost instantaneously. Some of their means of delivering the poison verge on the ghoulish. One species of cone snail extends a proboscis that looks like a piece of bait. As the fish approaches, expecting a meal, it quickly becomes one instead. The snail shoots a poison-tipped harpoon into the fish's mouth, instantly killing the fish, which is then quickly devoured.
After completing a Ph.D. in chemistry at Caltech, Toto returned to the Philippines anxious to use his newfound training to help his native land. His lab at the university had little sophisticated equipment, and even less of a research budget. Toro decided to look for a project that would focus on local resources, since he lacked the funding for a project that required international travel. Remembering the cone snails, he made a few inquiries and was surprised to learn that hardly any research had been done to determine the chemical composition of the poison. And virtually nothing had been done to evaluate whether it had any commercial or therapeutic potential.
Toto hypothesized that the venom contained a single toxic component. He was surprised when his initial investigations indicated the presence of at least nine different poisons. Moreover, the poisons had a unique composition and shape, comprising a new type of compound which Toto christened "conotoxins." But his cone snail research languished when Toto accepted a teaching position in Salt Lake City, far from the coral reefs that offered a ready supply of cone snails and their conotoxins. It was in Salt Lake, however, that an iconoclastic undergraduate named Craig Clark, searching for a research project topic, asked a simple question that eventually proved to have dazzling implications.
"Professor Olivera," he asked, "what would happen if we introduced single conotoxins directly into the mouse brain?"
"The mice would die," Toto replied. "Better not to waste your time and my mice. Can't you find another project?"
The student decided to give it a try anyway. The result? Rodent bedlam. The mice that received one compound began dancing frantically, while recipients of another began dragging their hind legs, while others scratched themselves or started swinging their heads from side to side. It was immediately obvious that each compound had a very different and very pronounced effect on the nervous system. Further research revealed that one of these conotoxins could disrupt the ability of nerve cells to communicate with each other. If this compound could be demonstrated to interrupt pain signals as they traveled from the human spinal cord to the brain, it would represent a new painkiller that might be used in addition toor instead ofmorphine.
That is exactly what Toto and his colleagues have found in one particular conotoxin. Initially known as MVIIB (and now called ziconotide), this compound attaches itself solely to a part of the spinal cord known as the dorsal horn, through which pass the nerve cells that convey pain signals from the body to the brain.
Dr. George Miljanich, chief chemist at Neurex/Elan, the company that is commercializing the compound, said, "[The drug] works by blocking proteins in the nervous system called calcium channels [that are] required for synaptic transmission, that is, for the nerve cells to talk to each other and activate each other. By blocking calcium channels and suppressing synaptic activity, the system is suppressed, its activity is lowered, and many physiological effects can ensue from that."
Steve C. takes ziconotide on a daily basis and has found it so effective that he no longer takes morphine. In fact, he sleeps comfortably through the night for the first time in over two decades. And other pain sufferers have responded equally well to the still experimental new drug. Some patients, completely bedridden and mentally addled by their use of morphine, switched to ziconotide and were able to leave the hospital and resume living a normal life.
Ziconotide is considered hundreds of times more potent than morphine; it offers three major advantages over morphine and other opiate-derived drugs. First, it has proven effective in treating pain (like the phantom limb syndrome or neuropathic pain) that cannot be relieved with other drugs. Second, the human body appears not to develop tolerance to the drug. Third, it is not addictive. If and when ziconotide is approved for general use and enters the marketplace, its nonaddictive effectiveness promises a potential annual retail value as high as one billion dollars per year
Of course, not all promising leads result in new drugs. Current estimates are that only one of every ten thousand molecules that are investigated ever makes it into the pharmacy, the hospital, or the medicine chest. A recent issue of the Economist explained,
Substances emerging from [an] initial screening (now usually carried out in a tissue culture rather than an animal) are rarely powerful enough to be effective as they stand. The next step, therefore, is for chemists to fiddle with the exact arrangement of a promising compound's atoms ... in order to increase its potency [or decrease its toxicity, or both].... The "lead compound" which results from this tinkering is then subjected to further tests, this time generally in animals. These show how well it is absorbed by the body, how it stands up to the biochemical rigours it meets there, how poisonous it is, and what sort of side effects it might be expected to produce. Only then is it allowed to go into clinical trials in peoplefirst small ones to test its safety, and then much larger ones to prove its effectiveness for its intended job. If, after going through all this, the company thinks that it has a winner, it still has to persuade the regulatory authorities to agree. Only when a molecule has passed this final test does it pop out of the other end of the pipeline and on to the revenue line of the company's accounts.
This Food and Drug Administration (FDA) approval process consists of three separate phases. Phase 1 is comprised of safety trials in which low doses of the drug are given to just a few volunteers. The test subjects are monitored for harmful side effects over the course of several months. The next phase examines the effectiveness and safety of the drug in a small number of patients (up to several hundred) suffering from the disease in question. Phase 2 can take (on average) up to two years. In phase 3, however, the efficacy and safety of the drug is tested on a large patient population over the course of two to four years. If the results are positive, the pharmaceutical company files a New Drug Approval (NDA) request that is then usually approved by the FDA after the agency has reviewed the results, a process that takes about a year and a half. ABT-594, the poison dart frog derivative, is currently in phase 1, while ziconotide is in phase 3.
Perhaps the most exciting aspect of the cone snail research is that it currently entails much more than ziconotide. Each species may produce up to two hundred different venomsand there are five hundred species of cone snails. According to Toto, some venomous creatures, like sea snakes, produce venoms that contain only one paralytic agent, most assuredly not the case with cone snails. Toto Olivera said, "The cone snail's poison wallops its prey with a speedball that kills the fish on impact. It is like being hit with Amazonian arrow poison, botulism toxin, puffer fish poison and the shock of an electric eel all at once."
The upshot of having and studying these thousands of powerful chemicals is that their therapeutic potential is by no means limited to pain. A 1990 article in the Economist, suitably entitled "Skip the Escargots," noted: "At least part of the problem in some neurological and psychiatric diseases is that ion channels or receptors are stimulated too much or too little. If the receptor at fault in a particular condition is identified, a drug could be made with a molecule based on the conotoxin design. It would react only with that receptor and so would not trigger any of the side-effects that come with many of the existing, unselective psychiatric drugs."
Toto recently parted ways with the firm that is commercializing ziconotide to help start another company. "There are about five hundred species of cone snails," he told me, "and each species may produce two hundred different poisons. If you take out ziconotide, you still have nine thousand nine hundred and ninety-nine compounds left to study. And others that I am already investigating have the potential to do for epilepsy and other central nervous system disorders what ziconotide does for pain."
Yet poison dart frogs, cone snails, and many other species are disappearing faster than we can study them. Wild populations of the Ecuadorean dart frog that led to the development of ABT-594 continue to dwindle. The okopipi, a brilliant blue dart frog found only on a few tiny forest islands surrounded by grasslands in the northeast Amazon, is being threatened by unscrupulous wildlife dealers who illegally collect them for export. Another species was almost wiped out on the Panamanian island of Taboga by a German reptile dealer. And cone snails live on coral reefs, one of the world's most threatened ecosystems. How much has already been lost, and what medical miracles have been sacrificed as a result?
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