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Creature Comforts

Animals provide healing help for humans

by Mary-Russell Roberson

Animals have evolved intricate chemical strategies for obtaining food and for defending themselves against infection, disease, and predation. It seems only natural that those chemical compounds could have broader healing properties. In fact, the animal kingdom is like a drugstore, offering thousands of fascinating compounds, many of which can help heal humans in unexpected ways.

leech on leaf
Leeches are back—scientists have found new medical uses for these and other animals. (Premaphotos/ naturepl.com)

In 19th century European medicine, leeches were often prescribed as a treatment for headaches, fever, obesity, and many other maladies. We’ve since scoffed at how people considered bleeding-by-leech as a cure-all, but there’s no need to throw the leeches out with the bathwater.

Leeches, it turns out, have some valuable medicinal uses in the 21st century. These FDA-approved invertebrates are used in hospitals to improve the outcome of surgeries to reattach fingers, toes, flaps of skin, and other small body parts.

Surgeons use leeches to drain blood from a swollen area without damaging tissue as a needle would. The leech’s saliva contains anesthetic compounds so there is no pain. Perhaps more importantly, the saliva contains anticoagulating compounds that keep the wound slowly but steadily bleeding for hours.

While leeches are already in widespread use as postsurgical treatment, anticoagulating and anti-inflammatory compounds in their saliva are being studied as potential ingredients for drugs to treat congestive heart failure, strokes, and perhaps even arthritis. Scientists are working to isolate and identify as many compounds as they can from leeches all over the world, some species of which are endangered.

The leech is just one example of an animal that helps humans heal. Many prescription drugs were inspired by animals. The blood pressure drug Captopril is modeled on a peptide in the venom of the Brazilian viper. The leukemia drug cytarabine is based on compounds from a Caribbean sponge. And many more possibilities are under development. Scorpion venom is being tested as a treatment for brain tumors, and a compound from the internal organs of sharks has shown promise in treating ovarian cancer, prostate cancer, and macular degeneration.

From bees to frogs, members of the animal kingdom have the potential to offer a surprising range of medical help to humans.

Sweet Healing from Bees

The ancient Egyptians used to spread honey on wounds to speed healing. Four thousand years later, Jennifer Eddy does the same thing.

Eddy, assistant professor of family medicine at the University of Wisconsin School of Medicine and Public Health, first used honey several years ago as a last resort. Her patient, a 79-year-old man with type 2 diabetes, had large open ulcers on his feet that were continuing to worsen despite standard medical treatment. Nonhealing foot ulcers are a common and serious problem for diabetics, who have reduced sensation and poor blood circulation in their feet. The ulcers often require amputation of a toe, foot, or leg to stop the spread of infection. “Nothing we tried medically was working,” Eddy says. “He refused amputation and he was going home to die.”

bees on hive

Honey can kill microbes and treat wounds.
(John B. Free / naturepl.com)

Meanwhile, Eddy left for a honeymoon trip, where she happened to read a book about folk remedies. It mentioned using honey to treat wounds. Eddy remembered another book, The Healing Hand, written by one of her pathology professors, that described ancient Egyptians using honey the same way.

When she returned to work, she found reports in the medical literature supporting the healing powers of honey. Her patient agreed to give it a try. He stopped taking antibiotics, and once a day his wife spread a thick layer of supermarket honey on gauze squares that she taped on his wounds. To everyone’s delight, the wounds improved quickly and, after several months, healed completely.

In the last few years, more scientific studies have backed up honey’s benefits, and, in 2007, the FDA approved several medical-grade honeys for use in treating wounds. Honey attacks microbes on at least three levels, according to Eddy. First of all, honey has very low water content. “If you put it next to something that has water in it, like bacteria or a wound, it will suck the water out of it,” Eddy says. “So it dehydrates bacteria.” Second, it’s acidic, which wound-dwelling bacteria don’t like. (A drawback of honey therapy is that it may sting after application.) Third, honey contains an enzyme that leads to the production of hydrogen peroxide, which kills bacteria. Because honey kills microbes several ways, microbes have a hard time evolving resistance to it. Some studies show that honey helps uninfected wounds heal faster, too. Eddy says that’s because honey acts like a moist bandage that allows new skin cells to form around the edges of the wound. It also pulls water from the wound, reducing swelling and improving blood supply.

So why do bees need antimicrobial honey? There seems to be a logical explanation: Honey is their main food source, and it’s all they have to eat over the winter. If it were to get moldy or infested with bacteria, the entire hive could starve.

Today, Eddy is running a pilot study in the clinic at her university hospital to rigorously evaluate honey’s effectiveness in treating diabetic foot ulcers. Half of the patients are receiving the honey treatment, and half are being treated with a placebo that looks and smells like the real thing. Neither the patients nor the doctors will know which is which until all the wounds have been evaluated for healing. Eddy expects the results of the study to be available in about a year. While there is evidence that honey helps other kinds of wounds heal, Eddy is focusing on diabetic foot ulcers because of their cost to diabetics and to society. People with diabetic foot ulcers typically receive multiple courses of antibiotics, leading to the development of antibiotic-resistant bacteria. “Having a nonhealing wound helps grow those bad bugs,” she says. “Diabetic foot ulcers are a societal repository for some of the most resistant bacteria.”

The Secret First Aid Kit of Frogs

Imagine a frog with a cut on its skin. The frog spends its days swimming around in a bacteriainfested pond. Why doesn’t the cut get infected? About 20 years ago, that question occurred to Michael Zasloff, who is now professor in the departments of surgery and pediatrics and the director of surgical immunology at Georgetown University. At the time, he was doing work with African clawed frogs (Xenopus laevis) at the National Institutes of Health. His curiosity led him to discover the microbe-killing peptides produced by specialized glands on frog skin. Peptides are short chains of amino acids. “When the animal is injured, it releases a sticky gelatinous-like secretion that covers the wound completely and protects it,” he says. “It instantly kills any possible pathogen and adheres to that wound for a time sufficient for the skin to heal.”

African clawed frog
The African clawed frog produces peptides that can be used to treat infections. (Jessie Cohen/ NZP)

Frog peptides kill bacteria by damaging their membranes, a strategy that makes it hard for bacteria to develop resistance. “It is extremely difficult for a microbe to change the composition of its membrane,” Zasloff says.

Louise Rollins-Smith, associate professor of microbiology and immunology at Vanderbilt University Medical Center, studies the immune defenses of amphibians, in particular in relation to a devastating chytrid fungus (Batrachochytrium dendrobatidis) that is killing frogs around the world. She describes the frog skin secretions as a first-aid kit that may contain painkillers, antimicrobial agents, and antipredatory neurotoxins.

A few years ago, Rollins-Smith was discussing her work with some Vanderbilt colleagues who study the human immunodeficiency virus (HIV). The scientists wondered how the frog peptides would affect HIV. Viruses don’t have membranes, but some—including HIV and influenza—have “envelopes” that are similar to membranes. The team tested several frog peptides and found that they did kill HIV in the laboratory. “The activity that we saw was probably disruption of that envelope, which is required for infection,” Rollins-Smith says. She is hopeful that the discovery could one day lead to a topical cream or gel that could help prevent the spread of HIV.

Several drugs based on frog peptides are currently or soon to be in clinical trials, including pexiganan, which is based on the peptides Zasloff discovered in the African clawed frog. Zasloff thinks the drug he helped create will be on the market in the not-too-distant future. “Without question, we will start to see over the next few years the appearance of antimicrobial peptides as therapeutic agents for the treatment of infection,” he says.

A rich field of pharmacological study remains because each of the more than 5,500 species of frogs and toads produces several peptides, and they are all different. Unfortunately, amphibian populations are rapidly declining. The first-aid kits of many frogs are being overwhelmed by the rapidly spreading chytrid fungus. Other amphibians are dying out due to habitat loss, pollution, and climate change. According to a 2004 report from the Global Amphibian Assessment, about a third of the world’s amphibian species are threatened, and more than 40 percent are in decline. Smithsonian National Zoo scientists are leading efforts in amphibian conservation—particularly with chytrid fungus research—to help these valuable species.

From Lizard Spit to Diabetes Drug

Gila monster

Good poison? The venom of the Gila monster can do serious harm, but it also offers many potential medical applications. (Jessie Cohen)

Although rarely if ever fatal to humans, the bite of a Gila monster (Heloderma suspectum) is an extremely unpleasant experience. The lizard clamps down and doesn’t let go, “chewing” to release venom into the tissue of the victim. The venom causes excruciating pain and a host of other symptoms, from low blood pressure to nausea to irregular heart rhythm. In defense of Gila monsters, it must be said that they virtually never bite humans unless physically provoked.

“These lizards can’t sprint like most lizards; their top speed is a slow walk,” says Daniel Beck, professor of biological sciences at Central Washington University and author of Biology of Gila Monsters and Beaded Lizards. “Their venom is used for defense. It’s one of the most painful venoms there is.” Gila monsters eat bird and reptile eggs and young nestlings such as baby cottontail rabbits. Because their prey can’t run away, they don’t need venom to catch it.

Gila monsters, one of only two species of venomous lizards in the world, live in the deserts of Arizona, Utah, Nevada, New Mexico, and Mexico, where they spend up to 95 percent of their time resting underground.

Their venom, which is produced in modified salivary glands, consists of about a dozen compounds, including enzymes and peptides. In the 1990s, John Eng of the Bronx Veterans Administration Medical Center in New York discovered that one of the peptides, exendin-4, had potential as a drug to treat diabetes. The synthetic version, called exenatide (Byetta), was approved by the FDA in 2005.

Another component of the venom, gilatide, is being studied as a possible memory enhancer. Beck speculates that a memory booster in the venom would help attackers remember to stay away from the black-and-orange lizards in the future.

Laboratory studies have shown the levels of exendin-4 go up dramatically in a Gila monster’s body while it is eating, suggesting it may play a role in the lizard’s digestion of large infrequent meals. “They can go a whole year without eating at all, or they can eat ten or 20 meals a year,” Beck says. “They tank up when food is available and they store food very efficiently when it is not.”

As a diabetes drug, the synthetic version of exendin-4 works in humans in four different ways, according to John Buse, chief of endocrinology at the University of North Carolina School of Medicine in Chapel Hill, and the leader of a recent study of exenatide’s effectiveness. “Exenatide is like a steam roller for keeping the blood sugar from going up,” he says. When blood sugar is too high, the drug stimulates the production of insulin, helping the body’s cells take up sugar to use as energy. It also reduces a peptide called glucagon that elevates blood sugar. And it slows emptying of the stomach and makes people feel full fast, causing some people to lose weight. “The total weight loss over two years averages ten to 15 pounds,” Buse says, “but some people lose a lot more weight.”

Years ago, when Beck was tracking Gila monsters as a graduate student in Utah, he says people would ask him why he was studying these reclusive lizards instead of doing something more useful with his career. “Now there is this drug developed from their venom that’s helping people with type 2 diabetes,” he says. “It’s not necessary to justify biodiversity based on what it can do for people, but it’s nice to have examples of an animal that can help save people’s lives. If we didn’t have them around, we’d be diminished.”

Deadly Saviors

If you’re a shell collector, you’re familiar with cone shells—marine gastropods (snails) that live in tropical oceans around the world, mostly in shallow waters. They are prized for the beauty and diversity of patterns on their shells. Medical researchers also prize cone snails, but for a different reason—the diversity of their venom. Cone snails (Conus spp.) use venom to subdue their prey. About 80 percent of cone snail species eat marine worms called polychaetes, about ten percent eat other gastropods (including other cone snails), and about ten percent eat fish, according to Thomas F. Duda, Jr., assistant professor of ecology and evolutionary biology at the University of Michigan and a research associate with the Smithsonian Tropical Research Institute. “It’s probably the only gastropod that preys on living fishes,” he says.

cone snail
The cone snail's venom has compounds that can be used in pain relievers and other drugs. (Doug Perrine / naturepl.com)

When a cone snail senses prey nearby, it reaches out its proboscis—a long skinny extension from the mouth. If the proboscis feels suitable prey, a tiny harpoon-like tooth shoots out of the proboscis at 200 meters per second (about 400 miles per hour), and injects the prey with venom that paralyzes it in milliseconds. Cone snails occasionally sting human divers or collectors, causing pain, respiratory distress, and sometimes death.

Cone snail venom contains peptides called “conotoxins.” The conotoxins work by blocking ion channels, which are pores in cell membranes. The opening and closing of these pores control the flow of ions across cell membranes, which in turn control many basic cell functions.

Each species’ venom contains as many as 100 or more different conotoxins, all of which are probably unique to that species. With 500 to 700 species, that makes the genus a pharmacological treasure trove. A compound from the venom of the fisheating cone snail Conus magus has been isolated and synthesized as the drug ziconotide (Prialt), approved by the FDA in 2004 for the treatment of chronic severe pain. The drug must be administered by a pump directly into the spinal fluid.

“We’ve really only touched the tip of the iceberg,” says Jon-Paul Bingham, assistant professor at the University of Hawaii at Manoa on the island of Oahu. He says at least seven other synthetic drugs based on conotoxins are currently undergoing trials to treat ailments as wide-ranging as epilepsy, incontinence, and shingles.

Scientists around the world are continuing to look for more applications. For most scientists, the easiest way to get venom out of a cone snail is to kill it and dissect it. Bingham has worked out a reliable way to raise the snails and “milk” them for venom. “What we’re hoping to do is establish a venom bank, which will allow scientists all over the world to analyze the compounds for potential pharmaceutical application,” he says. “And we want to do it in a biosustainable manner. You don’t kill the goose that lays the golden egg.”

Bingham keeps 25 species of cone snails in tanks and carefully analyzes the conditions under which they produce the most venom, and how the makeup of the venom varies. Unlike snakes, scorpions, or spiders, cone snails have the ability to modify the make-up of their venom over several weeks, depending on the types of prey they encounter. “We’re like dairy farmers,” he says. “We want to make sure our cattle are happy, well fed, producing the maximal amount of milk they can, and we want to know if we can get more cream by changing their diet.”

In addition to collecting venom for others, Bingham and his students are also studying the venom for possible drug applications. He says, “Every time we milk, I wonder, ‘What’s in there that may be a revolution to molecular medicine?’” Unfortunately, some cone snail species may be declining or even going extinct. Duda says scientists don’t know enough about cone snail populations or their evolutionary history to have a picture of the overall health of the genus, but he suspects some may be in trouble.

Cone snails are associated with coral reefs, many of which are threatened. “Some Conus species are restricted to very small areas,” he says. “Some people have noted that with coastal development, some Conus are no longer present. We really don’t know if they are going extinct, but we can’t afford to lose them.”

—Mary-Russell Roberson is a ZooGoer contributing editor.