June 12, 2009 — -- The words "drug development" may conjure images of white-coated scientists, working at benches with pipettes and petri dishes.
But the real experiments have been occurring in nature for millennia, where life on land and sea has developed distinct chemical methods of survival -- from capturing their prey to identifying disease-causing microbes.
Thus far, humans have tapped a small but successful portion of the resulting cornucopia of compounds with the potential to cure disease.
Dr. Leslie Boyer, director of the Venom Immunochemistry, Pharmacology and Emergency Response Institute at The University of Arizona College of Medicine, points out that venomous creatures, who tend to be slow moving or rare and are generally outpaced by their prey, need a way to make their lunch hold still.
"They need to do something to the nerves, to the heart, to make the blood vessels leak," Boyer said. "Predators with no chewing teeth might need meat tenderizers, something to cause the tissue to dissolve, like digestive chemicals... There are examples in nature of chemicals that do all of those things."
And a chemical that performs a certain function in one animal could perform similar functions in another animal. Compounds that affect nerve cells could be effective for pain, muscle relaxants or other neurological indications. Venom that causes bleeding may contain anti-clotting factors useful for heart disease. Proteins that dissolve or loosen tissue have a multitude of uses.
Baldomero Olivera, a professor of biology at the University of Utah and the pioneer of drug research based on cone snail venom, continues to work on these creatures and points out that there is an enormous amount of basic science to do in this field.
"People are beginning to realize that almost all venoms have a complex pharmacological profile," Olivera said. "This is really a field in its infancy ... we know very little about the role of natural products in biological interactions."
But advancements in parallel fields, such as taxonomy, biochemical engineering, molecular imaging and technology have sped up the process of choosing and studying animals that may yield drug research benefits.
"We are becoming much more efficient," Boyer said. "[Different] scientific work is enabling scientists and physicians to learn faster where the good stuff is ... We are finding drugs hand over fist in these animals and we humans are going to benefit the most when we understand this tree."
The following is a list of animals that have contributed to medicine.
Frog Skin Antibiotics
Sir Alexander Fleming's discovery of penicillin in 1929, a happy accident, marked a new era of medicine in which antibacterial drugs offered new protection against many formerly fatal infections, including pneumonia, scarlet fever and venereal disease. But for the rest of the animal kingdom, this was nothing new.
"Every animal, from the simplest hydra to man, makes antimicrobial peptides," said Dr. Michael Zasloff, a professor of surgery at the Transplant Institute at the Georgetown University School of Medicine. "They serve to protect us and to live in harmony with bacteria."
Zasloff knows animals can protect themselves with antimicrobials because of a happy accident of his own. While conducting research using frog eggs at the National Institutes of Health in the 1980s, Zasloff noticed that the sutures on the female frog abdomens, following ovary removal, healed without becoming infected, even in their non-sterile tanks.
"In their skin, these animals stored high concentrations of powerful antibiotics of a particular type -- antimicrobial peptides," Zasloff said.
These compounds, evolved since the beginning of life on Earth, can be far more effective than conventional antibacterial medications because they recognize microbe membranes rather than microbial proteins and enzymes. Altering the membrane to develop resistance is far more difficult for bacteria and fungi than altering a protein.
Cases where this system fails and the body overreacts to microbes results in illnesses like Crohn's disease or cystic fibrosis.
Based on the antimicrobial proteins he found in frog skin, Zasloff completed a large phase three clinical trial on diabetic patients who get diabetic ulcers on their feet to see if a topical antimicrobial ointment would be effective against those infections. The trial was successful but the FDA requested another study on the ointment in the absence of other drug use by the study subjects. Zasloff put further experiments on hold but said a private company has taken charge of further experiments.
"But this is the most advanced of the drugs," Zasloff said. "It is one of those drugs that is moving forward."
You can find them in ancient Egyptian hieroglyphics -- Napoleon Bonaparte once decreed that all hospitals could not be without them and they even helped save limbs during the Vietnam War.
This ancient medic of the animal world has been used by man for thousands of years; it also happens to be a slimy bloodsucker that can eat ten times its own body weight in blood.
Today, medicinal leeches are used after severe trauma to help reattach digits, close wounds and help mend skin after plastic surgery.
There are approximately 650 species of these fresh water worms but only one, Hirudo Medicinalis, is approved by the Food and Drug Administration for medical use.
The approved leeches are the perfect size -- unlike Amazon leeches which would take more than their fair share of blood. It has just the right biting mechanism: three jaws with hundreds of sharp teeth that feed on the surface of the skin. They also secrete anti-coagulants which helps keep the blood flowing.
And it's this combination of adaptations that makes them perfect for saving limbs and skin.
"If you have a thumb that is reattached, the doctors will repair the arteries, tendons and muscles but the little veins that carry blood back to the circulatory system are damaged and traumatized," explained Rudy Rosenberg Sr. of Leeches USA Ltd., a medical leech distributor. "The blood pools in the reattached thumb and has nowhere to go, so you put the leech on the limb to suck out the extra blood until the veins redevelop."
Brazilian Arrowhead Viper
Venom from the Brazilian arrowhead viper, also called a Brazilian pit viper, was the basis for developing one of the first ACE inhibitors, a group of drugs used to treat hypertension and congestive heart failure.
Researchers isolated a molecule called bradykinin potentiating factor from the viper venom and found it is related to a class of molecules that stop angiotensis-converting enzymes (ACE) from blocking bradykinins, a protein that causes blood vessels to dilate and lower blood pressure.
Boyer pointed out that an animal such as a snake needs their prey to be still. Decreasing blood pressure could be a useful property for snake venom, since snakes require that their prey be still while they eat and digest them.
Bradykinin potentiating factors were eventually developed into the drug captopril, used to treat hypertension, cardiac conditions and to preserve kidney function in diabetics, and launched in 1975 by the pharmaceutical company Squibb, now part of Bristol-Myers Squibb, to great success.
The colorful Gila monster (pronounced HEE-la) is a scaly loner that lives in the deserts of the Southwest United States and northern Mexico. It scavenges for small eggs and small animals, spends most of its time underground, and is one of two species of lizards on Earth that produce venom.
It's this venom that makes the Gila monster a medical wonder as well as a natural curiosity.
"In the case of the Gila monster, they are cold blooded animals that in the winter hold very still," Boyer said. "To save energy, tissues like its gut, glands, pancreas, all stop being juicy and active. When the critter wakes up in spring, its venom liberates hormones into body that stimulate its organs to become robust again and ready to receive a meal. "
Dr. John Eng, an endocrinologist at Solomon A. Berson Research Laboratory, discovered this hormone in 1992 which he named exendin-4. The venom hormone was very similar to a hormone produced in the human digestive tract which is responsible for increasing the production of insulin when blood sugar is high. He also found that exendin-4 remained effective in the body longer than the human hormone.
The Gila monster's adaptive tricks now help thousands of diabetes sufferers.
In 2005 the Food and Drug Administration approved the drug Byetta, derived from Gila monster venom. The injectible medicine is effective at helping people with Type 2 diabetes maintain healthy glucose levels. The drug also slowed the emptying of the stomach, decreasing appetite and helping patients to lose weight.
When all other treatments fail and patients face losing life and limb -- literally -- these creepy crawlers are called in to do the job that doctors and modern medicine sometimes cannot.
Maggots are small, voracious eaters that love to feast on diseased and dying flesh. But their nauseating idea of a great meal is a life-saving asset for those suffering from chronic wounds and infections.
"I call them micro-surgeons," said Dr. Edgar Maeyens Jr., dermatological surgeon who practices in Oregon. "Those little guys can debride [clean] a wound better than any guy with a knife."
Maggots used to be standard treatment for wounds in the early 20th century, but with the discovery of antibiotics they fell out of common use. But maggots seem to be making a comeback as bacteria mutates and becomes resistant to antibiotics; more doctors are turning to maggots as a last resort before amputation.
"Maggots will turn a chronic wound into an acute wound in a matter of days by eating the chronic tissue and bacteria. From there the wound becomes treatable and can finally heal," Maeyens said.
These hungry insect larvae are sterile, work quickly and also cost less than traditional treatments.
"For just a few dollars and in just a few days you can do what months of treatment and tens of thousands of dollars could not," Maeyens said.
Goat-Made Spider Silk
We've all heard of Spider-Man -- but how about a spider-goat?
These transgenetic goats are very unique because they produce something out of the ordinary: spider silk. The same substance that makes up spider webs is created in their milk glands.
Spider silk is referred to by many scientists as bio-steel. Much like in the Spider-Man movies, spider silk has super tensile strength. If made in large quantities and threaded together researchers say it would be strong enough to produce bullet proof vests, parachute cords or to tether airplanes to aircraft carriers.
Spider silk can also be used to make artificial ligaments and tendons that support tissue, bone and nerve cells, holding them steady while they grow. These artificial silk parts then fall apart gradually, after the cells have been given enough time to grow.
But why goats? Spiders, unlike silk worms, tend to eat each other when placed together in large numbers. So scientists came up with a solution.
"The process is conceptually very simple. The spider silk gene for the silk protein is connected to DNA from the goat that controls in what tissue the protein is made. In this case it is the mammary gland and is made only during lactation," said Randy Lewis, a molecular biologist at the University of Wyoming who helped engineer the goats. "That cell is then combined with an egg to ultimately produce an embryo that has the gene incorporated into its DNA. The silk protein is then made when the female starts lactating."
Don't be fooled by the gracefully swirled and mottled shell or their sedentary nature. Cone snails are one of nature's most dangerous creatures and their toxic venom can be fatal to humans. But in the right doses, some of those compounds can be useful.
"We started working on cone snails, to be honest, because we had nothing else to do at the time," said Olivera. He had taken a position at a university in the Philippines in the 1970s and his lab was ill-equipped to handle any but the most basic scientific experiments. "I collected shells as a hobby as a kid and I knew certain types of cone snails killed people ... Our goal was to purify components of the venom that might be responsible for it's lethality."
A fish-eating mollusk, the cone snail uses a harpoon sting to deliver its venom and kill nearby prey.
"Cone snails don't have a lot going for them mechanically as far as catching their prey," Olivera said. "They probably use their venom for more purposes than most other animals."
Olivera cited defense against predators and competitive interaction amongst other cone snails as possible uses of the venom, which contains about 150-200 different compounds and these can be unique between cone snail species. The diversity of compounds offers researchers a pharmacological library of compounds to work with.
In 2004, the FDA approved the use of the pain medication ziconotide, marketed as Prialt, derived from one of the conopeptide proteins from cone snail venom. Other potential uses for compounds from the snail venom include drugs for neurological pain, epilepsy, heart disease and stroke.
Caribbean Sea Sponge and Coral
They may seem almost mundane; a simple sea sponge and coral on the bottom of the ocean floor.
You would never guess that something like this Caribbean Sea life might lead to the development of amazing future treatments for some of man's biggest medical challenges, including cancer and antibiotic resistant infections. But that is exactly what researchers hope for.
While coral reefs and other underwater life were dying around it, the some species of Caribbean sea sponges and coral continued to thrive. Upon closer examination, researchers found that a naturally produced antibiotic was helping them to survive. This antibiotic strips bacteria of their protective bio-films, making them easier to kill. Scientists estimate that 65 to 80 percent of all bacterial infections are bio-film based.
But the discoveries don't stop there.
A chemical called candidaspongiolide (CAN), which inhibits protein synthesis, can kill some cancer cells. The findings were published in the Journal of the National Cancer Institute.
"Our basic understanding of the relationship between animals and the chemical they produce has come a long way," Boyer said.
Researchers say there is much more research, tests and trials to complete but they hope it won't be long before it leads to effective new treatments in the future.
Maybe you think salmon belongs on a dinner plate, but you can find it at the pharmacy, too.
Calcitonin-salmon is the generic name for a class of drugs, which include Miacalcin and Fortical, used to treat bone loss.
Humans make calcitonin, a hormone that inhibits bone loss, in the thyroid gland. But in postmenopausal women and people with Paget's disease, the rate of bone loss increases. Extra calcitonin can prevent such bone loss and promote bone density.
"It's about getting clues from animals to help with human health," Boyer said.
Although fish have no thyroid glands, they do produce calcitonin hormones to regulate their own calcium levels from an endocrine gland in their neck. The synthetic version of this calcitonin from the coho salmon, the calcitonin-salmon, makes it into the final medical product for people with calcium regulation disorders.
The southeastern pygmy rattlesnake, found in the United States from North Carolina to Florida and west through Texas, is too small to pack a dangerous bite, but the venom has some startling properties.
A molecule in the venom leaves prey bleeding profusely, their blood unable to clot. This could speed death for the prey of these small snakes.
"Naturally occurring substances that can genuinely do harm, at different doses, maybe could be drugs," Boyer said.
This molecule from the rattlesnake venom was developed into eptifibatide, an antiplatelet drug that binds to platelets in the blood for a short time and prevents them from sticking together, or aggregating.
Eptifibatide is used to treat people with advanced heart disease, particularly those at risk for sudden heart attack. The drug prevents blood clots, which can block arteries and cause heart attack and stroke, from forming.
Every person in the world today who receives vaccines, antibiotics, or implanted medical devices such as pacemakers, has had their safety ensured by the blue blood of the horseshoe crab.
Unchanged for more than 200 million years, the crab's blood gets its blue color from copper in its system and its special properties that make the blood invaluable to modern medicine.
"People began to notice that if [the crab] got wounded and it got infected, their blood would gunk up and coagulate," said Eric Hallerman, director of the Horseshoe Crab Research Center at Virginia Polytechnic Institute and State University.
And that's exactly the way it's used today. A protein in the blood called Limulus Amebocyte Lysate (LAL) reacts to all kinds of microorganisms and can easily detect dangerous endotoxins that cause fever and can be fatal. Any contamination and scientists will see the blood react.
"Over millions of years the crab has been exposed to an awful lot of microbes," Hallerman said, "making them immune to a wider range of threats than any other animal."
When collecting the blood -- valued at $15,000 per pint -- the crabs are picked up by trollers who deliver the animals to a lab where they are bled. The crabs are then released back into the wild.
Hallerman's organization works with fisheries all over North America to make sure the crab populations remain high and that measures are taken to protect them.
"Humans looked to nature and nature gave us answers," Hallerman said. "Over 200 million years, the crab survived the asteroid that killed the dinosaurs, and survived human assaults on habitat. I know they'll be here long after we are gone."