The Good, the Bad and the Slimy
- Modern medicine is transforming detested
creatures and deadly toxins into potent life-saving tools.
- by Jon Nalick
It is axiomatic that no one will accept a medical treatment that inflicts more harm than the disease it treats. After all, even if injections of the Ebola virus could completely cure arthritis, not many folks would line up for a shot.
Still, as odd as that fictitious treatment sounds, the underlying concept of treating certain conditions with otherwise harmful toxins, germs and parasites is medically valid.
Keck School of Medicine physicians and researchers are examining-and in many cases treating-patients with several things that people, under normal circumstances, would usually avoid. These include leeches, rattlesnake venom, viruses and botulinum toxin-a paralytic poison once studied by the U.S. government as a potential chemical warfare agent.
Beneficial Bloodsuckers
John E. Gross, M.D.,
professor of
clinical surgery, uses leeches as an adjunct to microsurgery
while reattaching amputated limbs.
"In medieval times, the theory was that bloodletting removed 'bad humors' from the body and was a good thing. They used leeches to accomplish that," he says. Still, he notes, "It turns out it wasn't such a good thing."
With the advent of modern medicine and scientific methods, the use of leeches ended. But starting in the 1970s, surgeons regained respect for the little bloodsucker, whose body was seemingly tailor-made for establishing and maintaining blood flow to damaged digits and limbs.
"Whenever you're doing microsurgery, sewing on an amputated body part, the key is reestablishing the plumbing to get blood in and get blood out. But sometimes when you can't find a vein to get blood out, everything backs up, the flow stops and tissue begins to die," Gross says.
By sucking on the damaged body part, leeches provide an outlet for blood that would otherwise be trapped and unable to deliver oxygen and nutrients. Over the course of three to five days, the wounded area will grow new veins, permitting the healing to progress without the leeches' help.
Additionally, leeches-usually dark gray or black creatures about the size of a man's little finger- inject a chemical when they clamp onto the body that serves as a natural anticoagulant to keep the blood flowing.
"They have their own little drug delivery system. It's an advantage because when the leeches fall off, the bite area oozes a little bit and lets blood get out for another hour or two," Gross says.
Leeches swell to three times their normal size while feeding, then drop away from the body. They usually need to be replaced every few hours and a patient may require as many as 20 of them before the treatment ends.
"The leeches are medical grade, grown in captivity. The pharmacy here at the medical school stocks them because, although you only need them once a year or so, when you do need them, you need them in a hurry," he says.
Gross says that most patients do not mind the use of leeches.
"When they understand that it's the choice of having a leech on them and saving a limb, or having something amputated, they usually take to the leech quite well."
Terrific Toxin
Physicians and patients have also come to appreciate the beneficial uses of other, more obviously dangerous fauna such as the Clostridium botulinum bacterium, which kills an average of 110 Americans annually. The bacterium can cause fatal food poisoning when ingested or introduced into a wound. Nearly all fatalities are caused by accidental ingestion of contaminated home-canned food or by infants ingesting botulinum spores, commonly found in soil.
Classic symptoms of botulism, which typically appear 18 to 36 hours after eating contaminated food, include blurred or double vision, slurred speech, difficulty swallowing and muscle weakness. In severe cases, individuals may suffer whole-body paralysis that can stop a person's breathing.
"Botulinum is a poison. In the 1920s and 30s, the U.S. War Department studied it for possible use in chemical warfare," Gross says. "But about 20 years ago, ophthalmologists and neurologists started seeing its use for functional reasons."
In 1989, the U.S. Food and Drug Administration approved the use of botulinum toxin-trademarked under the name Botox-for certain movement disorders, precisely because of its usefulness in causing graded weakness. Specifically, they learned that injecting small amounts of the toxin into muscles around the eye could help treat the symptoms of strabismus ("lazy eye") and muscle spasms, with virtually no side effects.
Mark Lew, M.D., associate professor of neurology, adds, "It was used experimentally for involuntary contractions of muscles, spasms caused by irritation of facial nerves, dystonic writer's cramp, involuntary speech-and it rapidly became the treatment of choice for all these conditions. Now we commonly use it to treat muscles all over the body."
Botox offers an effective treatment option to 100,000 Americans who suffer from focal dystonia, a syndrome of sustained muscle contractions that can cause involuntary repetitive motion and abnormal posture.
"Botox has revolutionized the treatment of focal dystonia and other movement disorders. Prior to this, there were medical therapies that offered, at best, modest improvement, with often intolerable side effects. There are surgical alternatives, but none have shown a lasting benefit. Botox is not a cure, but it can radically improve a patient's quality of life and ability to function," Lew says.
In addition, Botox can also be used to treat post-stroke spasticity, excessive bladder contractions and hyperhydrosis (excessive sweating).
Recently, however, Botox has gained a following among people who want to smooth their wrinkles for cosmetic reasons. Physicians are using the toxin to relax or paralyze muscles responsible for wrinkles on the forehead and around the eyes and mouth, leaving the skin smoother and younger looking.
"Demand for it has really snowballed in the last 10 years. Patients know about it and ask for it. They like it so much that the only complaint is that it's not permanent. It lasts about three to four months," Lew says.
He adds, "People ask all the time if it's safe because it is a poison, but it's very dilute, medically pure and injected just into the muscle. It has no effect elsewhere in the body and no one is allergic to it. Complications occur infrequently and are limited to excessive local weakness that is transient."
Botox injections run about $300 to $400 each. But even that has not deterred people from getting the injections, making it the most popular cosmetic option, increasing 120 percent in one year, according to the American Society for Aesthetic Plastic Surgery.
Valued Viruses
Nori Kasahara, M.D., Ph.D., assistant professor of pathology and biochemistry, is trying to turn some of mankind's most tenacious enemies-viruses, including those that cause AIDS and the common cold-into potent tools that help cure certain kinds of cancer and hereditary diseases such as cystic fibrosis and hemophilia.
Viruses are essentially packages of genetic information encapsulated by a shell that has evolved to sneak past the body's defenses. Once the shell arrives at its target, it injects a genetic payload that commandeers the cell and forces it to replicate countless copies of the virus.
Adenoviruses, including those that cause the common cold, cause infected cells to replicate so many virus copies that the cell itself explodes and dies. Retroviruses, such as the virus that causes AIDS, insinuate themselves into the host cell's genetic code-and although they do not kill the host cell, they can give rise to potentially fatal infections and cancers.
But Kasahara strips the viruses of their dangerous payload and uses only the shell to deliver beneficial genetic information to where it is needed.
In this way, viruses can be modified to deliver missing genetic information to human cells to correct inherited deficiencies, such as the hemophiliac's inability to clot blood.
Kasahara says that for the last 10 years, engineering the viruses to do these tasks has been largely trial-and-error, "which means there were a lot of things that didn't work very well."
But with accelerating research in molecular biology, understanding how viruses work to infect cells has advanced enough that now, Kasahara says, researchers can make educated guesses about which viruses are most likely to prove useful for specific applications and how they can best be engineered.
"For example, we're using a replicating virus that can spread through cancerous tumors to deliver 'suicide genes,'" he says. Once the genes are delivered to cancer cells, they act as a homing device for toxic drugs that then zero in only on the cancer cells and kill them.
"I think we have the potential to get these applications into the clinic within five to 10 years' time," he says.
Potent Proteins
Francis S. Markland, Ph.D., professor of biochemistry and molecular biology, has been seeking a way to save lives with one of the more deadly killing tools of the animal kingdom: rattlesnake venom.
In fact, he and his colleagues have isolated two potentially beneficial compounds, one that may be able to dissolve life-threatening blood clots and one that may help prevent the spread of certain cancers.
"Most people, when they hear about this research, are surprised that these detested creatures produce proteins that are potentially clinically useful," he says. "We order venom from a Florida-based serpentarium. The supplier has been bitten so many times, he has become immune to most snake venoms."
Markland's team has isolated one enzyme, called fibrolase, which shows promise in dissolving blood clots such as those associated with heart attacks, strokes and deep-vein thrombosis.
The enzyme is present in the venom of numerous North American snakes, but is most plentiful in venom from the southern copperhead. Unlike other so-called "clot-busting" drugs now in use, which rely on a two-step process to dissolve blockages, fibrolase attacks clots directly, breaking apart the tangle of protein bonds that seal off arteries and veins.
Millions of years of evolution produced the enzyme, which helps keep the blood of the snake's prey from clotting and keeps the venom's other deadly toxins flowing freely through the body. Now, Markland hopes that its identification as a potentially beneficial substance can spur additional research to make it a useful life-saving tool.
Markland's team is also examining another factor in the same kind of venom-a protein called contortrostatin that has been shown to slow breast cancer progression in mice.
Contortrostatin belongs to a class of proteins called disintegrins, explains Steve Swenson, Ph.D., a protein chemist in Markland's lab. Scientists know that disintegrins keep blood from clotting, but Markland and his colleagues discovered that contortrostatin has other potentially helpful characteristics that may help the body battle breast cancer. One of them involves cancer spread.
"Cells in a tumor near blood vessels can move through vessel walls and flow through the blood to other parts of the body," explains Swenson. "Then, they adhere to another vessel wall, move through it and invade surrounding tissues."
But in lab tests, contortrostatin appears to inhibit cancer cells from moving through blood vessel walls, he says, resulting in fewer metastases.
The substance may also deter new blood vessels from forming around the tumor. Cancerous tumors need a supply of blood to keep growing, Swenson explains, so when researchers injected contortrostatin directly into mouse mammary tumors, they found it resulted in decreased tumor size.
But the road from mouse to human being is a long one. One problem is that when contortrostatin is in the blood, the
circulatory system quickly sweeps it to the liver for disposal, he says. "We need to find a way to target it directly to tumor sites."
Another issue: The protein only makes up about .01 percent of snake venom. Scientists must discover a way to synthesize it chemically instead of deriving it from snakes.
Echoing similar comments made by his colleagues, Kasahara called the ability to derive beneficial uses from potentially lethal compounds and microbes a pleasant irony.
"It's poetic justice of sorts that we are now taking things like viruses, which have often been the scourge of mankind and the source of so much disease and suffering, and turning them into useful tools for research and potential therapies," he says.
But with a nod to the adage that chance favors the prepared, he adds that, "Our ability to turn these swords into plowshares has really been made possible by the advance of basic knowledge. Further research will remain the foundation for future discoveries, applications and treatments."
Alicia Di Rado contributed to this story.
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