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Taking the 
Alternative Route to Medical Discoveries

April 25, 2013 By:
Carol Saline, Inside Magazine feature
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Imagine for a moment that it’s 1796. The respected British scientist Edward Jenner observes that milkmaids are uniformly escaping infection from the smallpox epidemic devastating the country’s population. 

He theorizes their immunity to the deadly disease is somehow related to their constant exposure to cowpox on the animals they milk, and he proposes the theory that injecting healthy people with a diluted form of cowpox would protect them from getting smallpox. 

His contemporaries must have thought he was crazy. Yet his thinking outside the box created the revolutionary concept of vaccines and saved millions of lives. Or consider, more recently, the problem of C.Diff, a virulent intestinal infection that causes violent diarrhea and sometimes colitis, and that has become resistant to antibiotics. It turns out the infection can be cured with a decidedly unconventional treatment known as a fecal transplant. This approach implants healthy donor feces into the intestines of C. Diff patients, where it cooks up good intestinal flora to attack and replace the bad. No doubt, when it was first proposed, some snarky lab tech must have blurted out, “That idea stinks!” Today, the fecal transplant procedure has become an accepted, effective treatment. 

Then there is Botox, one of the leading cosmetic procedures for erasing wrinkles. When San Francisco ophthalmologist Dr. Alan Scott began injecting the deadly botulinum poison into patients’ eyes to relax the muscles there enough to counteract the disease strabismus, no one could have predicted that his radical approach would succeed in revolutionizing the field of non-surgical cosmetic procedures.

While most scientific research follows carefully established pathways, it’s these radical detours off the beaten path that sometimes produce the most interesting medical discoveries. Here are four such examples coming from labs in Philadelphia.

The tau of research

At the University of Pennsylvania’s Perelman School of Medicine, an anti-cancer drug sitting on a shelf inspired a new treatment for Alzheimer’s disease. Researchers believe that Alzheimer’s stems from a group of brain anomalies, including one caused by a malfunctioning tau protein. Tau is essential in supporting the transportation network that ferries nerve cell messages from one receptor to another. When tau becomes flawed, it forms clumps and tangles that are unable to hold the brain’s rail system in place. The nerve transportation system falls apart and memory messages don’t get delivered.

In 1994, John Trojanowski, Ph.D, and a fellow researcher at Penn’s Center for Neurogenic Research recognized that one of the properties of the anti-cancer drug Taxel was its ability to repair damaged tau protein. They wrote a paper suggesting Taxel might have potential for treating the tau problem in Alzheimer’s. At the time, however, they couldn’t test their hypothesis because researchers hadn’t yet figured out how to produce Alzheimer’s in animal models (like mice). There were also problems with Taxel itself, in particular, difficulty in getting the drug past the brain/blood barrier. Their theory floated in limbo until 1999, when a mouse model for Alzheimer’s was finally developed and they could study their theory in a laboratory setting. “It was so exciting,” says Trojanowski, “as if mice had read our original paper and responded just like we’d predicted.”

Research often moves more like molasses than spilled milk; it took nearly a decade to isolate the compound in Taxel that repairs tau proteins and engineer a drug for Alzheimer’s that had none of Taxel’s disadvantages. Using the compound epoD, the research team ran controlled studies on aging mice infected with Alzheimer’s. The results were better than hoped for: EpoD not only prevented additional tau clumps from forming; it actually reversed tangle pathology and improved memory function.

These exciting outcomes attracted pharma giant Bristol Myers Squibb, which bought the rights to epoD and is investing big bucks in the human clinical trials needed to gain FDA approval. Sometime soon, patients in the early stages of Alzheimer’s might be able to halt or slow the progression of their disease because two scientists had a novel idea to use the properties of a drug developed for fighting cancer as the basis for a new drug to halt memory loss. Now, that’s unforgettable!

Creating the fabric of their lives

Meanwhile, a few blocks away, on the Drexel University campus, teams are working on two very different, highly original concepts, both supported by Drexel’s Coulter Foundation, which promotes biomedical innovations. The maternity “smart fabric” bellyband project is an effort across three unlikely disciplines. The first group is comprised of scientists at the Drexel College of Engineering involved in developing smart fabrics created by weaving normal fibers together with special gold, silver and stainless steel yarns that can pick up and conduct wireless electrical signals. The engineers are working in concert with Genevieve Dion, a fashion design professor at the institution’s Westphal College of Media Arts and Design who works with sophisticated industrial digital knitting machines. Dion’s special interest is wearable technology — designing clothing out of fabric embedded with electronic capability. The third member of the team is Dr. Owen Montgomery, chief of obstetrics and gynecology at the Drexel University College of Medicine, and the catalyst who sparked the collaboration.

Montgomery met Dion on a committee that, among other things, was exploring how smart fabrics could enhance nursing performance. He was fascinated by Dion’s knowledge of this new technology and he envisioned a use for it in high-risk obstetrics. Women in high-risk pregnancies have to wear cumbersome fetal monitoring contraptions to alert doctors to potentially dangerous changes in uterine contractions and fetal heartbeats. These strap-on devices combining a pressure gauge and an ultrasound device haven’t changed in 30 years. Because they have to be plugged in to a power source to transmit information, they literally tether an expectant mother to her bed. Smart fabrics excited Dr. Montgomery with their possibility of combining soft yarns and “smart threads” in a garment that could detect and deliver critical information and transmit it wirelessly to a computer. What if, he wondered, the restrictive fetal monitoring device could be replaced by a comfortable, smart fabric-knitted belly band that transmitted data to the obstetrician while a high-risk pregnant woman moved around her home?

The team expects to have their belly band prototype available this summer. There are already a half-dozen venture capital firms chomping at the bit to take the garment to market. “Here’s a great example,” says Montgomery, “where you bring together medicine, engineering and design to think about a problem, find a scientific solution and then create it for the real world. This will be the first of many applications.”

Putting their “finger” on it

In another collaboration at Drexel, Dr. Wan Shih, a scientist in the School of Biomedical Engineering (with a Ph.D in both physics and material engineering) and Dr. Ari Brooks, a breast surgeon in the College of Medicine, are close to producing a handheld device that can radically improve the detection of breast cancer without exposure to X-ray radiation. 

Cancer was the last thing on Shih’s mind when she began research in piezo (Greek for “pressure”) ceramics. When this material, which is far more sensitive to touch than a human hand, is charged with an electrical current, it can produce a measurable response to the slightest pressure. Shih learned that one reason physicians palpate the breast and abdomen during examination is that diseased tissue feels harder, denser and stiffer than normal tissue — sort of like the difference between touching a pane of glass and a marshmallow. That led her to wonder if piezo ceramics, which could quantify tissue stiffness, might have diagnostic possibilities. She posed the question to Brooks, who does manual breast examinations all the time, and he enthusiastically replied, “Absolutely!”

They designed a series of experiments on breast tissue proving that a delicate, finger-like ceramic device built by Dr. Shih could accurately identify the size and location of even the tiniest of tumors, many of which turned out to be cancer. It was particularly acute at picking up abnormalities in women under 40, who tend to have denser breast tissue and whose tumors are often missed by mammography. “I am convinced,” says Dr. Brooks, “that this device is 60 percent more accurate than my own hands, which are pretty darn good.” 

As a result of their successful experiments, the pair is well into the development of an inexpensive, portable prototype for a small hand-held, battery-operated electronic gadget that doctors can lightly move over the breast to ferret out hidden tumors. The next step will be testing it in clinical trials. “Our goal is not to replace mammography,” Dr. Brooks explains, “but to have a sensor that will select those women who should be sent for a mammogram to delve deeper into a suspicious lump.” This is welcome news to all those women who’d rather have a root canal than an annual mammography and aren’t thrilled about the annual exposure to X-rays either. And it holds enormous promise for countries like China and India, where breast cancer is on the rise, but there is a woeful shortage of mammography machines to find it. 

Mobilizing your microscopic army 

At Jefferson Hospital, doctors are using a unique form of immunotherapy to battle lethal brain tumors. There is an immense amount of research these days seeking ways to turn the body’s immune system into a strike force against cancer cells. Dr. David Andrews, co-director of the Brain Tumor Center at Jefferson Hospital’s Kimmel Cancer Center, thinks he’s got one that works. Over the last decade, he has been refining a technique to shrink glioblastomas, the type of brain tumor that killed Ted Kennedy. He describes them as “spreading in the brain like vanilla fudge,” which is why they are hard to remove. It’s nearly impossible to surgically separate the cancerous fudge from the vanilla brain tissue. Standard chemotherapy and radiation have been virtually useless as well.

Andrews wanted to find a mechanism to kill the brain cancer organically. His research succeeded in uncovering a way to deactivate the switch located on the surface of cells that tells them when to live or die. Once he could kill brain cancer cells in the lab, he turned to patients. Normally, immunotherapies are delivered with just a single inoculation. Andrews’ procedure is different. Surgeons start by removing as much of the glioblastoma as possible and coating some of the retrieved cells with an anti-growth factor that can disarm the critical on-off switch responsible for regulating cell life and death. To ignite this reaction internally, the specially treated cells are nested into a mesh chamber — where they can’t escape to do any harm — and implanted in the cancer patient’s belly. The foreign intrusion acts like a wound to attract antibodies. The chamber stays inside the abdomen only for a day or two and is then removed — remaining just long enough to rev up the body’s fighting force and send the immune system to war, imprinted with the message ordering cancer cells to die. 

Nine patients given this protocol have shown significant tumor shrinkage. “We are very excited with the results,” Andrews says. If all continues as expected and the complicated FDA questions and hurdles are met, he will design Phase Two clinical trials to test how his inventive approach stands up against chemotherapy and radiation. He is optimistic that within five years, his new form of immunotherapy will become the gold standard for fatal brain tumors and the diagnosis of glioblastoma will no longer be a death sentence. 

Carol Saline is the chief medical correspondent for Inside.

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