September 2001


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Honey, I Shrunk the Gene
Mini-gene key to new treatment for muscular dystrophy

Xiao Xiao is having a small prob- lem with his email account: It keeps getting jammed because people around the world are e-mailing him pictures of their sons who, if nothing is done, will die from muscular dystrophy. The photos started coming en masse after USA Today and other news organizations announced that Xiao had created a mini-gene for treating Duchenne muscular dystrophy (DMD).

When a child is born with DMD, which happens in one out of every 3,000 male births, there is no sign of disease. But sometime between his third and seventh birthday, his muscles begin to deteriorate. His steps become forced. He walks by propelling himself forward with waddling strides — back arched, belly thrown forward to balance against his weakening muscles. Around his twelfth birthday, he will be confined to a wheelchair, and it’s unlikely that he’ll live through his teens.

A healthy muscle cell is like a long tube that shortens every time a muscle contracts. As the tube shortens, its membrane shrinks with it to form a tight cellular ball. But for people with DMD, this process is laden with problems. DMD is caused by a mutation in the gene for dystrophin, the structural protein required for muscle cells to contract and relax normally. With time, their membranes lose the ability to shrink when needed, and the muscle cells become leaky. The end result: The cells die, and muscles stop functioning as the body replaces them with firm connective tissue.

Because DMD is a disorder caused by mutations in a single gene, researchers believe it’s an excellent candidate for gene therapy, which is one of Xiao’s areas of expertise. But there is one major problem: The gene for dystrophin is the largest gene known to science, which means it’s about 600 times too big for the viral vectors that deliver therapeutic genes to patients.

Xiao works with adeno associated virus (AAV), which is considered the safest vector around. Even in its natural state, it doesn’t cause human disease and is incapable of replicating without assistance from another specific virus, one not commonly found in humans. Until now, the bad news was that AAV can only carry very small genes. But Xiao found a way around that problem by shrinking the dystrophin gene to fit.

“Basically,” Xiao says, “we’ve streamlined it into a miniature version that lacks all the nonessential regions but retains functionality.”

And it fits inside AAV vectors, which Xiao has now injected into the muscles of animals that have a disease that mimics DMD. The results, he says, are promising. Dystrophin levels rise to near normal, and the disease state vanishes. Before the mini-gene is ready for use in humans, Xiao and his colleagues must complete the FDA required long- and short-term safety trials. Once safety testing is complete, they plan to head into clinical trials with patients within a few years. And it doesn’t look like they’ll have a shortage of willing participants. The hundreds of e-mails clogging Xiao’s computer are from parents in Japan, Brazil, and everywhere in between who want to know when they can sign their sons up for clinical trials.

“We’re working as fast as we can,” Xiao says with a smile. But even if it ties up his e-mail system, he doesn’t want the messages to stop. “They’re really a drive for me to keep going.”—Rebecca Skloot

Magnetic Attraction
Magnetized fluids could revolutionize hydraulic systems

Like a magician playing to his audience, Pradeep Phulé removes the cap of a plastic beaker and displays its contents. A slightly foul-smelling brew with the consistency of gray paint fills the container halfway. As he tilts the container back and forth, the grungy liquid sloshes around inside, coating the beaker’s sides. “Now watch,” he says, picking up a half-dollar-sized magnet and pressing it to the bottom of the beaker. Instantly the liquid freezes. Phulé turns the container upside down. Not a drop spills.

There’s no sleight of hand on the part of the materials science and engineering professor. After more than seven years of work, Phulé is close to unlocking the potential of so-called magnetorheological, or MR, fluids. They could revolutionize hundreds of applications that use hydraulic systems, including automotive suspensions and clutches, airplane controls, and earthquake dampers for high-rise buildings. MR fluids, which harden when exposed to magnetic fields, were discovered more than 40 years ago by the Ukranian-born engineer Jacob Rabinow. They consist of tiny particles of iron—less than one-tenth the width of a human hair—suspended in liquid.

When no magnetic field is present, MR fluids flow at the normal viscosity of its carriers. Near a magnet, however, the iron particles form strings (Phulé calls them necklaces or pull chains, for indeed, that is how they appear under an electron microscope) and cause the liquid to become stiff. Remove the magnet and the iron particles float free again. “The iron we use, believe it or not, is the iron used in cereal, if you eat a vitamin-fortified cereal,” says Phulé, whose patient and polite demeanor belies an infectious enthusiasm.

Some commercial possibilities of Phulé’s neat trick: Hydraulic systems using MR fluids would have virtually no moving parts. Electromagnets could replace mechanical valves prone to sticking or leaking. But commercial uses have been slow to develop. Before the recent work of Phulé and other researchers including those at Ford Motor Company, MR fluids were unable to develop sufficient hydraulic pressure to make them useful. Worse, the iron particles showed a tendency to settle out of the fluid after weeks or months, making the resulting goo worthless. Larger iron particles offered some hope because they form MR fluids with more potential strength. The downside is they also have more potential to cause the fluid to clump. “The principle is very simple,” he says wryly, “but it isn’t as simple as it looks.”

Fortunately, Phulé isn’t easily discouraged. A history buff and fan of early inventors such as Michael Faraday and Nikola Tesla, he has a quote from Thomas Edison on his door: “For every problem, there is a solution.” From his study of MR fluids, Phulé knew that researchers had been unable to keep the iron particles suspended in liquid. Early on, he and two students walked down the block to a supermarket to fetch corn starch and baby oil. Mixing the two together in the lab, they observed the movement of the particles.

After several false starts, he developed an MR fluid composed of four parts: a carrier liquid, iron particles, tiny particles of silica to break apart any clumps, and a polymer that coats and forms bridges between the various aggregates. “Pittsburgh has a lot of bridges,” Phulé says, smiling. But only one of those bridges—Phulé’s—is patented. His patent was approved in 1999 and assigned to Pitt after a considerable wait.

Now, with General Motors working on an MR suspension for an upcoming Cadillac, and makers of everything from joysticks to wheelchairs interested in thefluids, there’s no question that Phulé’s work has paid off. “I have a great deal of satisfaction when I see something that I invented that is used,” he says. “I would be really proud if I have invented something that benefits society.”—Jason Togyer

Cheating Sudden Death
Can public access to defibrillators save lives?

Serious as a church, 8-year-old John Beck wanted some answers. “Where did you go when you died, Grandma?” he asked Mitzi McGee. “Well, I really didn’t go anywhere,” McGee said. That seemed like enough. After thinking about it for a minute, John said: “I’m sure glad they sent you back.”

McGee, a 66-year-old homemaker, mother of eight and grandmother of 20 children, collapsed suddenly in her kitchen last October while making supper. Pulseless and not breathing, McGee was dead—in the simplest sense. But her brain was still alive. She might still be saved. Husband William, 72, punched 911 into the phone. Within minutes, Dormont police officers Ralf Zawischa and partner Tom Maloney arrived. Using three wires and sticky electrode pads, the officers attached the unconscious McGee to a small, battery-operated machine that rides with them in the cruiser.

Roughly the size of a laptop computer and a little heavier, the machine quickly analyzed the jumbled electrical rhythm of McGee’s heart. Next it determined that a big electrical jolt was needed to stop her heart from beating out of control. The machine, called an automatic external defibrillator, delivered a shock to McGee. The officers then started cardiopulmonary resuscitation. McGee remembers only waking in a hospital two days later. “Hey, these things work,” Zawischa says. “They are actually saving lives.” McGee is living proof.

One-time paramedic and UPMC emergency medicine doctor Vince N. Mosesso Jr. conducted the 1992 study in McGee’s borough and surrounding Pittsburgh communities that showed the life-saving value of having police carry defibrillators. Since then, reducing the number of deaths from sudden cardiac arrest has become Mosesso’s passion. Now, he has a powerful new tool. Last year Mosesso was named medical director of the newly formed National Center for Early Defibrillation. Housed at UPMC’s Center for Emergency Medicine of Western Pennsylvania, the independent, nonprofit center provides information about how to survive sudden cardiac arrest. It is also the only national clearinghouse dedicated to providing complete information about defibrillators. “I call it a one-stop shop,” says Mosesso.

What researchers know is that more than 600 people die each day in the United States because their hearts suddenly start beating chaotically. Within minutes, these hearts simply stop beating. If these people were shocked within the first minute of cardiac arrest, 90 percent could be saved. Every passing minute after that reduces the chances of survival by 10 percent. Mosesso is also overseeing the Pittsburgh part of a national two-and-a-half-year study, co-sponsored by the American Heart Association and the National Heart, Lung and Blood Association, that’s looking at whether easy public access to defibrillators can improve survival from sudden cardiac arrest. Pittsburgh is among two dozen cities where the study is being conducted. Early results are promising. Easily accessible defibrillators at O’Hare Airport in Chicago, for example, are credited with saving 10 lives. Zawischa says the payoff for saving McGee’s life was priceless: “Just the smile on her face,” he says. “That was payment enough.” —Kris Mamula

Breakthroughs in the Making

A prescription drug that is used to treat brittle bones significantly curbs the risk of some kinds of breast cancer, says Jane Cauley, associate professor of epidemiology at Pitt’s Graduate School of Public Health. Cauley was the principal investigator of a large-scale study that found that raloxifene reduced the risk of some breast cancers by 84 percent in post-menopausal women. The study involved 7,705 women with an average age of 66.5 years and a history of osteoporosis….A firefighter's one-time visit with a child who sets fires is not as effective in changing the child’s behavior as fire safety education and behavioral therapy, new research from the University of Pittsburgh has found. David J. Kolko, associate professor of child psychiatry, psychology and pediatrics at the School of Medicine found that therapy and education worked better in curbing behavior such as playing with matches or lighters than a home visit from a firefighter. Kolko’s findings were published in the March issue of the Journal of Child Psychology and Psychiatry….Watching hundreds of protein molecules form a protective coating around a single DNA molecule is like watching a carefully choreographed ballet, say University of Pittsburgh researchers Roger Hendrix and Robert Duda. Hendrix and Duda, both members of the Pittsburgh Bacteriophage Institute and the Biological Sciences Department, were the first to witness one of the main sequences of this microscopic virus dance in high resolution. Their findings were published in the April 27th issue of Science.

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