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 March 2002
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Noteworthy Endeavors

Extra Credit

Personalized prescriptions

You wake up sniffling and sneezing. It’s fall. Relief should be as close as some over-the-counter pill or a doctor’s visit and prescription, right? After all, so many of your friends and coworkers have shared miracle stories after taking Claritin, Allegra, or Zyrtec.

Truth is, any one of those allergy drugs might work wonders for you. Or maybe they won’t do a thing. Or maybe one would clear your nose but give you headaches. For years, Reggie Frye puzzled over how weight, gender, and smoking habits caused the same drugs to have very different effects in different people.

In recent years, his study got a boost from the Human Genome Project* and its impact on the fledgling field of pharmacogenetics. Frye, an assistant professor in the School of Pharmacy, shifted his focus to how an individual’s genetic makeup influences the effectiveness of prescription drugs. His research could lead to tailor-made drugs that work well because they are based on the person and not some standard formula. The result would be drugs that offer relief, minus side effects ranging from annoying to fatal.

Here’s the goods. With a blood sample and specialized analysis, Frye uses a person’s genetic fingerprint in the study of six enzymes that metabolize most drugs. He has identified six substances, called probe drugs that the body metabolizes by using one of those six enzymes.

For example, an enzyme called CYP1A2 metabolizes caffeine, which is one of the probe drugs. This understanding allows Frye to administer caffeine and measure how quickly it’s metabolized, then administer a particular medication for one or two weeks, and follow that by re-administering the caffeine. If the caffeine isn’t processed as quickly as before introducing the drug, Frye knows that the drug inhibits the activity of the CYP1A2 enzyme.

With Frye’s recipe, the relationship between any drug and the six metabolizing enzymes can be explored simultaneously. It’s called the Pittsburgh Cocktail. (The name won out over Steel City Cocktail. “We’re not that creative,” he deadpans.) As a result some drug makers have hired him to perform drug interaction studies on their products.

Not all drug makers have been as enthusiastic about the research, Frye points out. Some companies worry about hobbled sales of blockbuster drugs of identical formulation. However, Frye notes that HMOs are intrigued by the money-saving possibilities from more effective prescriptions. What’s more, a handful of private companies are pushing to make genotyping technology more affordable for widespread clinical use. As the field of genotyping expands, so too does Frye’s focus. Frye, who does research through the School of Pharmacy’s Center for Pharmacogenetics, UPMC’s Center for Clinical Pharmacology, and the Pharmacodynamic Research Center, is looking now at how heart failure and other diseases affect drug metabolism.

—Emily Tipping

Protein ballet

A tiny ballet is not something you expect to see under a microscope. But that’s the comparison Pitt biologists Robert L. Duda and Roger W. Hendrix use to describe hundreds of protein molecules assembling around a single molecule of DNA. Duda and Hendrix, both members of the Pittsburgh Bacteriophage Institute, were first to see the way proteins encircled DNA in a bacterial virus called HK97.

Unlike in cells, a protein coating is all that protects the core of a virus, where its genes are located. The findings—which were published in the prestigious journal Science—are important because they may lead to better ways of stopping the spread of viruses.

Duda and Hendrix were first to describe the virus’ protein coating as chain mail, the medieval armor. According to them, proteins surrounding the head of the virus, or capsid, protect DNA by forming two types of interlocking rings. First, as in all such bonds, these molecules link chemically. But Duda and Hendrix discovered the protein rings also link physically, which creates a formidable wall, just like chain mail. Hendrix compares the coating to two separate rings of people who interlock both their hands and arms with people in the other ring. “No one had conceived that it existed,” Duda says about the structure.

In 1998, Duda used the term “chain mail” to describe the uncanny ability of the HK97 virus to resist laboratory-induced separation. The discovery explains how certain bacteria-attacking viruses, called bacteriophages, protect themselves. A team of collaborators verified the observations in 2000. The capsid starts with separate and distinct protein molecules. In the grand finale of the process, these proteins form a tightly locked sphere of 420 molecules. The proteins unite in a complex molecular choreography, which Duda and Hendrix call a protein ballet.

The ballet they saw was protein molecules as they wiggled, slipped, and slid into place around DNA. Hendrix says the protein dancers first assemble into a loosely organized structure, then progressively move and change shape until they become intertwined, forming a remarkably tough structure.

Molecular ballet is un- charted territory in biology, and there are some good reasons to continue the study. According to Duda, bacteria-attacking viruses are models for biological processes because they illuminate the behavior of extremely complex molecular structures.

Studying the protein ballet may yield new insights into how to assemble proteins in human beings. Learning to interfere with the assembling process, on the other hand, could stop the spread of a virus. Another possible benefit of the research is the creation of thin protein fabrics for tissue engineering, says Duda. Understanding the behavior of bacteriophages could save lives in another way as well. Phage therapy, an idea first toyed with around 1917, involves using bacteriophages to attack harmful bacteria. With the advent of antibiotic-resistant strains of bacteria, phage therapy might be making a comeback, says Duda.

—Robin Clarke

Faces of evil

She’s arranged quiet meetings with them in coffee shops, hotel rooms, private homes. In some cases, Pitt sociology professor Kathleen M. Blee spent more than a year studying their writings, tracking down the women, earning their trust, and finally traveling to interview them on their turf. No names, no physical descriptions. That’s Blee’s credo when she sits down to chat with racist American women about how they ended up as white power skinheads or neo-Nazis or members of the Ku Klux Klan.

Imagine such a meeting; a quilting bee certainly doesn’t spring to mind. But maybe it should. Blee’s new book,* Inside Organized Racism: Women in the Hate Movement, puts an unexpectedly normal face on violent thought. She talked to women of all ages around the country, including an active skinhead in the unassuming shape of a 90-year-old woman. The women cooked for racist group picnics, published their own newsletters, and had the same concerns as other mothers about crime in their schools and communities.

Blee sought to learn how women drifted into these groups and why they stayed. Some partied to music with a white power message. Others latched onto racist propaganda out of fear of growing crime. What stood out, Blee says, is how intelligent, well-read people could join groups with cataclysmic ideas about violence in such a casual way.

What she found most alarming in her latest research is the growing number of women who are fueling hatred of minorities. Some neo-Nazi groups count women among more than half of all new recruits. Nationwide, Blee estimates women make up 25 percent of the white supremacist movement. While the media play up white power as a male movement, women are the dangerous element. They offer family connections and stability, Blee explains. Adding to the strength of white power groups today is—ironically—their dwindling size. In the 1920s, membership in the KKK alone topped 5 million. Today, Blee estimates that 50,000 people are members of all racist groups combined. Smaller groups mean fewer marginal members who can rat on the others.

As an interloper in this hidden world of hatred, Blee notes she often had her own personal reasons to be nervous. She matter-of-factly says she would not attempt this kind of research again.

—Emily Tipping

Breakthroughs in the making

Grass not always greener: An increasing number of college graduates are staying in the Pittsburgh area to work after finishing school, a Graduate School of Public and International Affairs study finds. Among more than 2,000 graduates who were surveyed, big increases were found in all job categories between 1994 and 1999, says political science professor Susan Hansen. The findings are from the first comprehensive survey of graduates from Pitt, Carnegie Mellon University, and Duquesne University. The full study is available at http://www.gspia.pitt.edu/cldproject.

High voltage: Excess electricity generation capacity in Pennsylvania will prevent the kinds of power shortages and price hikes seen in California, according to Pittsburgh Economic Quarterly. Of the top nine states in power usage, Pennsylvania has the biggest excess capacity, according to the Pitt Center for Social and Urban Research Journal.

Seeing results: Daily vitamins can reduce the risk of vision loss related to age, researchers at the University of Pittsburgh School of Medicine have found. Dietary supplements containing high-dose antioxidants and zinc significantly reduce the risk of advanced age-related macular degeneration and associated vision loss, says Thomas R. Friberg, who led the Pitt arm of a national study involving 4,757 people between the ages of 55 and 80. The supplements did not reduce the risk of cataracts and had no benefit for people who were not already at high risk of vision loss.

*—denotes an external link. Links to external websites are offered for informational purposes only and the information there is not guaranteed or endorsed by the University of Pittsburgh or its affiliates.


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