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Stalking The Mutating Monster

Stalking The Mutating Monster

Stalking The Mutating Monster

Lethal. Wily. Relentless. The influenza virus killed millions of people last century. This century, virologist Andy Pekosz hopes to prevent such pandemics with a universal flu vaccine.

By Melissa Hendricks

The influenza virus is a wily and relentless foe. Each year, it infects about 1 billion people worldwide and kills hundreds of thousands. And when influenza evolves into a pandemic strain, as it did three times last century, it can kill tens of millions.

Stripped to its essence, however, the virus that has brought down populations and caused untold misery is one of the simplest organisms on the planet. It consists of merely eight genes. Humans, on the other hand, have some 20,000 genes.

"Influenza does a few things and it does them really, really well," says Andy Pekosz, PhD. Such Spartan efficiency is what first attracted Pekosz to virology. And now virologists such as Pekosz, an associate professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology, hope to borrow from influenza's own playbook, using a simple and eloquent strategy of their own to defeat the virus.

Their goal is a universal vaccine, one that will protect against not just this year's strain of influenza or next year's but any strain of the virus, including the most deadly of all—a version that has the potential to launch a global pandemic.

The details of the plan suggest it should work. But beautiful plans have failed in the past. Only exhaustive experimentation will test its merits.

IT'S GRANT-WRITING TIME, and Pekosz's fifth floor office is covered with papers. Federal funding for research on influenza has steadily risen since 2003, when the H5N1 influenza virus struck poultry in Asia. Public health authorities feared that avian influenza—the "bird flu"—could mutate into a virus that could spread from person to person and spark a pandemic.

It hasn't. But if it did, the impact could be devastating because the human population has no immunity to the H5 strain. Various scientists and government agencies predict a pandemic could kill tens to hundreds of millions of people worldwide, and cost billions of dollars. Although the precise figures vary, what's not in dispute is the merciless nature of pandemic flu. Witnesses to the 1918 global influenza pandemic described an illness that progressed with violent speed—faces turning bluish-black as oxygen drained from the victims' blood; patients coughing so hard they tore abdominal muscles and rib cartilage; others gasping for breath as fluid filled their lungs.

Pekosz is acutely aware of the "15 minutes of fame" accorded new and newly emerging diseases. In addition to influenza, he also works on SARS, the virus that received a flurry of attention when it struck in 2003. "It made big headlines," he recalls. "There was tremendous worry and concern bordering on hysteria." These days, he asks, "when was the last time you heard about SARS?"

Likewise, Pekosz worries that concern about pandemic flu may dissolve from people's consciousness, although he and many other influenza experts believe the threat remains. He flips through the papers on his desk, apologizing for the clutter, then picks up a copy of an editorial that appeared recently in the journal Nature. It asserts that another flu pandemic is "inevitable."

The versatile, eight-gene influenza virus ferociously evades scientists' best efforts against it. "It's almost inevitable. You introduce one pressure, and the virus will find a way around it," says Andy Pekosz.

In an office with few decorations, one figure on a shelf high above Pekosz's desk attracts the eye. It is the head of an Icelandic sheep with impressive horns, gazing outward. It came from Neal Nathanson, one of his two mentors at the University of Pennsylvania, where Pekosz earned his PhD. Nathanson, a legendary virologist, spent many years studying a retrovirus that is endemic in the breed. Because the virus does not infect people, some might question the merits of such research. But such basic science is essential to medicine, says Pekosz. Scientists can often infer how a virus will affect people based on studies that show how a similar virus interacts with an animal.

Pekosz's own research in graduate school focused on the mosquito-borne La Crosse virus (a major cause of pediatric encephalitis in North America). Since then, he has specialized in human respiratory viruses, such as influenza and SARS, always attacking questions from a basic science angle. Even his current research on an influenza vaccine grew out of earlier studies aimed at understanding the virus's basic components, its genes and proteins. His research motto might have been, Know your enemy—intimately, molecule by molecule.

UP CLOSE, THIS tiny organism—a mere 100 nanometers in diameter—looks like a spherical pincushion. This sphere contains the virus's genetic material, RNA—home to those eight genes—while the "pins" poking from this cushion consist of various types of protein macromolecules. These proteins are the reason scientists have struggled so hard to combat influenza.

Like the craftiest fighter in the ring who has unlimited moves for dodging an opponent, influenza has an extraordinary ability to change the composition of its surface proteins. This talent, the result of an exceptionally high genetic mutation rate, enables influenza repeatedly to evade the "enemy," whether that enemy be antiviral drugs or the human immune system.

"It's almost inevitable," says Pekosz. "You introduce one pressure, and the virus will find a way around it." To illustrate this phenomenon, he escorts a visitor down six flights of stairs to his basement laboratory. The cramped rooms contain the customary centrifuges, incubators and flow hoods. Stacked throughout the lab, on shelves and countertops, lie scores of Petri dishes. Pekosz indicates a stack of plates in a corner of the lab. Each is divided into 96 individual wells.

The wells contain influenza virus and mammalian cells that are prone to viral infection, along with various doses of the antiviral drug amantadine. In addition, each well contains a special dye used to gauge cell vitality; in the presence of live cells, the dye is activated and will reflect blue light.

Victims of the 1918 flu pandemic coughed so hard they tore abdominal muscles. Their faces turned bluish-black as oxygen drained from their blood. They gasped for breath as fluid filled their lungs.

Pekosz holds up one of the dishes. Some of its wells glow bright blue. Others are clear. The clear wells, he notes, indicate cell death due to the appearance of mutant viruses that have resistance to amantadine.

They took only three days to emerge.

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