Smallpox virus, single virion, as seen by negative stain electron microscopy. This virion is from a diagnostic specimen that came to the Centers for Disease Control in 1966 as part of the World Health Organization Global Smallpox Eradication Program. Magnification about x150,000.
Micrograph from F. A. Murphy, School of Veterinary Medicine, University of California, Davis.

Dr. Barbara Sherry tries to produce a safer smallpox vaccine.

Electrostatic surface plot of AbrB protein (bottom) binding to one of its DNA targets, with areas of blue being positively charged and areas of red being negatively charged. The blue area in the middle is a pair of alpha-helices that bind to the DNA (top).

Smallpox virus, growing in the cytoplasm of an infected cell. Thin section of infected chick embryo cell. Mature virions are brick-shaped, but immature forms are also visible. Magnification approximately x25,000.
Micrograph from F. A. Murphy, School of Veterinary Medicine, University of California, Davis.

When envelopes containing anthrax started showing up in the mail at government and media offices in October 2001, creating a nationwide public health scare, Dr. John Cavanagh found a new research target. Likewise, when worries about a terrorist-stimulated epidemic renewed interest in smallpox vaccination, Dr. Barbara Sherry knew she had the expertise to find a safer vaccine for the alarming number of people exhibiting adverse reactions to the existing serum.

The age of bioterrorism has opened new avenues of research for biologists trying to tackle pathogens like anthrax and smallpox, with many adapting ongoing studies to address changing priorities—both national and personal.

Cavanagh, a biochemist, has studied the protection systems of bacteria for years in an effort to create better antibiotics. Following the anthrax attacks three years ago, he turned his attention to that organism, which acts through “unbelievably tough” spores. “You can boil them in water or bang on them with a hammer, and they just laugh at you,” he says. Anthrax generally isn’t harmful unless inhaled. Even then, he says, it can be treated with antibiotics if caught early enough. But because it produces flu-like symptoms, it often isn’t diagnosed in time and is fatal in 80 percent of those cases.

The bacterium does its deadly work when its spores germinate inside someone’s lungs, releasing three toxins. One delivers the others to cells, a second fights off the cellular immune system, and the third kills cell growth. “Separately, they are harmless, but they work together to become lethal,” Cavanagh says. “It’s really a nifty set-up.”

Working with the Scripps Research Institute and the University of Maryland on $2 million in National Institutes of Health grants, Cavanagh is focusing on a protein, AbrB, that controls all three toxins. He’s using a similar bacterium to look for a way to stop AbrB in its tracks. Blocking the control protein is a more promising approach than going after one of the individual toxins, he says: “Why not head things off at the pass and stop the nasty stuff from being made in the first place?”

Cavanagh is taking two approaches to the problem. First, he is looking for something that the protein finds more attractive to attach itself to than its normal DNA targets. Also, by using nuclear magnetic resonance spectroscopy to develop three-dimensional images of the protein, he can study its shape and how it moves. That could suggest a way to grab AbrB from behind and prevent it from attaching. “We’re trying to outcompete processes that have been around for a million years,” he says.

Meanwhile, Sherry is trying to address a problem of a more recent variety. Smallpox immunizations were a routine part of childhood in previous generations until the World Health Organization declared the disease eradicated in 1980. After 9/11, the U.S. government set out to resume mass vaccinations of Americans to head off a potential smallpox epidemic if terrorists were to spread the virus across the country.

Officials started inoculating thousands of military personnel and emergency first responders, but immediately halted the program after one in about every 2,000 recipients exhibited myocarditis, or damage to the heart tissue. “A small number of problems was reported with the vaccine back in the 1950s and ’60s, but clearly, it becomes a major problem when you plan on immunizing 10 million people,” says Sherry, a molecular biologist in the College of Veterinary Medicine who specializes in viral infections in the heart. She has teamed with a Duke University professor on a two-year, $500,000 National Institutes of Health grant to find the cause of the adverse reactions and possibly develop a safer version of the vaccine.

Sherry is injecting the existing vaccine and a modified version of it—both contain a weakened virus—as well as a more virulent pox strain into cultures of mouse heart cells to find if the virus itself infects the cells or merely launches a chain reaction in which the cells die amid the toxic atmosphere created in fighting off the infection. “Sometimes, the systems the body uses to protect itself do have downsides,” she says.

To target ten cell factors that might be responsible for the adverse reactions, Sherry and her assistants—all have been vaccinated without problem—are genetically manipulating the smallpox virus to see how the heart cell cultures respond to the variations. They hope to discover a gene they can remove to prevent myocarditis without reducing the efficacy of the vaccine. “You can’t just blindly go in and make a different virus and hope it will work,” she says. “Millions of people will be depending on it to work.”

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