CAN A KILLER turn into a healer? Researchers are exploring the use of toxins produced by the anthrax bacteria (shown) as therapeutic tools.
JEFF JOHNSON

Biologists have devoted many years to studying how the anthrax toxin invades a cell and does its killing work. In the past two decades, researchers have discovered how the toxin forms a pore that provides an entryway for two other toxin proteins to get into a cell's inner recesses and wreak havoc.

The toxin's breaking-and-entering strategy has not gone unnoticed by scientists seeking new ways to deliver vaccines into cells. And the lethality of one of the proteins has attracted the attention of investigators who have shown an interest in marshalling its killing power to combat tumors.

The idea of using a notorious pathogen as a therapeutic tool did not immediately generate an enthusiastic audience. Yichen Lu, a researcher at the Harvard University School of Public Health, remembers telling the director of the vaccine branch of the U.S. Food and Drug Administration in 1999 of his plans to use anthrax in an HIV vaccine. He described how a version of the toxin could be genetically engineered to eliminate its pathogenicity and how it could deliver a protein from the AIDS virus into an immune cell called an antigen-presenting cell. Once processed there, pieces of the protein would be displayed on the cell surface. That would induce production of killer T cells by the immune system that would then attack and kill the virus throughout the body. Lu remembers clearly the response of the FDA official when he suggested how important it was to move ahead with a safety test of the anthrax-derived vaccine on army soldiers: "She said, 'You're crazy.'"

As early as this fall, however, the U.S. Army plans to initiate a clinical trial to test the safety of just such a vaccine on a few dozen civilian volunteers from the Washington, D.C., metropolitan area. At about the same time, a safety test of an HIV vaccine using an anthrax delivery system might be launched in Botswana as part of a research program the Harvard School of Public Health maintains there. Despite its association with bioterror, such a vaccine is expected to have a good safety profile. It does not use an altered version of a live virus, which might revert to its pathogenic form, and it should also be relatively easy to produce in large quantities.

Still, the desultory results for AIDS vaccines so far dictates caution [see "Hope in a Vial," by Carol Ezzell; Scientific American, June 2002]. John G. McNeil, deputy director of the division of retrovirology at the Walter Reed Army Institute of Research, notes that the vaccine developed by Lu and his associates has produced promising results in mice and rabbits but adds that it is still too early to make any pronouncements about its effectiveness in humans. "We don't have a clue what the immune effects will be," he says.

Interest in anthrax as an immunodelivery truck extends beyond HIV. Before taking a research position at Harvard in 1999, Lu had headed development of anthrax research at Avant Immunotherapeutics, a biotechnology company in Needham, Mass. There he studied using the toxin to transport antigens--the active part of a vaccine that generates an immune response--for not only HIV but also hepatitis B. If the initial army-sponsored trials prove a success, Lu plans to use the modified anthrax toxin in vaccines for hepatitis B and Epstein Barr virus at Nan Kai University in China, where he holds a position as head of the university's vaccine laboratory.

Penetrating Cells

Michael N. Starnbach of Harvard Medical School has several graduate students working on vaccines that marshal the anthrax toxin's cell-penetrating abilities. In particular, his laboratory has studied vaccines for the pathogenic bacteria Listeria monocytogenes and for Chlamydia trachomatis. Many of these investigations have centered at Harvard, taking advantage of basic research on the biology of the anthrax toxin carried out there by biologist R. John Collier. [See "Attacking Anthrax," by John A. Young and R. John Collier; Scientific American, March 2002.] A collaboration between Starnbach and Collier produced, in 1996, the first published study on using anthrax as a delivery system for a vaccine.