Beyond bug-killing ‘nukes’

In the late 1960s, when antibiotics and vaccines had all but vanquished smallpox, polio, and rheumatic fever, Surgeon General William H. Stewart, M.D., appeared before Congress and declared, “It is time to close the book on infectious disease.” Within a few years, medical school microbiology departments, including Yale’s, were closed down across America.

This declaration of victory was premature, says Jorge E. Galán, Ph.D., D.V.M., the Lucille P. Markey Professor of Microbial Pathogenesis, pointing out that scores of new and deadly infectious diseases have emerged, including HIV/AIDS, Legionnaire’s disease, and Lyme disease. And tuberculosis, sexually transmitted diseases (STDs), and influenza are still very much with us, sometimes in stubbornly drug-resistant forms.

In the late 1990s, then-Dean David A. Kessler, M.D., lured Galán, renowned for his work on the Salmonella bacterium, to Yale to launch the Section of Microbial Pathogenesis (SMP), a program distinguished by a multidisciplinary and holistic approach to the study of microbial pathogens. Bacteria, viruses, and parasites have developed elaborate survival strategies over evolutionary time, but in tandem, we humans have evolved our own mechanisms to deal with them.

The SMP’s mission is to gain a deeper understanding of microbial pathogens within the context of the host cells they infect and the immune systems they sometimes defeat.

While earning a doctorate in veterinary medicine at The National University of La Plata (UNLP) in his native Argentina, Galán’s clinical work with animals sparked an interest in infectious diseases. Finishing first in his class with what he calls a “ridiculously high GPA,” he was awarded a fellowship to study in the Ph.D. program in microbiology at Cornell University, which had a longstanding academic relationship with UNLP.

After postdoctoral work on Salmonella in the laboratory of Roy Curtiss III, Ph.D., at Washington University in St. Louis, Galán moved on to Stony Brook, and then to Yale, where he has built the SMP into a team of seven distinguished scientists who bring a diversity of research methods to bear on infectious diseases ranging from tuberculosis to Legionnaire’s disease to tropical parasitic diseases.

One insight that has emerged from recent research, Galán says, is that it may be time to rethink the militaristic jargon—microorganisms “attack,” hosts “mount a defense,” and so forth—that has so permeated his field. Most of the time, pathogens go about their business without causing great harm, he says, and the blunt antibiotic weapons we use to treat infections can do more harm than good in the long run.

“Conceptually, antimicrobials haven’t changed since Fleming came up with penicillin,” says Galán. “We kill the bugs.” Because such a strategy attacks very basic biological processes, normal bacterial flora can also be targeted, potentially causing serious side effects, and any microbes that survive are highly resistant. “Using ‘nukes’ because we don’t know enough about the culprit,” says Galán, “will be history very soon.”

Galán’s own research toward this end focuses on the Salmonella type III protein secretion system, made up of a syringe-like tube, or “needle complex,” through which the bacterium injects bacterial proteins into host cells, modulating their function for the bacterium’s own advantage. In 2005 Galán joined forces with electron microscopist Vinzenz M. Unger, Ph.D. (see related story), to produce the first three-dimensional image of the needle complex in all its terrible beauty, pointing the way to the development of precise new anti-Salmonella regimens.

“This is truly an exciting time in terms of what the field is going to be able to contribute to the solution to the pressing problem of infectious disease,” says Galán, “and our group is going to be in the thick of it.”