- By Erica Westly
TB or not TB?
Bill Jacobs’s laboratory at the Albert Einstein College of Medicine in the Bronx sits in front of what was once a 500-bed tuberculosis sanitarium. For Jacobs, the now-decrepit facility serves as both a reminder of the past and a warning of what could happen if effective weapons against a wave of new drug-resistant strains of TB aren’t developed soon. “We’re basically back to where we were before drugs,” he says.
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Jacobs, 54, has been in the TB field for more than 20 years. Although he started his academic career as a mathematics major, today he is known as the grandfather of tuberculosis genetics. “Before him, Mycobacterium tuberculosis genetics was a totally intractable problem,” says Christopher Sassetti, a bacterial genetics researcher at the University of Massachusetts, Amherst. “Most of the work was focused on trying to understand the cell biology of the pathogen.” Today, Jacobs, a Howard Hughes Medical Institute investigator, runs one of the largest, most technologically advanced TB labs in the world.
Walking into Jacobs’s biosafety level-3 lab for the first time is a little unnerving. As we pile on item after item of safety gear—shower caps, masks, gloves, and thick plastic suits that cover even our shoes—Jacobs repeatedly assures me how safe the lab is, saying I have a better chance of contracting TB on the subway (not exactly a comforting thought for someone who regularly takes public transportation).
“We’re basically back to where we were before drugs.”
Inside the lab’s steel doors, a group of researchers shoots a training video while another conducts cell culture experiments. In the animal room, the most protected area of the lab, a one-of-a-kind apparatus that Jacobs helped design infects mice with TB through a series of pumps, then transfers the cages through the wall into a culture hood in the next room so no one has to handle them directly. The technology allows Jacobs’s staff to work with strains of extensively drug-resistant TB that most other labs in the field wouldn’t touch.
One of the most exciting discoveries to come out of Jacobs’s lab in the past few years came from a former postdoc. Rainer Kalscheuer, now at Heinrich-Heine University in Germany, was searching for genes and proteins that made some TB cells more treatment tolerant than others. After doing a microarray analysis, Kalscheuer wanted to investigate a metabolic intermediate enzyme called GlgE, but Jacobs balked. “I told him a group at Harvard had already shown that glgE was an essential gene that can’t be manipulated,” Jacobs remembers. But Kalscheuer persevered and found out that glgE could be knocked out and studied if grown in the right culture medium.
The insight would lead Kalscheuer and Jacobs in an unexpected, but fruitful, direction.
The key to creating viable glgE knockout strains turned out to be trehalose, a cell wall carbohydrate. TB bacteria that lacked glgE died instantly when trehalose was present, but survived if it was removed. The Harvard group had used medium that contained trehalose without realizing it because the carbohydrate, used as a preservative, was an unlisted ingredient.
The next step for Kalscheuer and Jacobs was figuring out the functional relationship between the two proteins. GlgE had been implicated in glycogen metabolism, but the connection with trehalose was unclear. Finally, after a painstaking series of suppressor genetics experiments, they elucidated the biochemical pathway: Glycogen and glucose produce trehalose; an enzyme known as trehalose synthase converts the trehalose into maltose; then, the maltose becomes maltose-1-phosphate, the protein that GlgE converts into glucan. When glgE is knocked out, maltose-1-phosphate accumulates, which kills the tuberculosis bacterium.
Now that Jacobs knows how glgE mutations can kill TB, he is trying to find a drug company willing to work on a project to exploit the bacterial weakness. “The GlgE gene is a great potential drug target because there’s no human homologue,” which means TB cells would be affected without harming human cells, Jacobs explains.
Back in his office, Jacobs shows me photographs from one of his first visits to South Africa where the incidence of drug-resistant TB is particularly high. All of the patients were housed together in a crowded ward, with nothing separating them from the hospital staff. “That was the only time I was ever scared of getting infected,” he recalls. Today, Jacobs has several collaborators in South Africa and is helping to build a state-of-the-art TB research facility there. The goal is to get more African researchers using the latest diagnostic technologies, but equally important, Jacobs says, is encouraging new drug development. “One drug is not enough,” he says. “Our collaborators in Africa say they need at least three new TB drugs.”
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