[Photo courtesy Michigan State University]
By Natasha Berryman
Michigan State University’s Robert Abramovitch has genetically engineered a green-glowing protein to find latent tuberculosis, a tiny triumph that promises to have a big impact in the fight against one of the world’s deadliest diseases.
The CDC estimates that one-third of the global population, more than 2.3 billion people, is infected with latent TB. “When Mycobacterium tuberculosis (MTB) infects humans, our immune system walls off the infection by building a granuloma — a tumor — around the bacteria, which is why you seem totally healthy if you have latent TB,” explains Abramovitch, MSU assistant professor of microbiology and molecular genetics.
“The granuloma doesn’t kill the bacteria — instead, the bacteria change their physiology so they can survive inside,” says Abramovitch. The bacteria sense environmental cues and then substantially slow their growth, changing the way they use and make energy to survive inside the granuloma. Abramovitch hypothesizes that oxygen plays a pivotal role in this process.
“MTB needs oxygen to grow,” he says. “We believe that the bacteria have the ability to sense that the oxygen level around them is decreasing — a state known as ‘hypoxia.’ When they sense that the environment has become hypoxic, that’s their cue to say, ‘OK, we need to hunker down.’”
The bacteria remain dormant — having optimized their ability to survive for years in a stressful environment — until they sense that the environment favors growth. Once that happens, MTB initiates a genetic pathway that leads to the active state of the disease.
Lighting the Path to Drug Discovery
“If you just look at MTB cells in a test tube,” explains Abramovitch, “you can’t tell if they’re adapted for regular oxygen levels or low oxygen levels, because the bug doesn’t have a natural signal that indicates its physiological status.” But by genetically engineering a protein that glows green when MTB is transitioning to a dormant state, Abramovitch is able to catch the bacteria in the act of “hunkering down.”
That innovation alone promises to give scientists the upper hand in finding a faster-acting cure for TB. “Inhibiting the ability of the bacteria to establish dormancy may shorten the course of antibiotic treatment, thus eliminating the disease more quickly and reducing the emergence of drug-resistant TB,” Abramovitch says.
“Normal TB takes about six months to treat and requires daily antibiotics,” he explained. “If you’ve ever taken antibiotics for two weeks, you know you’re likely to miss at least one dose – everyone does. The problem is that when people don’t stringently complete the six-month drug course, they can breed drug-resistant TB. The dormant, slow-growing bacteria are harder to kill, resulting in the long treatment course required to cure TB.”
Abramovitch is already exploring pharmaceutical drugs that will prevent the bacteria from sensing changes in the environment and establishing a dormant state. To identify compounds that disrupt the hypoxia-sensing ability of MTB, Abramovitch employs an experimental method called high-throughput screening to quickly screen thousands of compounds in large batches. By running the MTB biosensor strain through a drug screen, Abramovitch can identify compounds that turn off the green signal, which indicates that the compounds have successfully disabled MTB from sensing the hypoxia cue to transition to dormancy.
Solving World Health Challenges
Abramovitch’s work on the biosensor was funded in part by MSU AgBioResearch and a Bill and Melinda Gates Foundation Grand Challenges Explorations award. The Gates award recognizes scientists who take a non-traditional approach to solving persistent, global health challenges; providing an initial grant of $100,000 (successful projects can receive up to an additional $1 million).
“I took the biosensor approach because it created an opportunity for me to do basic research that could be readily translated into a real-world, drug discovery platform,” he says. “The Gates Foundation, MSU AgBioResearch, and the Michigan Initiative for Innovation and Entrepreneurship funded my projects because they’re non-traditional and connect basic research with applied research. You have to try new things — you never know what’s going to work. And even though TB drug discovery hasn’t seen many new advances, we still have to try.”