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The Patient Scientist

The Patient Scientist

The Patient Scientist

For centuries the tenacious bacterium that causes tuberculosis has eluded humanity's attempts to kill it quickly, but one researcher may have landed a better solution.

Mycobacterium tuberculosis,
meet Ying Zhang.

By Margaret Guroff

In 1986, when Ying Zhang started his PhD studies and learned he would be researching tuberculosis, he was baffled. "I thought TB was cured," recalls Zhang, now a professor of Molecular Microbiology and Immunology at the Bloomberg School. "I thought it was not a problem."

This is a common misconception even today, but it is a dangerous one. As Zhang soon found out, the life-threatening disease caused by Mycobacterium tuberculosis—a scourge since ancient times—had long defied easy cures. Though its multiplying, rod-shaped bacteria can usually be slaughtered with antibiotics, a sometimes-spherical, dormant form of the bugs cannot. These so-called "persister" bacteria, which evolved to help the species survive stress such as starvation, are thought to slumber for months or even years inside a patient's own immune cells, which themselves nestle within the lungs or other organs. Then the persisters awaken and turn back into replicating rods.

"These bacteria are smart, I can tell you," says Zhang, MD, PhD, sitting at a paper-stacked table in his office. "It's not easy to get rid of them."

What's more, TB is on the march worldwide, fueled by the emergence of drug-resistant strains and by a growing population of vulnerable potential hosts: people with HIV. Tuberculosis, once called "consumption," causes symptoms that include wasting, pallor and coughing up blood. Though six months of an antibiotic cocktail can cure most cases, the disease still kills 2 million people a year. And one-third of the world's population is thought to be infected with TB, which can lie dormant for a lifetime, waiting for an opportunity to strike when the immune system is weakened. (Only about one-tenth of TB infections ever cause symptoms.)

"Research is like fishing. One has to be persistent and have good luck to catch the 'fish.' 'Chance is always powerful.' Let your hook always be cast. In the pool where one least expects it... will be a fish." Ying Zhang

Zhang has spent the past 20 years delicately trying to pick the lock of this diabolical microorganism. A quiet, focused man who earned an MD in his native China and a doctorate in England before joining the Johns Hopkins faculty in 1995, Zhang is responsible for major advances in understanding how M. tuberculosis bacilli attack the body's tissues and how the bacteria become resistant to antibiotics. "Ying is a very, very intriguing guy," says William R. Jacobs, Jr., PhD, of the Howard Hughes Medical Institute, a leading researcher of the genetics of TB. "He's low key, but his contributions are very important."

Now, Zhang's lab is studying what may be the most vexing question of all: how to annihilate stubborn "persister" TB bacteria. In a typical case of full-blown TB, a patient might have 1 billion active bacilli, which succumb to antibiotics within a couple of weeks. But the patient might also have 1,000 to 10,000 persisters that survive the antibiotics. "This is the biggest problem facing tuberculosis control right now," Zhang says.

Humans have contracted tuberculosis for as long as there have been humans, prehistoric skeletal remains show. At times, the disease was thought to be inherited, because frequently more than one family member got it. Some societies even considered TB a sign of vampirism, with a family's first victim accused of returning to slowly drain the life from those who remained. Eventually, TB was recognized as a contagious disease and patients were confined to sanitaria, rural institutions where fresh air and rest sometimes allowed the symptoms to remit.

In 1720, the English physician Benjamin Marten correctly guessed that TB was caused by "wonderfully minute living creatures," but it wasn't until 1943 that researchers developed the first drug that could kill these creatures: streptomycin, an early antibiotic. This one drug alone could not cure the infection, but before long other antibiotics were added to the mix. At last, some TB patients were cured, albeit after as long as two years of daily medication designed to attack the tenacious persisters as they awoke.

In 1952, researchers created a drug called pyrazinamide (PZA), which is still the only medicine that is proven effective against any persister TB bacteria. Even PZA cannot harm persisters that are truly dormant, but it kills the ones that are just beginning to stir. Zhang likens the active and dormant cells of a TB infection to the yin and yang symbols of Chinese philosophy—that is, the opposite and complementary parts of any whole. "Within the persisters there is a small population that want to grow; they want to revert," he says. With the advent of PZA, which doesn't kill actively growing cells, those yearning persisters could be knocked off earlier, and tuberculosis treatment time was cut to six months—the so-called "short course" that is still standard today. "It sounds long," Zhang admits, "but it's the best we have."

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