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A vaccine against vampiresThe genetics of TB holds the key

Trujillo-Paumier
Tohei Yokogawa among fish tanks. He stayed up nights to learn whether zebrafish sleep.
TB fighters Erin Heinemeyer (left) and Gregory Dolganov use PCR to unveil the bacterium’s weaknesses.

For much of history, the ghastly events triggered vampire hysteria: A healthy person grew pale and exhausted, began to cough. He shunned light, breathed raggedly through blood-spattered lips and died a slow, wasting death. Then, the same symptoms struck others.

Doctors now recognize labored breathing, pallor and a blood-laden cough as signs of advanced tuberculosis, not the kiss of the undead. But the condition remains as vicious — and nearly as mysterious — as ever.

“Our understanding of the biology of TB, particularly during the latent phase, is almost zero,” says Gary Schoolnik, MD, professor of medicine and of microbiology and immunology. Schoolnik is leading Stanford researchers who are part of an international Bill and Melinda Gates Foundation team.

The research need is acute for this disease, which kills 2 million a year. TB care is faltering, particularly in developing countries. The current TB vaccine confers only weak immunity. And when the organism is in its latent phase, it resists treatment.

So the Stanford researchers are conducting a TB stakeout. They want to learn what happens, on a molecular level, when the bacterium that causes TB emerges from its lung-granule hideaway.

“It’s difficult to attack someone in full armor,” says Gregory Dolganov, MD, PhD, a researcher on Schoolnik’s team. The scientists hope what they learn about the transition from latent to more vulnerable, active TB will lead them to new proteins they can target with vaccines.

Tuberculosis is so evasive that the team had to invent a brand-new surveillance technique to track it. The first step in measuring gene activity is gathering the strands of messenger RNA that TB churns out, because they bear the instructions for building new proteins. But because the bacteria take up a tiny volume of the total tissue sample, their genetic instructions are hard to discern. The tissue Schoolnik’s team studies comes from the lungs of TB-infected monkeys and humans.

The new technique, “two-step multiplex real-time polymerase chain reaction,” selectively amplifies the TB gene signal. Laboratory technician Erin Heinemeyer starts with known gene sequences from both humans and the bacteria. She converts mRNA instructions to DNA, then uses several specially designed sets of primers — short pieces of single-stranded DNA that bind only to tuberculosis genes. These primer sets prompt a chain reaction that reels off copies of many TB genes simultaneously. With enough copies to outnumber the monkey or human genetic sequences, scientists finally see what TB is up to. Every step in designing the new protocol was complicated by the fact that early-stage TB lesions are hard to find in the lung, and that the mRNA molecules the scientists measure are extraordinarily fragile. “It’s the hardest thing I’ve ever done,” Schoolnik says.

Once Schoolnik’s team identifies critical genes, it shares findings with data miners in San Diego and vaccine scientists in Denmark. Each group contributes important expertise to the tuberculosis challenge — but the progress of the project ultimately depends on mRNA sequences spit out of a microwave oven-sized machine at Stanford.

If all goes well, the collaborators will advance medical science to combat one of the world’s deadliest ailments.

And vampires everywhere will lose their appetites. —Erin Digitale

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