David M. Wagner left, and Paul S. Keim of Northern Arizona University. / Pat Shannahan, The Arizona Republic
PHOENIX -- On a construction site in the Bavarian town of Aschheim, a suburb of Munich known mostly as the location of a BMW test track, work crews on a housing project in the 1990s unearthed an ancient cemetery and, with it, clues to a mystery.
The clues were locked away in rows of 1,500-year-old teeth.
Archaeologists concluded that many of the people buried at the cemetery had died of the plague. Further testing revealed that the bodies were interred sometime in the sixth century, probably around the year 543.
That would make them victims of the Justinian plague, an outbreak named for a Roman emperor who succumbed to it, a plague that killed almost half the world's population.
Many questions lingered about that ancient plague, but one that intrigued scientists was this: Was the strain of disease from that plague the same one that struck Europe in the Black Death, the same one that is still alive in rodents today? Had the Justinian plague, after ravaging half the world, died out, gone extinct - or could it happen again?
The search for those answers would lead halfway around the globe, to a laboratory with tight surveillance in the pine trees of northern Arizona.
The investigation by experts there would be wrapped up with other investigations, of human victims, of rats from Madagascar, of native prairie dogs on the Colorado plateau. And it would depend on those teeth.
"It turns out the teeth are almost like a time capsule for DNA," said Dave Wagner, a biologist at Northern Arizona University. "And the teeth stay intact in skeletons."
Wagner and fellow scientist Paul Keim have devoted their professional lives to understanding a disease most people think of as an ancient memory. But they know the plague is alive and well, across the Southwestern United States. And research could be what stands between the bacteria and another outbreak.
That's why an international team of scientists called in the NAU experts and put them in a room with samples from the teeth from Germany to try to unravel the mystery. What caused the Justinian plague?
"Because plague is a blood-borne pathogen, there would be plague in the teeth of victims," Wagner said. "But it was still like looking for a needle in a haystack."
Tracking a killer
Wagner never set out to become a plague hunter, never imagined himself searching for infected fleas in dying prairie-dog colonies across northern Arizona or tracking rats through the back alleys of Madagascar.
He wanted to study wildlife - emphasis on life - and trained as a wildlife biologist. He was tracking prairie dogs in 1999 when he started seeing more dead rodents than expected and more live fleas. The prairie dogs, he realized, were dying of the plague, a not-uncommon cause of death in colonies across the Southwest.
Wagner's fascination with what was killing prairie dogs led him to Paul Keim, a biologist and researcher at NAU.
Keim had earned the nickname "bioterrorism warrior" in 2001, when he analyzed samples of anthrax sent to government offices in Washington in the weeks after the Sept. 11 attacks and helped find the man believed responsible for sending the spores.
His detective work grew out of his scientific work studying infectious diseases and understanding how their origins and molecular makeup could help protect public health. Much as an anthropologist might test the DNA of a person to find he had ancestors from ancient Europe or Africa, Keim could analyze a bacteria's molecular structure and figure out where - or, in the case of a bioterrorist, from whom - it came.
Working together at NAU's Center for Microbial Genetics and Genomics, Keim, the center's director, and Wagner, the associate director, have become two of the world's leading experts on the plague. They pick through the pathogen's DNA to learn more about why it has persisted through the centuries and how it could yet kill millions more people.
By charting the genome of the plague bacterium mostly found in animals, breaking its genetic code, researchers can track outbreaks and identify strains particular to a region or to a point in time, however long ago.
"There is fascination with the plague," Wagner said. "It has that history. But the strains we have today are equally capable of causing disease. The difference is how we react to it."
Rodents and fleas
Plague is an infection caused by the bacterium Yersinia pestis. It is most often spread to humans through flea bites. Bacteria carried by the fleas spreads into the bloodstream and attacks the lymph system. As the bubonic plague, it causes fever, headache and swelling - akin to a particularly bad case of the flu, Wagner said.
Left untreated, bubonic plague can develop into the far-worse septicemic plague. Skin and tissues can turn black and die, a grisly hallmark that helped create the term Black Death.
When that infection attacks the respiratory system, the disease becomes pneumonic plague. From there, it can spread directly from one human to another, as scientists suspect it did in the ancient plagues.
Scientists have long believed rodents and fleas helped spark those plagues. Improved hygiene and changes in rodent populations quelled the spread of the fleas, and the disease.
Modern medicine has since turned the plague into a curable disease
"Plague is a dangerous disease," said Keim. "But there are lots of drugs that can work on plague. It's very treatable."
Fewer people realize the same bacteria live on, even today.
The Southwest grew into a hot spot for the plague in this country, Keim said, because the pathogen became endemic among prairie dogs, the native rodents whose colonies dot the high plateaus.
That's where NAU researchers find the plague today.
When the researchers and students plan field trips to a potentially infected prairie-dog colony, they undergo training about how to protect themselves from flea bites or dead rodents. They are examined before the trip and their health monitored after.
"We've never had a single person come down with the plague," Keim said.
In a lab on the third floor of NAU's Applied Research and Development Building, behind a series of three doors secured with electronic locks and monitored by video cameras, Keim, Wagner and student researchers study the plague, analyzing samples of bacteria from hunting expeditions as near as Lake Mary Road outside Flagstaff and as far-flung as Madagascar, off the coast of southeast Africa.
"Plague is a word sometimes used generally, but what we're studying here is 'The Plague,'" Keim said. "It is still of historical importance. These are events that affected who we are and what we are today."
NAU scientists work with other research institutions and government agencies to better understand the plague pathogen. The campus center is closely aligned with the Phoenix-based Translational Genomics Research Institute.
Cedar Mitchell, an NAU junior in microbiology, spends part of her time in the lab sequencing the DNA of plague samples. She has helped devise a computer program that would help doctors in Madagascar identify plague strains and perhaps anticipate new outbreaks.
"If they find an outbreak in, say, the highlands and one in a port city, they can see if they are from the same sources," she said. Knowing that could help treat victims or warn people who could be at risk.
"Once you fingerprint everything, you can see what strains are active," Wagner said. "The hope is they can do it in real time. We want to take our existing research somewhere that it can be used."
There is another part of NAU's plague work that Keim and Wagner talk about in less detail. It is part of the reason the lab is so secure and is inspected and tested frequently by federal agencies.
"Plague can be used as a biological weapon," Keim said. "It has been, even back in the time of the Justinian plague."
U.S. authorities believe the Soviet Union was trying to develop an aerosol version of the plague bacteria that could be dispersed as a weapon. It could still be used by terrorists. If scientists could extract and identify DNA fingerprints from 1,500-year-old plague strains locked away in a Bavarian cemetery, perhaps they could do the same with a bioterrorism weapon. That could help point authorities to the source, just as Keim did with the anthrax spores - another infectious bacterium - in 2001.
What scientists hoped to discover in the 1,500-year-old teeth was whether the plague that killed more than 100 million during the Justinian outbreak was a strain from the Yersinia pestis bacterium that caused the Black Death and continues to spread today.
The teeth never actually made it to Flagstaff, in part because the NAU lab has built such a reputation in plague research. To satisfy the standards set in the field of ancient DNA about avoiding contamination with modern-day DNA, the teeth from the Aschheim cemetery were taken to McMaster University in Ontario.
Samples from two individuals were ground into molecules from which DNA could be extracted. Wagner and NAU's genomics center provided the expertise to analyze the DNA and help construct the genome.
"This is the oldest bacterial genome ever produced," Wagner said. "We were able to go back in time and find something that went extinct."
The map of the genome offered an answer, but left some of the mystery intact.
The NAU scientists helped conclude that the strain of plague was separate from the one that caused the Black Death and still exists today. The Justinian bacteria had died and left no descendants. It was, as the scientists say, an evolutionary dead end.
For plague sleuths, questions remain. Why did the Justinian strain die out? Why did the next outbreak not occur for another 600 years? And if the plague is just as dangerous as it ever was, could it explode across the globe once more?
Keim and Wagner say the world is a far different place now. Cities are cleaner. Rats are better controlled. Antibiotics are readily available. And research is helping public-health agencies contain the disease.
"We don't think we're going to see new large-scale plague pandemics," Wagner said. "Not because the organism has changed. It's just as deadly as it always was. But humans have changed."
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