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Last Updated

03 Nov 2002

Source: Los Angeles Times, May 6, 2002.

An Empire's Epidemic

Scientists Use DNA in Search for Answers to 6th Century Plague

By THOMAS H. MAUGH II, Times Staff Writer

By the middle of the 6th century, the Emperor Justinian had spread his Byzantine Empire around the rim of the Mediterranean and throughout Europe, laying the groundwork for what he hoped would be a long-lived dynasty.

His dreams were shattered when disease-bearing mice from lower Egypt reached the harbor town of Pelusium in AD 540. From there, the devastating disease spread to Alexandria and, by ship, to Constantinople, Justinian's capital, before surging throughout his empire.

By the time Justinian's plague had run its course in AD 590, it had killed as many as 100 million people -- half the population of Europe -- brought trade to a near halt, destroyed an empire and, perhaps, brought on the Dark Ages. Some historians think that the carnage may also have sounded the death knell for slavery as the high demand for labor freed serfs from their chains. Justinian's plague was a "major cataclysm," says historian Lester K. Little, director of the American Academy in Rome, "but the amount of research that has been done by historians is really minimal."

Little is hoping to do something about that. In December, he brought the world's plague experts together in Rome to lay the groundwork for an ambitious research program on the pandemic. A book resulting from the meeting will be published this year.

Modern techniques for studying DNA have begun answering long-standing questions about the evolution of the plague bacillus, how it infects humans and what can be done to counteract it.

While a 6th century plague might seem an esoteric subject, Little and others think that it has great relevance in a modern world that is continually threatened by emerging diseases. A second pandemic of plague struck Europe in the Middle Ages -- the so-called Black Death -- killing 25 million people and once more producing widespread social disruption.

A third pandemic began in China in the late 19th century and spread to North America, where a large reservoir of the disease remains active in animals throughout the Southwest.

An outbreak occurred in Los Angeles in 1924-25, but was contained.

Plague could become a tool of bioterrorists. Russian experts have long argued that plague is a much more frightening prospect than anthrax. As part of their germ war efforts during the Cold War, Soviet scientists developed strains of plague resistant to antibiotics used to cure infections. Unleashing such organisms could potentially have a devastating effect on modern society.

Understanding Justinian's plague could also lead to insights into other types of disasters, man-made and natural, adds UCLA historian Michael Morony.

"People were dying faster than they could be buried," he said. "I find myself wondering how society survived. That's a relevant question to try to understand."

Plague is caused by a bacillus called Yersinia pestis, identified in 1894 by the Swiss bacteriologist Alexandre Yersin. The bacterium once killed more than half the people it infected but is now routinely controlled by such antibiotics as streptomycin, gentamicin or tetracycline.

Plague Still Kills

2,000 People a Year

About 2,000 deaths from plague are still reported worldwide every year, a handful of them in the United States. Naturally occurring strains resistant to antibiotics have been observed recently, however, and scientists fear that their spread could lead to large outbreaks.

Y. pestis is carried by rats and other animals. It can be transmitted to humans by direct exposure to an infected animal. Most often, however, it is carried by fleas that bite the infected animals, then bite humans.

People bitten by such fleas develop agonizingly painful, egg-sized swellings of the lymph nodes -- called buboes -- in the neck, armpit and groin. Hence the name bubonic plague.

Some authorities recognize two other forms of plague, one called pulmonary or pneumonic, in which the lungs are affected, and one called septicemic, in which the organism invades the bloodstream, but all are the same disease, Little said.

Because of its possible use in bioterrorism, researchers have been actively studying the plague organism. In October, a British team from the Sanger Center in Cambridge reported that they had decoded the complete DNA sequence of Y. pestis, a feat that could help to control outbreaks.

"The genome sequence we have produced contains every possible drug or vaccine target for the organism," said Dr. Julian Parkhill, the team's leader.

Genetics shows that the closest relative of Y. pestis is a gut bacterium called Yersinia pseudotuberculosis, which is transmitted through food and water and which causes diarrhea, gastroenteritis and other intestinal problems, but is rarely fatal. Y. pseudotuberculosis may be the immediate ancestor of Y. pestis, but it is not transmitted by fleas. Last month, researchers apparently discovered why.

Bacteriologist B. Joseph Hinnebusch and his colleagues at the National Institutes of Health's Rocky Mountain Laboratories in Montana reported that the key is a gene called PDL, which is carried by the plague bacterium, but not by the one that causes diarrhea.

Although they do not yet know how it works, PDL allows Y. pestis to survive in the gut of the rat flea. Artificially produced strains of the bacterium without the gene are destroyed in the flea's gut and thus cannot be transmitted to humans.

Hinnebusch and his colleagues believe the bacterium acquired the gene from other soil bacteria by a process called horizontal transfer, somewhat akin to a form of bacterial sex. The transfer probably took place 1,500 to 20,000 years ago, they said, setting the stage for full-scale epidemics of plague. "Our research illustrates how a single genetic change can profoundly affect the evolution of disease," Hinnebusch said.

Some scholars have argued that Y. pestis was not the cause of the Black Death and, by implication, of Justinian's plague as well. Jean Durliat, a French expert on the Byzantine Empire, argued in the 1980s that contemporary literary accounts of Justinian's plague were overblown and exaggerated, and not supported by archeological evidence.

Last year, British historians Susan Scott and Christopher Duncan published "Biology of Plagues," arguing that death spread through Europe much too rapidly in the 14th century to be caused by Y. pestis.

They believe that the Black Death must have spread through human-to-human contact and argue that it might have been caused by the Ebola virus or something similar.

Anthropologist James Wood of Pennsylvania State University made a similar argument last month at a meeting in Buffalo, N.Y.

"This disease appears to spread too rapidly among humans to be something that must first be established in wild rodent populations, like bubonic plague," Wood said. "An analysis of monthly mortality rates [among priests] during the epidemic shows a 45-fold greater risk of death than during normal times, far higher than usually associated with bubonic plague."

But molecular biology may be on the brink of answering questions that history cannot. One unique feature of the plague virus is that it accumulates inside the teeth of its victims, where its DNA can be protected for centuries, or perhaps even longer.

Molecular biologists Michel Drancourt and Olivier Dutour of the University of the Mediterranean in Marseilles, France, reported in 1998 that they had identified Y. pestis DNA in human remains dating from 1590 and 1722. Two years later, they reported a similar finding in remains dating from 1348.

That evidence is "pretty impressive," said Little, and indicates that Y. pestis at the very least played a role in the Black Death.

The Marseilles team is continuing to study other remains from the period to document how widespread the infections were. Meanwhile, archeologists are searching for plague cemeteries from the time of Justinian to perform similar studies.

Mass Graves Found

In Gaza to Be Studied

Archeologist Michael McCormick of Harvard University has already identified eight mass graves in the Gaza Strip, Turkey and Italy where he expects to find human remains dating from the 6th to the 8th centuries. Remains have yet to be exhumed, however.

Some researchers speculate that a particularly virulent form of Y. pestis was responsible for Justinian's plague or the Black Death, just as an unusually pathogenic form of the influenza virus caused the worldwide flu pandemic in the early 20th century. Analysis of human remains could yield clues.

Theoretically, McCormick said, if DNA is found in the remains, it could be possible to grow the organisms in the laboratory and see if it is, in fact, more virulent.

One of the "major social issues" arising from the great mortality of the plague "is that it tends to raise the value of labor," Little said. "There are not enough workers around anymore. You can't find servants and, when you do find someone, they tend to charge outrageous amounts."

Little and others believe that this increased premium on labor was the final blow to slavery during the Justinian plague and that it similarly brought an end to serfdom during the Black Death.

Historians obviously still have a lot to learn about these pandemics, but valuable first steps have been taken, Little said. With the increasing assistance of molecular biologists, he added, the final pieces of the puzzle may now fall into place.