Published online 4 October 2001 | Nature | doi:10.1038/news011004-12


Black Death's DNA

The plague bacterium joins the ranks of completed genomes.

Knowing the plague pathogen's genome sequence should speed the search for vaccines and treatments.Knowing the plague pathogen's genome sequence should speed the search for vaccines and treatments.The Plague by Arnold Boecklin.

Short of the DNA of one of the four horsemen of the apocalypse, we now have the next best thing. Researchers have sequenced the plague bacterium's genome1.

The 4.65 million DNA letters will be "the basis of all future work", on plague, says Julian Parkhill of the Sanger Centre, Cambridge, UK, who led the sequencing project.

The sequence will be critical in the design of antibiotics and vaccines to treat the disease. It is a yardstick against which potential new plague threats - whether created by natural selection or as biowarfare agents - can be measured.

It will also teach us a great deal about how infectious diseases evolve. The plague bacterium Yersinia pestis is a recent descendent of the benign, gut-dwelling bug Y. pseudotuberculosis. "Two thousand years ago it gave you a mild tummy ache," says team member Brendan Wren, a geneticist at the London School of Hygiene and Tropical Medicine.

Flea jump

Within a few hundred years - an evolutionary eye blink- Y. pestis learned to leap between fleas and mammals, to live in the blood instead of the intestine, and to cause the swelling, coughing and haemorrhaging of mediaeval nightmares. It did so by kitting itself out with a new genetic wardrobe, probably pinched from other microbes.

Key to the bacterium's rapid evolution could be a tendency to shuffle chunks of its chromosome. This seems to be common in pathogens, says infectious disease researcher Mark Achtman of the Max Planck Institute for Infection Biology, Berlin.

Y. pestis carries genes for insecticidal toxins that are now deactivated but may have helped it make the first jump into fleas. Indeed the bacterium's new lifestyle left it with about 150 such pseudogenes - redundant, gene-like stretches of DNA no longer switched on in the organism. In time these may decay or be lost from the sequence altogether.

The sequence also boasts many candidate disease-causing genes, although "at this stage the evidence is only circumstantial", says Rick Titball, another member of the sequencing team, who studies plague at the UK Defence Science and Technology Laboratory, Porton Down.

To pin these genes down, researchers will need to sequence other closely related bacteria, such as Y. pseudotuberculosis, says Achtman. Looking at the plague genome in isolation reveals all sorts of changes, "but they're not necessarily linked to increased virulence," he cautions.

Comparisons between the three plague strains should also help. Each strain is associated with a particular pandemic. Antiqua caused the first recorded plague between 500 and 700 AD; Medievalis caused the mediaeval Black Death and the Great Plague of seventeenth-century London, among others. Orientalis, the dominant modern strain, is the one that has now been sequenced.

“The plague is only a sideshow to what Y. pestis is really doing”

Julian Parkhill, Sanger Centre

Plague's youth as a disease may explain its drastic symptoms. Many researchers believe that evolution pacifies pathogens, in order to reduce hosts' immune response. Many damaging infectious diseases - tuberculosis, anthrax and typhoid - seem to have originated in the past few millennia.

But the main drive in Y. pestis ' evolution is probably to move better between rodents and their fleas, which bite humans only as a last resort. "The plague is only a sideshow to what Y. pestis is really doing," says Parkhill.

Lying low

These days, bubonic plague - cause of the characteristic underarm swellings - can be treated with antibiotics if diagnosed early enough. Public hygiene can prevent its flea-borne spread.

But the disease still kills about 2,000 people each year, mostly in Africa and Asia, and the incidence is rising. A recent case in Madagascar was resistant to multiple antibiotics. "It's a worrying trend," says Titball.

“Plague still kills about 2000 people each year”

In a small percentage of cases, bubonic plague reaches the lungs, becoming pneumonic plague, with mortality close to 100%. No one knows what causes this transition.

Pneumonic plague also spreads through the air; it is thought to have caused the major historical pandemics. Today an unsuspecting carrier on a plane from an infected area could trigger a severe outbreak.

Titball's team has a plague vaccine currently in clinical trials. Even if it works, there's no telling how long the vaccine will be effective he says: "New vaccines, antibiotics and diagnostic tools are urgently needed." Because the bacterium can lurk in animals, it is unlikely that we will ever eradicate it.

Weapon of war

Plague is the original biological weapon. In 1347, the Tartars, laying siege to the Genoese-controlled Black Sea port of Caffa, hurled the bodies of their plague victims over the city walls. When infected Genoese sailors returned to Italy, the Black Death killed one third of Europe's population between 1347 and 1351.

There are concerns that governments or terrorists could spread plague again. Scientists defecting from the former Soviet Union claimed to have developed an antibiotic-resistant strain of Y. pestis, for example.

“It would be a complex challenge for a terrorist group to release it into the air”

Rick Titball
UK Defence Science and Technology Laboratory

This has led to a debate about whether releasing genomic information for virulent diseases, such as plague or smallpox, might aid malicious science. Titball believes in openness. "The information available is of much greater advantage to people defending against biological warfare than to those intending to use it," he says.

Besides, Titball adds, "it's not a difficult organism to culture, but it would be a complex challenge for a terrorist group to release it into the air".

"These are pretty dreadful diseases already," Titball points out. "We should focus on fighting them in the form they're already in, rather than worrying about theoretical future threats." 

UK Defence Science and Technology Laboratory

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