Palague's gene code cracked

[Guest guest]

FYI / MM

Saturday | October 13, 2001

Plague's gene code is cracked

New understanding of bacterium may help explain its deadliness

10/08/2001

By ALEXANDRA WITZE / The Dallas Morning News

Related content• En español One of humanity's greatest scourges has revealed its deadly secrets. Biologists have decoded the genetic makeup of Yersinia pestis, the bacterium that causes plague. On the surface, the rod-shaped bacterium looks simple. But studies of its DNA reveal a crazy quilt of 4.6 billion pairs of chemicals, stitched and restitched together over time.

The genetic flexibility of Y. pestis may help explain its deadly nature – especially how the plague, known in some historical periods as the Black Death, managed to kill 200 million people over the course of history.

The research may also help scientists develop better drugs to fight plague, which has long been considered a possible biological warfare agent. Antibiotics work if given soon enough after infection, but there is no effective vaccine available to prevent plague in the first place.

Scientists hope that details of the bacterium's genetic makeup, or genome, will suggest new ways to diminish the threat of plague. Up to 3,000 people worldwide still die of the disease every year.

"Having the genome sequence means you have every possible vaccine target or drug target," says team leader n Parkhill of the Sanger Centre in Cambridge, England. "It's a new beginning for research on the disease."

The genome, which was described last week in the journal Nature, is unlike that of other disease-causing organisms.

In just a few thousand years of evolution, the genetic makeup of Y. pestis appears to have undergone several dramatic changes. Other disease-causing organisms, such as E. coli or salmonella, have remained mostly the same after 100 million years of evolution, says Dr. Parkhill.

"Finding a related organism that can flip around sections of its genome is actually quite surprising," he says.

The genes of Y. pestis are a patchwork of missing and repeating DNA chunks. Many of its genes appear to have been lifted from viruses, as well as from other bacteria.

The plague bacterium was born between 1,500 and 20,000 years ago from the bacterium Y. pseudotuberculosis. The two bacteria are genetically quite similar but drastically different in the diseases they cause. Y. pseudotuberculosis, which is present in animals, soil, and water on every continent, produces only a minor gastrointestinal illness in humans.

Emilio , a biologist at Lawrence Livermore National Laboratory in California, leads the team that is decoding the genome for Y. pseudotuberculosis. When that research is finished, in the next six months to a year, scientists hope to compare the two genomes side by side for clues to what makes Y. pestis so nasty.

Already, the researchers have found that Y. pestis contains two major genetic elements not found in its cousin organism, which may help it better survive in fleas. Comparatively, Y. pestis is also missing other chunks of genes, whose absence may render it more malignant in humans.

"Whatever change there is, in going from one [bacterium] to the other, might explain why this organism is suddenly so virulent," says Dr. .

Something definitely happened to Y. pestis in its recent history, says n Wren of the London School of Hygiene and Tropical Medicine. "It's gone from an organism that gives you a mild tummy ache to one that's devastating and has shaped Western civilization," he says.

Three waves of plague have struck humanity, each caused by a different strain of Y. pestis. The so-called ian plague began in Egypt and swept across Europe in the sixth, seventh and eighth centuries. The episode known as the Black Death killed 20 million to 30 million people – one-third of Europe's population – in the mid-14th century. Modern plague has killed more than 12 million people in China and India alone since it arose in 1855.

The recently studied Y. pestis strain came from a Colorado veterinarian who died in 1992 after being sneezed on by a plague-infected cat he was trying to rescue from under a house.

Plague can strike in several forms; each is caused by Y. pestis but differs in its symptoms depending on how it was contracted. Bubonic plague, characterized by "buboes," or swollen lymph nodes, is usually transferred to humans by the bite of an infected flea. Pneumonic plague, characterized by fever, chills, and breathing difficulty, is caught by inhaling aerosolized droplets carrying the bacterium.

Experts say Y. pestis is a potential bioweapon because terrorists theoretically could spray aerosolized bacteria over a city, triggering cases of pneumonic plague. The disease, in that form, is usually fatal unless antibiotics are given within 24 hours after infection. (Bubonic plague is less deadly, but even so, 1 in 7 of all plague cases in the United States are fatal.)

Biologists have already deciphered the genomes of other disease-causing organisms, including those that cause meningitis and cholera. So far, nobody has developed a vaccine directly from that information, but it's only a matter of time, scientists say.

"People are still learning how to use genomes to the best advantage, but they are learning fast and things are changing fast," says Keim, a biologist at Northern Arizona University in Flagstaff.

Dr. Keim uses DNA "fingerprinting" techniques, as would be used in a court case to identify a suspect, to study bacteria that could be used as biological weapons. By examining very specific areas of the genome, he can identify slightly different versions of the strains of plague. That information, in turn, could help pinpoint the source of any suspected bioterrorism bug.

Meanwhile, other scientists are working on ways to render the bacterium harmless once it gets inside humans. ston, a molecular biologist at the University of Texas Southwestern Medical Center at Dallas, develops "genetic vaccines" that aim to disarm a specific disease-causing gene in an organism. Knowing the genome of plague, Dr. ston says, will help him better identify which genes to work on.

"It reduces the complexity of the search about twentyfold," he says.

Someday, such studies – which are conducted in animals – may help in developing a better human vaccine.

The plague vaccine that was licensed for use in the United States was discontinued by its manufacturers in 1999 because of side effects and questions about its potency. It was never available to the public, only to the military and laboratory workers who might be exposed to the plague.

It also worked only for the bubonic plague – not the pneumonic form that is a more likely outcome of a bioterrorist attack.