LONDON ¿ The genome of the bacterium that causes plague has been sequenced, revealing an ¿Aladdin¿s cave of riches¿ to help researchers study why some bacteria kill while others are harmless. The new sequence delivers dozens of targets into the hands of scientists attempting to design new drugs and vaccines to combat plague.

Brendan Wren, professor of microbial pathogenesis at the London School of Hygiene and Tropical Medicine and one of the 30-strong team of researchers who worked on the sequence of Yersinia pestis, said it was clear that the plague bacterium had evolved relatively recently from its close relative, Y. pseudotuberculosis, which is a mild gut pathogen.

He told BioWorld International, ¿This is evolution in the fast lane. The genome sequence reveals how Y. pestis gained big sections of DNA that allowed it to go into new hosts ¿ fleas and rats. It then mixed its genes around before entering a phase of genome decay because it no longer needed the genes it had when it lived in the gut. The fascinating thing is that all this happened in an evolutionary blink of an eye, probably during the last few thousand years.¿

Y. pestis has a natural reservoir in rodents, whose fleas become infected when they feed. When the rat dies, the fleas can pass on the bacterium if they bite humans. Y. pestis transmitted in this way causes bubonic plague: the lymph nodes form swellings called buboes. In the most severe cases, the infection disseminates around the body, including the lungs. The pneumonic plague that follows is rapidly fatal and spreads readily by droplet transmission.

In the Middle Ages, the ¿Black Death,¿ as it was known, wiped out about a third of the population of Europe, killing an estimated 200 million people. Plague is still endemic in many countries: in 1994, for example, an outbreak of pneumonic plague in Surat, India, killed 855 people. Even today, about 3,000 cases a year are reported to the World Health Organization.

Julian Parkhill, project manager at the Sanger Centre in Hinxton, UK, told BioWorld International, ¿This is a very important organism for us to try and understand because it has killed so many people in the past and has the potential to kill more.¿

Parkhill discounted ideas that publishing the genome sequence could help those who wanted to use Y. pestis in terrorist attacks. ¿The problems that terrorists would face in growing this bacterium in bulk, in keeping it viable and in dispersing it are not the kinds of problems that would be helped by the molecular information we are releasing,¿ he said. ¿But the genome sequence will provide all the information scientists need to make new vaccines and new drugs.¿

One vaccine, he added, already is undergoing trials at the Defense Science and Technology Laboratory at Porton Down, UK.

Parkhill, together with colleagues from the Sanger Centre, Porton Down, the London School of Hygiene, London-based St. Bartholomew¿s Hospital and London-based Imperial College report their data in a paper in Nature titled: ¿Genome sequence of Yersinia pestis, the causative agent of plague.¿ The Wellcome Trust, one of the UK¿s largest biomedical research charities, funded the research.

Parkhill said, ¿We found that Y. pestis has a very fluid genome, with large sections moving around within the genome during the growth of the organism. This is quite unusual and we are not sure of the biological significance of this finding. The genome also has large amounts of horizontally transferred DNA ¿ DNA that has been exchanged with other bacteria.¿

Analysis of these genes, and comparison with the genomes of other organisms, has allowed the team to conclude that some of the genes are important in allowing the bacterium to interact with its current mammalian hosts, while others help it to interact with its insect host. ¿We can also see remnants of genes in the genome that used to be important for Y. pestis when it used to be a gut pathogen,¿ Parkhill said.

Wren described the 150 genes that Y. pestis had lost through decay of its genome as ¿an Aladdin¿s cave of riches¿ for him to study. ¿These are the redundant remnants of an enteric lifestyle,¿ he said. ¿We can now go back to other gut pathogens and identify which genes are important for this way of life.¿

No one knows, Wren pointed out, what the reasons were for the rise and fall of the three plague pandemics, or what might trigger the next one. There might be clues, however, in the 21 so-called ¿islands of pathogenicity¿ present in the Y. pestis genome. These are regions poor in cytosine and guanine, the signature of DNA that has come in from other organisms, Wren said. Because they have contributed to Y. pestis¿ transformation from harmless gut pathogen to fatal infective agent, they clearly warrant further investigation.

Wren suggested that it might be possible to mount these sequences on DNA microarrays. ¿Thus, at a glance you could very efficiently interrogate the genome of any isolate worldwide to see if it has gained these key segments of DNA,¿ he said. ¿It would also allow us to dissect out at the genetic level what makes a bacterium pathogenic.¿