Genome sequence aids war on tuberculosis.

Scientists often turn to military metaphors when they describe how the body tries to fend off infectious agents. Immune cells turn into valiant soldiers rallying to a noble cause, while bacteria and viruses become the merciless invading army to be defeated.

In that sense, microbiologists are best viewed as spies studying the enemy to determine its strengths and weaknesses. In the ongoing fight against the bacterium that causes tuberculosis, which claims more lives annually than any other infectious agent, these spies have now collected a long-awaited body of intelligence. In the June 11 Nature, they unveil the complete DNA sequence of the bacterium's more than 4,000 genes, laying bare all its potential weapons and defenses.

With such information, scientists hope to pinpoint novel targets for drugs. Moreover, by identifying bacterial molecules that trigger immune responses, they may find new leads to vaccines. "The sequence marks a new phase in the battle against one of mankind's most successful predators," writes Douglas B. Young of the Imperial College School of Medicine in London in a commentary accompanying the report on the Mycobacterium tuberculosis genome.

Scientists from the Pasteur Institute in Paris and the Sanger Centre in Hinxton, England, spearheaded the sequencing project. They found that the microbial genome consists of more than 4.4 million base pairs, the protein-encoding sub-units of DNA.

Unlike many bacteria, M. tuberculosis has a complex cell wall, and many of the newly identified genes play a role in creating this protective barrier. One unexpected finding is that the tuberculosis bacterium has more than 250 genes devoted to metabolizing lipid molecules. This suggests that the microbe may obtain much of its energy by digesting lipids of its host, says Stewart T. Cole of the Pasteur Institute.

The researchers have also identified a large number of genes that appear to encode proteins secreted or displayed on the surface of cells. Such proteins may be useful in vaccine development because the immune system responds to them more readily than to the bacterium's internal proteins. Since a vaccine is considered the most likely way to defeat tuberculosis, Cole predicts that investigators will quickly test the vaccine potential of these proteins in animals.

The discovery of two families of novel proteins, whose genes account for about 10 percent of the whole genome, surprised scientist. "This is a huge class of proteins that has been completely overlooked by conventional biochemistry and microbiological approaches," says Cole. "People will be working quite hard to see what they do."

Their resemblance to certain proteins of other bacteria suggests that the newly identified components may help M. tuberculosis disarm the immune system. Another possibility, says Cole, is that the newfound proteins enable the bacterium to change its appearance continually and evade detection.

Cole and his colleagues narrowly beat out another group, the Institute for Genomic Research (TIGR) in Rockville, Md., that has also been sequencing M tuberculosis. The TIGR project should be complete in a month, but it will not duplicate the effort of Cole's group, which sequenced a strain of M. tuberculosis studied since 1905. TIGR is sequencing a strain recently isolated from a patient. By comparing genomes, scientists hope to understand why some strains spread more easily or initiate disease more quickly.

"It's looking like, on average, there's some difference every 5,000 base pairs," says Claire M. Fraser of TIGR. "It's really quite amazing that there are so many [sequence] differences popping up, and I think they will give us some very profound insight into biological differences between strains."