Syphilis Genome Sequenced

A new assault on the syphilis pathogen has yielded the entire sequence of this microbe's genetic code. The genome, reported in tomorrow's Science, is already revealing clues to what makes the spirochete so tenacious and how it might be defeated with a vaccine.

If left untreated, syphilis can lead to insanity, cardiovascular problems, and death. Penicillin will knock out the spiral-shaped bacterium, called Treponema pallidum, but there is no vaccine. One reason is that "it's a bug that knows very well how to evade the immune system," says Sheila Lukehart, a microbiologist at the University of Washington, Seattle. The spirochete is also difficult to study because it refuses to grow in culture dishes.

Knowledge of T. pallidum's genes could help microbiologists sidestep this problem. About 8 years ago, Steven Norris and George Weinstock--both microbiologists at the University of Texas Health Science Center in Houston--began characterizing the genetic makeup. Progress was slow until 1995, when researchers at The Institute for Genomic Research (TIGR) in Rockville, Maryland, showed they could rapidly sequence microbes in just a single step, by so-called "shotgun" cloning (Science, 20 October 1995, p. 397). Under the direction of TIGR's Claire Fraser, the team was able to finish the sequence in 18 months.

The complete collection of genes revealed "a metabolically crippled organism," says Norris. This spirochete has very few sets of enzymes for building complex molecules, such as the building blocks of DNA. Instead, it steals essential molecules from its host. This strong reliance on the host is what makes the organism so hard to culture, Norris says.

The most exciting features of the genome are some unexpected repetitive sequences, says Lukehart. These stretches represent a family of very similar genes that may explain the organism's ability to evade the immune system. Lukehart speculates that the spirochete easily recombines the genes for surface proteins, so that the immune system does not recognize them. This could allow some spirochetes to survive the immune system's initial assault and reemerge years later. Lukehart and Norris think that these so-called TPR proteins provide the best targets for a vaccine, because antibody experiments suggest they stimulate a powerful immune reaction.

But even before these efforts yield a vaccine, the new sequence may help public health workers battle the disease. Both Lukehart's group and a team at the Centers for Disease Control and Prevention (CDC) in Atlanta have already come up with schemes to track the strains based on the TPR genes, which vary from one strain to another. "That's a very important part of understanding the transmission of infection," says CDC physician Michael St. Louis.