Rockville team maps germ's genetic code Bacterium called leading cause ofulcers, stomach disease


ROCKVILLE -- In a tour de force of computer-aided biology, scientists have decoded the full genetic instructions of the bacterium that causes ulcers and other stomach disease and have figured out many of its strategies.

The advance is likely to lend new impetus to research on the bacterium, Helicobacter pylori, which is a leading cause of human illness. The microbe is thought to live in almost half the world's people, though usually without causing disease. In the United States it is found in 30 percent of adults and more than half of the people over 65, with a prevalence in lower socioeconomic groups.

The Helicobacter genome has been deciphered by Jean-Francois Tomb and a team of scientists at the Institute for Genomic Research in Rockville, directed by J. Craig Venter.

Possession of the microbe's full instruction set, or genome, gives researchers invaluable information. Like a general who learns the enemy's order of battle, researchers now stand to know everything the organism can do and how it does it. The knowledge will help to understand which strains cause disease and to design new drugs and vaccines.

"I think it will have tremendous significance and will enable studies in many important directions," said Dr. Martin Blaser, director of infectious diseases at Vanderbilt University.

The bacterium was suggested as the agent of stomach ulcers as recently as 1983 and is now thought to cause 90 percent of such cases. Conventional medical wisdom until then and for a decade afterward held that excess stomach acid, induced by stress, was the cause of ulcers, and that theory, indicating treatment based on reducing stomach acid, created a market for two of the world's best-selling drugs, Tagamet and Zantac.

The surprising upset of established theory was accomplished after work by two Australian physicians, Barry Marshall and Robert Warren, and led directly to therapy based on antibiotics. But the antibiotics are expensive, especially in developing countries where infections often recur, raising the need for different and better treatments.

The ability to decode a bacterium's genome is a recent technical achievement that has not yet become routine. The Helicobacter genome is the fifth bacterial genome to be published and those of a dozen others, mostly pathogens, are in various stages of completion.

Biologists expect that when a critical mass of deciphered genomes is available, many details about the armament and evolution of bacteria will become apparent.

Venter said he started the project about two years ago because a company, Genome Therapeutics of Waltham, Mass, claimed it had completed the DNA sequence but declined to publish it. The claim turned out to be incorrect, he said, but also made it hard for his nonprofit institute to raise money for its own effort.

Dr. Bernd Seizinger, chief scientific officer of Genome Therapeutics, said he welcomed Venter's sequence, which is of a different strain of the bacterium. Seizinger said the company had completed 99 percent of the sequence, all that was necessary for commercial reasons, as part of a $22 million contract with Astra AB of Sweden, but could not publish the sequence because of its proprietary value.

Venter's institute bore the cost, $1 million to $2 million, out of its own money.

The genome is being made freely available.

"We paid for it ourselves and are giving it away for free," Venter said. "We are hoping it will attract some funding for us in the long run."

The bacterium turns out to have 1,667,867 units of DNA, the chemical that embodies the genetic code, arranged in a single, circular chromosome. Arrayed along the ring of DNA are the coding sequences for 1,590 genes.

The team led by Tomb has figured out the role of many of these genes by delving into computer databases that record the already sequenced DNA of genes of known function from other organisms. By comparing the Helicobacter genes with those on file, he has guessed what many are designed to do and the overall strategies that they enable the microbe to perform.

This computer-based approach, working from gene to function, is the opposite of the microbiologist's usual tactic, which is to study some property of a microbe and work backward to the gene that underlies it. The computer approach is also immensely faster because it lays bare the organism's bag of tricks at a single stroke.

Pub Date: 3/08/98

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