KEY TO ANTHRAX'S TOXICITY IS IN ITS GENETIC CODE
05 May 2003
Source: Washington Post, May 5, 2003
Key to Anthrax's Toxicity Is in Its Genetic Code
By Rick Weiss, Washington Post Staff Writer
Capping nearly three years of dogged analysis, a Maryland-based team of scientists has unveiled the entire genetic code of the bacterium that causes anthrax. The work, on a strain virtually identical to the one used in the 2001 postal bioterror attacks, lays bare many of the molecular tricks by which the notorious microbe wreaks havoc and presents new targets against which researchers can aim novel drugs, vaccines and bioterror detection devices.
By comparing the full genome of the anthrax bacterium to those of its medically benign bacterial cousins, researchers are piecing together the story of how a relatively mild-mannered soil-dwelling bacterium acquired the ability to infect healthy human beings, overcome their immune defenses and kill them with toxins.
It's important to find out how the anthrax agent, Bacillus anthracis, became homicidal, said Claire Fraser, president of the Institute for Genomic Research in Rockville (TIGR), who oversaw the gene-sequencing effort. The current epidemic of severe acute respiratory syndrome (SARS) is the latest reminder that microbes are constantly changing and testing the limits of human defenses. Both the virus that causes SARS and the bacterium that causes anthrax are the offspring of less virulent forebears, Fraser noted, and studies of the killers' family trees can reveal much about their lingering vulnerabilities.
"I certainly believe that in our battle with infectious disease agents we've not met all our enemies, and we'll continue to see newly emerging diseases come onto the scene," Fraser said. "And here is where the power of genomics is so great. It allows us to look across all these genomes and find out where some of these bugs came from and where they're going."
Actually, the new work is not all that new for many scientists. In keeping with the federally funded project's commitment to openness, the team placed its findings in a publicly accessible database as the work progressed. Although the full sequence was published last week, in the May 1 issue of the journal Nature, microbiologists have been using the data for months in their efforts to understand the microscopic menace.
Indeed, said Paul Keim, an Arizona State University microbiologist who has aided the federal investigation of the 2001 mailings, "We really would not have been ready for the anthrax letters if we'd not had much of the sequence in hand by then. The openness has been real important."
Within a few months after those mailings, scientists at TIGR released a partial genetic analysis of the "Florida strain," which killed five people and sickened 17. And Keim and colleagues showed that it was virtually identical to the "Ames strain" long studied by the U.S. Army at Fort Detrick, Md. TIGR is working with the FBI to see if detailed genetic fingerprinting studies can determine the source of the mailed spores, Fraser said, adding that she was "not at liberty" to say more.
But while research on the Florida strain is focused on parts of the B. anthracis genome, the new analysis takes a more sweeping approach. It sets in exact order all 5,227,293 letters (known as "bases") of molecular code written on B. anthracis's single chromosome. It also makes a first-pass reading of that code in an effort to see what, precisely, makes anthracis tick. (Two mini-chromosomes, or plasmids, inside each cell carry an additional 276,506 bases, which had already been sequenced.)
The team worked with a sample of the Ames strain obtained from Porton Down, the British biological warfare facility. Porton Down got its samples years ago from Fort Detrick, which had grown its stock from the infected remains of a dead cow in Texas. Confirming last year's preliminary findings, the new work shows that the Porton strain differs from the Florida strain by only 11 of the more than 5 million bases.
But the raw sequence was just the beginning. By looking for telltale "spelling" patterns within the seeming chaos of those millions of genetic letters, the team was able to find 5,508 stretches of DNA that appear to be genes. Each gene is a string of code that spells out the directions for making something the bacterium needs. The functions of almost one-third of B. anthracis's genes remain a mystery for now. But the rest have genetic hallmarks that hint heavily at what they do, Fraser said. Many of those are potential Achilles's heels.
For example, said Timothy Read, the microbiologist who led the work with Fraser, the team was surprised to find more than a dozen genes on the main chromosome that may contribute to the bacterium's toxicity. Until now, almost all the scientific focus on B. anthracis virulence has been on a well-known toxin made by a gene on one of the bacterium's plasmids. The current vaccine works by triggering an immune response against that plasmid toxin, but it could be that a vaccine aimed at some of the newly discovered toxins would work better or faster, Read said.
The team also found genes that appear to be involved in protecting the bacteria while they reside in the soil for years as hardy spores. This includes some genes that repair the sunlight-induced DNA damage that occurs while spores rest dormant outdoors. The researchers also found genes that make the bacteria impervious to the biochemical weapons used by disease-fighting white blood cells -- genes that scientists might want to disable with new drugs.
Other genes offer clues about the bacterium's genetic heritage. The team found three genes for attacking the gut linings of insects, suggesting that a recent ancestor of B. anthracis may have had "an insect-infecting lifestyle." Compared to their more benign relatives, anthrax bacteria are well endowed with genes for "digesting" a high-protein diet. Read speculates that a relatively harmless predecessor of B. anthracis acquired some of these genes, either from other microbes or by mutation, conferring upon that innocent bug a predilection for decaying carcasses. The microbe's virulent genes and toxins, he said, amount to "a few tricks so that in some cases it can make its own carcasses."
By identifying DNA snippets that are truly unique to B. anthracis, the new work could speed development of more accurate bioterror detection systems and diagnostic tests to tell whether a person is ill with anthrax, said Paul Jackson, a B. anthracis expert at Los Alamos National Laboratory in New Mexico. But a lot more work remains to be done, he said -- including difficult studies to see how the microbe's thousands of genes interact -- before the work gets translated into new drugs or vaccines.
"We have the blueprint, and we know what it says," Jackson said. "Now we have to see how it works."