http://www.nytimes.com/2001/10/24/national/24GERM.html

 

October 24, 2001

THE RESEARCH

Scientists Report Gains in Knowledge of Bacterium

By NICHOLAS WADE

cientists reported two major advances yesterday in their understanding of the anthrax bacterium — discoveries they hope will be the basis for a new generation of effective treatments.

The advances could lead to the development of drugs custom-designed to interfere with the anthrax toxin at different stages of its operation, the scientists said. One kind of drug would decoy the toxin that the bacteria release into the bloodstream, mopping it up before it can reach a target cell. Another would sabotage the part of the toxin that attacks a vital inner component of cells.

Antibiotics and a vaccine used by the military are effective defenses against anthrax, but doctors would like to see new approaches. Some strains are resistant to antibiotics or can be made resistant, while the cumbersome vaccine involves six shots and an annual booster.

At a news conference yesterday, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health, noted that similar discoveries about H.I.V. had rapidly led to the development of AIDS drugs.

The anthrax discoveries, which followed years of research, are to be reported in the journal Nature on Nov. 8. But they were published online yesterday for subscribers because of the intense public interest in the disease.

The Life Cycle of Anthrax     Understanding Anthrax     Patient Assassin: Anthrax Germs Turn the Body Against Itself (October 23, 2001)

In one discovery, scientists from Harvard Medical School and the University of Wisconsin said that after a decade's search they had found the receptor on the surface of cells that was targeted by the anthrax toxin.

The scientists, led by Dr. R. John Collier at Harvard and Dr. John A. T. Young at Wisconsin, were in a race with another anthrax expert, Dr. Stephen Leppla of the National Institutes of Health.

A new technique developed by one of Dr. Collier's students, Dr. Kenneth A. Bradley, helped to fish the receptor out just as the team was giving up hope.

Possession of the receptor protein may help biologists invent ways of fooling the anthrax toxin. The part of the protein that sticks out of the cell could be manufactured as a drug and injected into the bloodstream; the anthrax toxin might then attack the drug instead of living cells.

Dr. Collier said no new therapy could be developed immediately, but he added, "There is no question in my mind that with the tools we have we can conquer this organism."

The other advance reported yesterday was the determination of the exact three-dimensional structure of the lethal factor, the component of anthrax toxin that is injected into certain cells of the immune system. The factor destroys the cells, forcing them in their death throes to release an excessive amount of natural inflammatory agents that throw the body into lethal shock.

The discovery was made by Dr. Robert C. Liddington of the Burnham Institute in San Diego, and a team of scientists that included both Dr. Collier and Dr. Leppla. Dr. Liddington is a specialist in X-ray crystallography, the art of determining the precise physical shape of a protein molecule by mapping the position of each atom in its structure.

Dr. Liddington's team has worked out the exact structure of lethal factor, a principal component of anthrax's three-part toxin. The other components are edema factor and protective antigen, so called because it is the target of the current anthrax vaccine. Protective antigen's actual role is to latch onto cell receptors. The protective antigen then collects lethal factor or edema factor from the bloodstream and injects them into the target cell.

By working out the exact anatomy of lethal factor, Dr. Liddington has provided the information required by drug designers to synthesize small chemicals that would interact with lethal factor and block its function. The factor has a groove that precisely fits its target protein inside the cell. Chemists should be able to design a drug that fits the groove too, but then stays and blocks it.

The Harvard-Wisconsin team discovered the receptor for protective antigen by growing cells in the laboratory on a diet that included a mildly mutagenic chemical. Their hope was that one of the mutations would render inactive the gene that makes the unknown receptor.

Testing the cells with anthrax toxin, they found one line of cells that was immune because it no longer made the receptor. Dr. Bradley then infected the immune cells with a series of viruses, each one carrying a different gene-carrying region of the cell's DNA. One virus restored the cells' ability to make the receptor. That enabled the researchers to identify the gene. The protein it makes is a novel receptor of unknown function.

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