By Andrew Pollack

An oily mixture resembling salad dressing that can blow up anthrax bacteria. A toxin detector made of a slice of living rat brain on an electronic chip. A drug that would kill all bacteria and another that would boost a person's immune system to withstand any pathogen.

These are all ideas, some far off and some surprisingly close at hand, that are being pursued in what could become the nation's newest medical battle -- the war against bioterrorism.

Since Sept. 11, the government has been stepping up efforts to improve the nation's ability to respond to a germ attack. Much of the focus has been on improving the public health system's ability to spot an outbreak, quarantine the infected and deliver medicines. Another focus has been to accelerate production of vaccines for anthrax and smallpox.

But experts say it is also necessary to develop much better technology to detect, diagnose and treat biological agents. That is partly because there are dozens of pathogens that might conceivably be used in an attack, including some unnatural ones made by genetic engineering, and it would be impractical to develop vaccines for all of them.

A Pentagon advisory panel estimated it would cost up to $3.2 billion to develop just eight vaccines. So new approaches beyond vaccines are needed that can address a wide range of possible agents.

"How do we deal not only with the known and anticipated threats like anthrax, but also the ones we haven't thought of?" said Dr. Stephen S. Morse, director of the Center for Public Health Preparedness at Columbia University and formerly manager of a Defense Department germ defense research program. He said the approach of making vaccines for individual pathogens "is needed, it has value, but it's not sufficient for where we want to be in the future."

Dr. Andrea Branch, an associate professor at Mount Sinai School of Medicine who has advised the Pentagon on responding to germ warfare, said public health measures might prevent an infection from spreading, but new medicines are needed to treat those already infected.

Even before Sept. 11, dozens of biotechnology companies and academic laboratories were working on projects financed by the Pentagon or other government agencies to develop new bio-defense techniques. Now, some of those doing such work say they being urged to speed up the pace, but also not to talk about their work so much.

The new battle will be fought with the tools of biotechnology, genomics and immunology. The genomes of microbes can now be sequenced in a matter of weeks, giving new insights into their structure. In the last two weeks one group of scientists at Harvard Medical School reported finding a gene variation that makes mice resistant to anthrax, and another group said it had designed a molecule that protected rats against normally lethal doses of anthrax toxin.

Indeed, unlike some other areas of defense-related research, bio-defense work will have numerous civilian spinoffs, since doctors must respond to new pathogens that arise naturally, like H.I.V. and West Nile virus.

"The war's been on for as long as people have been on this earth," said Dr. David A. Relman, associate professor of medicine at Stanford. "It didn't start on Sept. 11."

Dr. Relman is working on ways to identify the pathogens in a biological attack. "These are products that are going to be used by every clinician in the world," he said, "whereas detectors for sarin nerve gas are not going to be used by your routine public health function."

Spurring much of the research has been the Defense Advanced Research Projects Agency, or Darpa, the Pentagon's central research organization. The agency spent $166.8 million on biological defense research in the fiscal year that ended last month. The work is mainly aimed at protecting soldiers, though the same techniques could help civilians.

Other parts of the Defense Department have their own research programs, as do other agencies. The National Institutes of Health spent about $49.7 million on research for bio-defense last fiscal year, the Centers for Disease Control and Prevention $46.6 million and the Department of Energy, which runs national laboratories, $39.6 million, according to a report issued last month by the General Accounting Office. All those figures seem likely to grow in response to the Sept. 11 attacks.

Darpa prides itself on doing long- range, highly innovative research that often fails but can have a huge impact if it succeeds. It was Darpa research that eventually led to development of the Internet and stealth aircraft. An agency spokeswoman said no interviews on bioterrorism were being given. But outsiders and the agency's own Web site paint a picture of a wide range of projects, some fairly bizarre.

"There are times I say, `There's no way this is going to work,' " said Dr. Carol Shoshkes Reiss, a professor of biology at New York University who advises Darpa. But some of the programs have made good progress, she said.

Among the most unusual projects is one at the University of Montana to train bees to sniff out chemical or biological agents. Dr. Michel Baudry, a professor of biological sciences at the University of Southern California, is trying to build a sensor by putting a slice of rat brain on top of an electronic chip that can sense the brain tissue's reaction when exposed to a harmful substance. This is the high-tech equivalent of the canary in the coal mine.

The Department of Energy has also been working on biological and chemical agent sensors that might monitor the air in public places. A major challenge is to avoid false alarms, which would cause needless evacuations, disruptions and panic. A monitor that continuously sniffs the air for biological agents might take 100 million measurements a year, and even one or two false alarms might be unacceptable, the Energy Department says.

But sensing an infectious agent or toxin is just the first step.

There must also be ways to determine if people are infected and to identify the pathogen involved -- and to do it quickly. Many germs produce symptoms similar to the flu, making it hard to tell there has been an attack. Moreover, in some cases, by the time the symptoms appear, the infection has spread and those infected are beyond treatment.

Cepheid, a biotechnology company in Sunnyvale, Calif., hopes to supply the Army with prototypes of a device that can do a genetic test for a pathogen in 30 minutes, compared with the hours or days it now takes.

But some bugs do not immediately go into the blood or other bodily fluids that can be easily sampled.

"In the body the bugs have to amplify to a certain level before you can detect them," said Dr. C. Richard Lyons, an associate professor of medicine at the University of New Mexico Health Sciences Center in Albuquerque. "It may be too late at that point."

Dr. Lyons said a quicker approach might be to analyze an infected person's response to the pathogen rather than try to isolate the bug itself. The levels of various proteins in the blood, which could be measured in minutes, might be different for different types of pathogens, he said.

Dr. Relman at Stanford hopes to identify which genes in human cells are turned on or off in response to exposure to different agents. "We do know that gene expression patterns change very quickly in response to an infection," he said.

Other projects aim at preventing infections or treating them once they occur. Dr. James R. Baker Jr. at the University of Michigan has developed what he and colleagues jokingly refer to as a salad dressing that can kill many types of microbes, including hardy anthrax spores.

They say the disinfectant concoction, made of microscopic droplets of soybean oil suspended in water, is safe enough to apply to the skin or to equipment, to spray into the nose to stave off infection and even drink in small quantities.

Dr. Baker explained that when some regular salad dressings are shaken, bubbles of oil get dispersed in the water. Those bubbles contain energy from the shaking, which is stored as surface tension. This energy is released when the oil droplets coalesce again.

Dr. Baker's disinfectant has extremely tiny bubbles, about 200 billionths of a meter across, which have extremely high energy but are prevented from coalescing by detergent. "But a bacterium is like a big oil droplet and they coalesce with it and blow it up," he said.

Ted Annis, chief executive of NanoBio, a company set up to sell the product, said it could be ready to use in six months if the company can get $5 million to complete its testing.

Isis Pharmaceuticals in Carlsbad, Calif., is trying to develop drugs that can kill virtually all bacteria. "There are molecular common denominators of life, and if we find them and make drugs that bind to them, then it won't matter what bug is used and how it's been modified," said Dr. David J. Ecker, a vice president in charge of the project.

Dr. Ecker said the company had found stretches of RNA, a key molecule of life, that are common to all bacteria and to a wide variety of viruses as well. But he said the Defense Department would not let him discuss how close the company is to finding drugs that could disable this RNA. Another effort is to improve the human immune system to help a person withstand all pathogens.

Dr. Arthur M. Krieg, a medical professor at the University of Iowa and chief scientific officer at Coley Pharmaceutical Group in Wellesley, Mass., believes that certain DNA sequences common in bacteria but not in people are recognized by the human immune system as a sign of infection. So giving these DNA segments as a drug might put the immune system on high alert.

Of course, biotechnology can be used not only for defense but for offense. Terrorists might try to use genetic engineering to make pathogens resistant to common antibiotics or vaccines or even to create entirely new pathogens. So new defenses might always be needed.

"The image I have in my mind was who was going to develop the bomb first, Germany or the United States," said Dr. Branch of Mount Sinai. "Now there is a different kind of race."

New York Times October 9, 2001