Bioweapons Research Proliferates

Photos courtesy of Engineering Animation, Inc. BIOLOGICAL DEFENSE: Among the tools to counter effects from biological weapons, bioengineered red blood cells (above) can patrol the circulatory system, sponging up viral particles and carrying them to the liver for destruction. Synthetic macromolecules, or dendrimers (right), can capture viral particles and prevent further viral destruction of healthy cells. Biological weapons have been around since medieval warriors hurled plague-ridden corpses over city walls to destroy their populations. Today what was once called "germ warfare" is even more threatening because of the ability to genetically alter pathogens. Recent events in the Persian Gulf and the United States have riveted attention on the "weaponization" of bacteria, viruses, and toxins. "Every time something happens with Saddam Hussein or there is a potential terrorist incident, it's a reminder that we aren't in a position to defend ourselves. So government, academia, and private industry are building defenses against bioweapons," says Patricia Irving, president of InnovaTek Inc. in Richland, Wash., which is developing devices to detect airborne pathogens. In October 1997, a United Nations special commission discovered evidence of bioweapons in Iraq; a month later, Iraq barred a U.S. team from inspecting suspect facilities, nearly precipitating war. On the bioterrorist front, in February 1998 two men were arrested in Las Vegas, Nev., for allegedly transporting anthrax bacilli for the purpose of creating a weapon. Authorities dropped the charges within days, however, when the FBI determined that the men had a vaccine strain, which they reportedly were stockpiling in case of attack by Iraq. And between the Iraq and Las Vegas incidents, President Bill Clinton announced last January in his State of the Union address his intent to strengthen the 1972 Biological Weapons Convention (BWC) "with a new international inspection system to detect and deter cheating." On the domestic front, more than 100 U.S. cities began biowarfare preparedness programs in the summer of 1997 as part of the federal Defense Against Weapons of Mass Destruction Act of 1996. Recent legislation has also made it harder to obtain cultures of pathogenic organisms. "If you order Ebola virus, for example, from the American Type Culture Collection [in Rockville, Md.], they can't just mail it to you. The lab must be registered, and the CDC [Centers for Disease Control and Prevention] must investigate the lab to see if proper controls are there," explains Zachary Selden, a policy associate at Business Executives for National Security, a Washington, D.C., organization concerned with biowarfare issues. But reaction to a possible bioweapons threat has been a long time in coming, maintains Marie Chevrier, senior research associate at the Belfer Center for Science and International Affairs at Harvard University. "Bioweapons have not been on people's radar screens, and it hadn't reached a high enough policy level until recently because of interagency arguing. The Federation of American Scientists [FAS, a private, nonprofit policy organization] issued a report in 1990 with recommendations for BWC verification protocols," she says. A biological weapon delivers highly virulent and incapacitating pathogens or their toxins. A millionth of a gram of anthrax can kill a person; a gram of aerosolized botulinum toxin can kill 1.5 million people. "Dozens of species of bacteria have been used or could be used. Or, someone could genetically engineer a new microorganism or make one antibiotic-resistant or more toxic," explains David Ecker, managing director of combinatorial drug discovery at Isis Pharmaceuticals Inc. in Carlsbad, Calif. Adds Jonathan Tucker, director of the biological weapons nonproliferation project at the Monterey Institute of International Studies in Monterey, Calif.: "When delivered through the air, bioweapons are tasteless, odorless, and invisible, making it difficult to know you are under attack until it is too late." Federation of American Scientists (founded in 1945 as the Federation of Atomic Scientists) 307 Massachusetts Ave. N.E. Washington, D.C. 20002 (202) 546-3300 Fax: (202) 675-1010 E-mail: fas@fas.org Defense Advanced Research Projects Agency (DARPA) 3701 N. Fairfax Dr. Arlington, Va. 22203-1714 (703) 696-0104 http://www.darpa.mil/ U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) 1425 Porter St. Fort Detrick Frederick, Md. 21702-5011 (301) 619-2285 Fax: (301) 619-4625 http://140.139.42.105/USAMRIID.htm Although bioweapons are called "the poor man's atomic bomb" because disease-causing bacteria and their toxins are relatively simple and cheap to produce, they aren't easy to deliver in a way that can inflict mass casualties. "Using a biological agent as a weapon of mass destruction requires disseminating it through the atmosphere as an aerosol cloud--a suspension of microscopic particles--from a low-flying aircraft, a moving vehicle, or an urban rooftop," Tucker points out. "The agent particles must be the right size to be inhaled deep in the lungs and enter the bloodstream, where the microbes replicate to cause disease. But preparing and disseminating a biological aerosol to infect large numbers of people is technically challenging and requires expertise beyond what an ordinary microbiologist can do." The U.S. had an offensive bioweapons program until President Richard Nixon halted it in 1969, before the BWC was signed in London, Moscow, and Washington on April 10, 1972. Almost every country has signed this treaty, but the problem has been enforcing it. Today bioweapons research in the U.S. is strictly defensive, with stiff penalties for efforts to create such weapons, notes Gregory Wallance, a former federal prosecutor and partner at Kaye, Scholer, Fierman, Hayes, and Handler in New York City. Much of the defensive research is conducted at or funded by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick in Frederick, Md., and the Defense Advanced Research Projects Agency (DARPA), part of the U.S. Department of Defense based in Arlington, Va. "The bread-and-butter microbiology is done at USAMRIID, and most if not all of it is unclassified. The high-tech arm is DARPA," says Mark Wheelis, a professor of microbiology and a bioweapons historian at the University of California, Davis. USAMRIID's 1998 budget is $25 million, with $3 million supporting extramural medical biological defense research. DARPA is entirely extramural and funds innovative ideas. Of a total 1998 budget of $2.04 billion, $60.8 million funds biological warfare defense, with $88 million slated for FY1999. THE MESSENGER: A programmed cellular messenger travels to the inside of the nucleus and activates the suicide gene, which causes the lymphocyte to sacrifice itself and prevent further viral replication. Bioweapons defense research includes developing vaccines, antibiotics, air-filtration devices, and biosensors, in addition to conducting epidemiology studies. Microbiology research takes center stage before the fact, but the focus would shift to public health specialists in the event of actual use. "Unless terrorists provided advance warning or a delivery device was found, we wouldn't know that a biological aerosol attack had occurred until the disease had incubated for a few days," notes Tucker. "Then lots of people would begin showing up in emergency rooms with nonspecific symptoms. We would need an effective system of disease surveillance to recognize that people had been infected with an exotic agent. Patients with anthrax, plague, or tularemia respond to antibiotics administered before the onset of acute symptoms." Other life sciences are also useful to bioweapons defense. Irving applies her expertise in acid rain at InnovaTek. "I did my Ph.D. work in aerosol science and air pollutants, on small particles of acidic sulfate aerosols that can impact on the human respiratory system. This is very much related to biological weapons," she remarks. The company's devices capture and concentrate particulates, which can then be passed to sensor and detection devices. One such detector is being developed by two researchers from Virginia Polytechnic Institute and State University in Blacksburg: William Velander, a professor of chemical engineering, and Kent Murphy, an associate professor of electrical engineering. A polymer containing antibodies specific to certain pathogens is coated onto optical fibers, through which an ultraviolet laser passes. Antibodies that bind pathogens in the air change the optical signals. "We would like to make an array of sensors in one support system, to measure different agents," says Murphy. Research at Isis picks up where detection leaves off, seeking a way to cripple pathogens. The company's $2.5 million DARPA-funded project scans bacterial genomes to identify uniquely microbial genes to exploit as molecular Achilles heels. "The variety of the dozen or so microorganisms whose genomes have been sequenced is quite enough for us to mine to identify RNA sequences common to all bacteria," says Ecker. So far, they have found six. Next, computer modeling will identify small molecules that could bind to and silence the RNAs, and then combinatorial chemistry will be used to synthesize thousands of variations on those themes, eventually yielding new antimicrobials. Engineering Animation Inc. in Ames, Iowa, is exploring the big picture of defensive bioweaponry. Staff molecular biologists, anatomists, and multimedia artists created a short 3-D video that follows deadly viruses into the lungs to the bloodstream, where they encounter a microscopic arsenal of antibodies, antisense agents, and cell-death triggers. One scenario depicts red blood cells binding to pathogens and escorting them to the liver for dismantling, a strategy based on research by Ronald Taylor, a professor of biochemistry at the University of Virginia. "The feel and pace is like a battle in the body, and these agents are the advance troops," explains Adrian Sannier, vice president and general manager of interactive production at Engineering Animation. The video was done for DARPA to show to nontechnical audiences. Biological warfare has a colorful history. The earliest reference is a Sanskrit treatise from 100 B.C. to 100 A.D. that instructs royalty to mix their food with antidotes to poisons. During the French and Indian War, the British gave Indians smallpox-bearing blankets. From 1932 until 1942, the Japanese field-tested microbial menaces, killing thousands. Adolf Hitler, however, objected to biowarfare, perhaps because of his fear of microbes, suggests Erhard Geissler, a professor of genetics at the Max Delbruck Center for Molecular Medicine in Berlin. "There were medical experiments with people in concentration camps using bacteria, but they were to develop vaccines and drugs against war diseases such as typhus," he explains. In 1973, the Soviet Union's Biopreparat, part of the Ministry of Defense, was established, and at its peak in the late 1980s, it included 50 research and development and production facilities that employed more than 100,000 workers. "It controlled the world's second-largest antibiotics industry and produced many biopharmaceuticals and veterinary products. But until September 1992, Biopreparat was simultaneously being used as an ostensibly civilian front for the Soviet/Russian biological weapons program," says Jonathan B. Tucker, director of the chemical and biological weapons nonproliferation project at the Monterey Institute of International Studies in Monterey, Calif. Russian President Boris Yeltsin officially halted offensive bioweapons research in 1992. The U.S. offensive bioweapon effort began in 1942 but never approached the scale of the Manhattan Project, the effort during World War II to develop the atomic bomb, according Mark Wheelis, a professor of microbiology at the University of California, Davis. "There was a well-funded, coherent, ambitious, broadly designed program to develop actual weapons, to be delivered in shells, missiles, and bombs," he says. A facility at Fort Detrick in Frederick, Md., stored 5,000 bombs loaded with anthrax spores; a production facility operated in Terre Haute, Ind.; and Mississippi and Utah had test sites. President Richard Nixon nixed the program in 1969, citing obsolescence because conventional and nuclear weapons were a sufficient deterrent, Wheelis adds. By 1973, the bioweapons and records had been destroyed. Today, a sealed, four-story building at Fort Detrick contains fermentation tanks once used to grow anthrax bacilli and other pathogens, providing testimony to the old U.S. offensive program. Recent bioterrorism incidents are rare. The only known U.S. case was the deliberate contamination of restaurants with Salmonella typhimurium by the Rajneeshee cult in Les Dalles, Ore., in 1984. Cult members seeded salad bars with the bacteria, sickening more than 750 diners, none fatally. "The plot was to put people out of action during a county election so that the cult's preferred candidates would win," recalls Tucker. And in March 1995, the Aum Shinrikyo sect released the nerve gas sarin in a Tokyo subway, following failed attempts by the group in 1993 to release anthrax spores from a building and botulinum toxin from a vehicle, and a 1992 trip to Zaire to obtain Ebola virus for weaponization.--R.L. At the heart of controlling bioweapons is the "dual-use" dilemma--a weapons facility resembles a microbiology lab. "Any discovery in pathology or epidemiology can be applied to benefit mankind or misapplied for a malevolent purpose," says Wheelis. For example, investigators at the State Research Centre for Applied Microbiology in Obolensk, Russia, reported a genetically engineered strain of anthrax that resists the Russian vaccine (A.P. Pomerantsev et al., Vaccine, 15:1846-9, 1997). Most bioweapons experts interpret the work as vaccine research, Selden notes, but some critics see it as legitimizing past efforts to design vaccine-resistant anthrax. Arthur Caplan The BWC bans the development and production of biological weapons, but not research on infectious diseases, which is essential for progress in medicine and public health. But "the line between research and development is often blurred, and it is difficult to distinguish between offensive and defensive work on dangerous pathogens and toxins," comments Tucker. That blurring concerns the Biotechnology Industry Association (BIO) and the Pharmaceutical Research and Manufacturers of America (PhRMA), both based in Washington, D.C. These organizations abhor biowarfare but acknowledge that inspections of all facilities capable of microbe weaponization could "open the door to the potential for industrial espionage," such as sampling proprietary agents, according to Selden. Scientists from the FAS and PhRMA met in Geneva the week of March 9 to discuss ways to strengthen BWC compliance protocols without compromising commercial efforts. They identified specific "triggers" that should be considered as sufficient for a facility to have to file a declaration that it is not producing bioweapons. These triggers include very-large-scale microbial production capabilities, participation in biodefense work, and use of a pathogen that could be used in a bioweapon. Meanwhile, efforts are well under way to develop procedures for checking compliance with the BWC. An international ad hoc group is meeting for 11 weeks this year to negotiate procedures for inspecting facilities, but they haven't agreed yet on whether to call for inspection of all declared facilities, or just those suspected of violating the treaty. "The hope is by the end of 1998 to have a conceptual framework, and by the end of 1999, protocols to go back to the convention for ratification," says Alan Goldhammer, director of technical affairs at BIO. The time to take biowarfare seriously has come, says Chevrier. World War I involved chemicals and chemical weapons; World War II involved physicists and atomic bombs. Now attention is turning to the life science community, which is trying not to follow in the footsteps of the physical scientists. Concludes Irving: "We were focused on the high-tech stuff, and we weren't paying attention to what really is a low-tech weapon. Now that the Cold War is over and high-tech threats are less, the threat of bioweapons is more obvious." Ricki Lewis is a freelance science writer based in Scotia, N.Y. She can be reached online at rickilewis@nasw.org.

Bioweapons Research Proliferates

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Photos courtesy of Engineering Animation, Inc.

BIOLOGICAL DEFENSE: Among the tools to counter effects from biological weapons, bioengineered red blood cells (above) can patrol the circulatory system, sponging up viral particles and carrying them to the liver for destruction. Synthetic macromolecules, or dendrimers (right), can capture viral particles and prevent further viral destruction of healthy cells.