Germ wars: beset by controversy, the U.S. military is using genetic engineering to design defenses against biological weapons.
In 17 years as an Army virologist at Fort Detrick in Frederick, Md., Neil Levitt found his work a risky business. On several occasions, he says, his supervisors issued him a gas mask to screen out toxic fumes emitted by a faulty ventilation system. In another incident, he recalls, a malfunctioning exhaust hood blew radioactive iodine onto his face. And once he discovered that several liters of a debilitating virus had inexplicably disappeared from a lab freezer.
Levitt, who worked for the Department of Defense's Biological Defense Research Program (BDRP), says he repeatedly asked officials overseeing his work to investigate the safety violations. But the Army denied some of his requests and ignored others, he says, leading him to resign in 1986. With the Foundation on Economic Trends, a Washington, D.C.-based environmental action organization, Levitt sued the Department of Defense (DOD) for violating national environmental law. In an out-of-court settlement of that suit, the DOD agreed to conduct environmental impact studies of its biological warfare research facilities (SN: 2/28/87, p. 132).
Levitt's lawsuit helped spotlight and expand a long-running but largely low-key controversy among some biological scientists over military germ research. While the upfront issues center on safety, larger questions of national defense and international relations are so intertwined in the dispute they seem almost inseparable.
Critics of the BDPR contend that "accidents waiting to happen" at DOD-funded laboratories require a revamping of the nation's biological warfare program. Inadequate safety enforcement risks the well-being of scientists in the labs and of residents living nearby, they argue. But behind the immediate personal fears and concerns for public health, they acknowledge, lie more complex issues of national security and international treaty.
In the preliminary draft of its environmental impact statement on the overall BDRP, forced by Levitt's suit and released in January 1988, the DOD says the program poses no significant risks to researchers or the publicf falls within the allowances of the 1972 Biological Weapons Convention treaty; and represents a vital defense against potential biological warefare threats. While information concerning those threats is classified, Army science advisers stated in a report issued last year that "there is reason to believe that at least one nation, USSR, continued the development of an offensive biological weapons capability after signing the treaty."
The Biological Weapons Convention treaty, signed by 111 nations including the United States and the Soviet Union, prohibits the development, production and stockpiling of biological weapons except for defensive purposes. However, it "does not preclude research into those offtensive aspects of biological agents necessary to determine what defensive measures are required," according to a 1969 statement issued by then-National Security Adviser Henry Kissinger.
This exceptional troubles Levitt and others, who view offensive and defensive research as indistinguishable, says Jay Jacobson, an infectious-disease specialist and epidemiologist at the University of Utah School of Medicine in Salt Lake City: "It's like testing a vest against bullets. You first need to have the bullets." Intensifying complaints by critics in recent years has been the BDRP's use of genetic engineering -- a technology unanticipated by the drafters of the treaty. Molecular biologist Keith Yamamoto of the University of California, San Francisco, notes that scientists can now create microorganisms that can cause deadly diseases for which no cures exist. "Using gene cloning destroys the distinction between offense and defense, and gives a loophole in the 1972 treaty," Yamamoto says.
Senate subcommittee hearings this past summer evaluated the safety of biological can chemical warfare research facilities. Testimony included Levitt's and that of Jeremy Rifkin, director of the Foundation on Economic Trends. Rifkin, best known for his outspoken opposition to genetic engineering, accused the DOD of failing to update safety policies as it expanded its budget for research on disease-causing organisms from about $16 million in 1980 to about $90 million in 1986.
The biological weapons issue has sparked debate in other political, scientific and public circles. During the past few years, the Army has sought to scale up its biological warfare research facility at the Dugway (Utah) Proving Grounds. But nearby residents have protested the facility ever since the Army accidentally released nerve chemicals there in 1968, killing thousands of sheep. Following a lawsuit filed against the DOD by Rifkin, the Army agreed earlier this year to back down on its plans for expanding the facility. Moreover, more than 600 biological researchers have signed pledges to refuse DOD funds for their work, and a bill is pending in Congress to implement the Biological Weapons Convention treaty as U.S. law. Supporters contend a domestic law would be more effective at deterring violators than the existing treaty.
Biological weapons existed for centuries prior to the 1972 treaty. The Greeks and Romans poisoned drinking water with decaying corpses 2,000 years ago. During World War II, the Japanese experimented on prisoners of war with plague, anthrax, smallpox and other diseases. But not until this decade have scientists gained the capacity to design novel biological weapons surreptitiously and with ease. The nature of genetic engineering makes it almost impossible for one nation to verify whether another is complying with the treaty, says Col. David Huxsoll, Commander of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, the BDRP's leading medical research facility. He and other military planners say the United States must defend against the possibility of terrorists or hostile nations manipulating genes to build weapons.
The military says its strategy is to defend against as many perceived threats as possible. For example, DOD-sponsored scientists are seeking defenses against viruses that cause yellow fever, Rift Valley fever, Korean hemorrhagic fever and dengue fever; bacteria causing botulism, anthrax and plague; various snake-venom and animal toxins; and several parasitic organisms. The plans call for the development of drugs and vaccines capable of deterring several related biological weapons rather than only a single agent. One way to do this, says Leonard Smith of USAMRIID, is to find a common means of attack shared by a group of agents and to learn which proteins participate in the attack. Then, the theory goes, scientists could create a vaccine designed to make the body produce antibodies against those common proteins. Investigating a dozen toxins from several snake species, Smith has found several that appear to target a single protein at the junction where nerve signals are transmitted between cells. "This provides hope for finding a single vaccine against several different toxins," he says.
In similar work, John Middlebrook of USAMRIID has examined several related bacterial and snake-venom toxins to find a common "neutralizing epitope," a section of a toxin protein at which an antibody can block the toxin's activity. Among 14 or 15 different toxins studied so far, he has identified one antibody that neutralizes as many as four different toxins.
Parallel efforts in virology seek to create vaccines against several different genetic varieties of one virus. Joel Dalrymple of USAMRIID is attempting to improve the existing vaccine against the virus causing Rift Valley fever, a disease common in sub-Saharan Africa and spread to humans by mosquitoes. The vaccine now routinely given to U.S. military personnel has drawbacks: It is expensive, requires three injections and may not work against all 33 to 38 varieties of the virus. Dalrymple and his co-workers have identified two proteins in the virus' outer coat, one of which, G2, appears to induce immunity in mice. They are now producing antibodies to various pieces of G2 to see which best protect the mice against Rift Valley fever. The researchers hope that cloning the genes coding for those protein segments will lead to a more effective vaccine.
Still another technique uses a harmless "carrier" virus to transport into the human body immunity-inducing pieces from the protein coats of several different viruses. As a first step in building such a "polyvalent" vaccine, Dalrymple is examining the alphaviruses, which can cause fever, arthritis and death, and are found mostly outside of the United States. He is focusing on three different species of alphavirus to determine which genes to include in the polyvalent vaccine.
If successful, such efforts could benefit civilians as well as the Armed Forces. But skeptics contend the military's research goals are unrealistic. Even if BDRP scientists produced a vaccine effective against many different viruses, they say, enemy scientists could mutate an agent's genes to create an entirely new organism against which the drug or vaccine would not work. "Nature does this herself: A virus changes its clothes and comes back wearing a different coat," notes Yamamoto. "The military cannot make an infinite number of vaccines to an infinite number of agents."
BDRP scientists maintain that their goals, though far off, are attainable. "I won't accept the criticism that the number of viruses out there is overwhelming and too numerous to make a vaccine," Dalrymple says. "It is possible to make a vaccine against all alphaviruses causing human disease." He won't stop making vaccines against single strains of alphavirus while waiting for this to happen, he adds.
In more basic research, DOD-supported scientists seek to identify which proteins and genes of various biological agents are responsible for causing disease symptoms, and which might be prime targets for drugs and vaccines. Lt. Col. Martin Crumrine of USAMRIID, Donald Robertson of Brigham Young University in Provo, Utah, and their collaborators are studying Bacillus anthracis, the bacterium that causes anthrax. Anthrax is endemic in parts of Africa and elsewhere, but only a few cases of the disease occur each year in the United States, usually in workers who contract it from woolly animals such as sheep or goats. Anthrax symptoms include skin ulcers, gastrointestinal pains and severe and sometimes fatal pneumonia.
Bacillus anthracis produces three toxin proteins. The existing vaccine contains one of the proteins, called protective antigen, which induces antibody production in the immunized host but is slow to take effect and requires repeated immunizations. Crumrine has cloned the protective antigen gene into Escherichia coli and Bacillus subtilus bacteria. If all goes well, he says, the bacteria will produce large quantities of protective antigen in a form suitable for use as a vaccine, which should be easier to produce and should work better than the existing vaccine. His preliminary experiments indicate that the protective antigen produced by B. subtilus protects guinea pigs against anthrax without harming the animals.
Using a different strategy, Robertson is selectively mutating B. anthracis genes. He hopes to destroy the toxicity but not the overall chemical structure of the proteins for which the genes code. The resulting mutated and harmless bacteria, when used as a vaccine, would "fool" the human immune system into beefing up its defenses against B. anthracis. "Compare the recombinant anthrax protein to a car with its motor removed," Robertson explains. "The car lacking a motor looks identical to a car with a motor, but it does not run."
Although Robertson's and Crumrine's methods are essentially those used by molecular biologists to create vaccines against influenza, the AIDS virus, hepatitis B and other infectious agents, there are those who oppose military sponsorship of such studies. Critics say the knowledge acquired through such research -- better understanding of a bacterium's genetic makeup, the function of each piece of each gene, its preferred growing conditions and ways to clone and produce its toxins -- could be used to produce toxic proteins of a more dangerous nature.
"By separating and distinguishing parts of the molecule that make it infectious from the antibody-causing parts, scientists could make toxins that would have no antibody-eliciting section," Yamamoto says. Agents altered in this way could be used only offensively, he contends.
Another factor troubling some people is that the basic research often involves the transfer of hazardous genes into genetically altered varieties of bacteria that live naturally in humans. Microbiologist Richard Novick, director of the Public Health Research Institute in New York City, says he "could see how this research could easily be perverted to build incapacitating agents." Novick, a civilian scientist, in the 1960s refused a DOD proposal that he introduce penicillin-resistance genes into a pneumonia-causing bacterium. "This would have been a disservice to the human population," says Novick. In the early 1980s, he again turned down DOD funds, this time for his studies of Staphylococcus bacteria, whose toxins attack the human gut and are a leading cause of food poisoning.
Novick and Yamamoto describe scenarios in which recombinant DNA techniques could lead to the creation of more dangerous toxins. By linking one toxin gene onto another toxin gene, they say, scientists could form "double-edged toxins" that could injure a cell in two ways. For example, one toxin could poison a cell while a second toxin inactivates the cell's enzyme normally responsible for degrading the first toxin. They also envision scientists attaching a toxin to another protein whose job is penetrating certain cells, as a means of selectively poisoning those cells. Such "coupled toxins" already are being studied as a means of fighting cancer and AIDS (SN: 12/3/88, p.358).
Military scientists argue that their biological warfare research will not result in such frightening scenarios. They say they work at incapacitating potentially hazardous agents, rather than turning them into weapons. In defensive research, USAMRIID's Huxsoll explains, scientists look at a virus' chemical nature, it size and structure. They learn what it infects, how to cripple it and how to grow it in limited, laboratory quantities. On the other hand, he says, scientists making a weapon would look at how to stabilize the virus, make it more potent and disseminate it, and how to grow it in large quantities.
Military scientists add that biological defense research often ends up benefitting public health efforts in areas neglected by other research efforts. Michael Buchmeier of Scripps Clinic in La Jolla, Calif., a recipient of both DOD and National Institutes of Health funds for his research on the often deadly Lassa virus, says: "It is difficult to get money to study diseases such as Lassa fever. We've gone to major companies and been refused funds. One agency with a good track record is the Army." Buchmeier says Lassa fever is a substantial public health problem in African countries, such as Sierra Leone, where it accounts for approximately 30 percent of the hospital deaths and a substantial number of miscarriages.
Critics counter that such military supported research has other international consequences. Growing and working with biological agents within an Army-supported research facility not only draws the nation closer to using those agents as weapons, but also leads other countries to suspect the United States is performing offensive research, they argue.
"If the United States makes a vaccine against a biological warfare agent, it provokes other countries to make other biological weapons," Jacobson says. "This leads to an escalation of weapons, as in occurring in the nuclear arms race." Shifting the DOD's biomedical research to civilian agencies, such as the National Institutes of Health and the Centers for Disease Control, critics contend, would reduce what Rifkin terms a micro-biological version of "missile-gap paranoia."
With such a dichotomy of opinions, a modified biological defense effort acceptable to both sides seems unlikely. However, at this summer's Senate hearings, subcommittee chairman Carl Levin and Army representatives agreed that DOD-sponsored laboratories should abide by the same safety guidelines as the National Institutes of Health and the Centers for Disease Control. both critics and some biological warfare researchers are increasingly discussing the necessity of an open research program, a sort of "global defense," as Jacobson calls it.
Dalrymple explains why the military may support such a defense: "If I could build a vaccine and put it in the literature, it would be a deterrent to any evil person thinking to put out these agents as weapons."
Biomedical ethicist Thomas Murray, of Case Western University School of Medicine in Cleveland, cites another reason for openess. He Believes people are afraid of biotechnology because they are aware that groups or individuals with mixed motives might create dangerous organisms, or that well-meaning researchers might do so unintentionally. "Fears," he says, "are seriously exacerbated by secrecy."
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|Title Annotation:||includes related article|
|Date:||Dec 17, 1988|
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