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Anthrax Antibiotic-resistant anthrax. Plague-Ebola hybrids. Soviet researchers used genetic engineering to try to create such "superbugs" in the 1980s. What could defend against them?
Future Germ Defenses
by Judith Miller, Stephen Engelberg, and William Broad

The futuristic military research by Soviet scientists presented America's biodefenders with a grim challenge. The vulnerability of soldiers and civilians to attack was growing. In what appeared to be a quiet biological arms race, much of which took place behind closed lab doors, offense was outpacing defense.

Even before gene splicing became routine, a germ agent could be perfected in a few years, while a vaccine often took a decade to make and win approval. More than a decade after the Gulf War, America's vaccine against botulinum remained experimental. Antibiotics were losing the war against pathogens, which were performing their own, natural genetic engineering, mutating beyond the reach of the most powerful drugs.

In the late 1990s, the Pentagon dramatically increased funding to find new ways of fighting infectious disease, pouring hundreds of millions of dollars for biodefense into the Defense Advanced Research Projects Agency, or DARPA, the little-known agency that had invented the Internet and stealth technology. DARPA, an arm of the Pentagon, had no laboratories or scientists of its own. Its managers wanted to underwrite the most audacious research they could find. The hope was to spur avenues of inquiry that industry had ignored or abandoned. It was understood from the beginning that the research was high risk, that many of the projects would fail.

Vaccine being drawn into syringe Could a single vaccine guard against an onslaught of various different germs?

A vision of the future
The first director of DARPA's Unconventional Countermeasures Program, Shaun Jones, had his own clear vision of the future. A doctor and Navy commander who had been a member of the Navy's elite commando unit, the SEALs, Jones had traveled the world on secret missions. He believed that defense against germ weapons required radical new approaches.

The medical breakthroughs of the late 20th century had often been driven by profit. Pharmaceutical companies had made billions targeting individual diseases or maladies. There were blockbuster drugs to fight allergies, to slow baldness, to restore sexual prowess. Jones wanted to go in the opposite direction, to search for breakthroughs that would provide widespread protection.

One focus was multivalent vaccines that could prime the body's immune system to ward off a range of microbial threats. Someday, perhaps, researchers could come up with a single shot that conferred immunity against, say, plague, anthrax, and botulinum. Jones was also fascinated by the potential of antiviral drugs. The viruses, which infiltrate and hide in human cells, had largely escaped medicine's weapons. But Jones believed new research might yield new ways to attack viral enemies like smallpox.

DNA Fragments of "naked DNA" from pathogens are today being tested as a new form of vaccine.
Pioneers of genetic science
A young colleague of Nobel laureate Joshua Lederberg's, Jones used the clout of the eminent scientist to recruit talent for his projects. Among the first researchers he signed up was Stan Cohen, the Stanford pioneer who, with Herb Boyer, had made the first recombinant DNA breakthrough in 1973. By 1998, the program had scientists working on 43 different projects.

Stephen A. Johnston of the University of Texas's Southwestern Medical Center in Dallas was typical. He had long nurtured blue-sky ideas. And the National Institutes of Health, the main source of federal funding for biomedical researchers, had consistently rejected his proposals as unlikely to work and unsuitable for financial support.

Backed by a DARPA grant, Johnston used the new biology to break a pathogen's genes into hundreds of different bits that he then injected into hundreds of mice. His next step was to infect the mice with the original pathogen. Typically, most fell to the onslaught, but a few exhibited resistance. In that way, Johnston discovered which DNA parts could be used to bolster the immune response and fight disease. He called the innovative method Expression Library Immunization, or ELI. "The basic idea is to let the immune system tell you what works," he said. Peers hailed his research as surprising and elegant.

The promise of DNA vaccines
Johnston's research represented a major advance for gene vaccination, a young field that promised to revolutionize the science of immunization. Traditional vaccines use weakened or killed versions of disease organisms, or inactivated toxins or proteins from pathogens, to give the body's immune system advance warning of infection and time to build up defenses. Gene vaccines were just bare DNA—often plasmids. When injected into the body and incorporated into cells, the genes expressed a limited set of the pathogen parts that were nonetheless sufficient to trigger the immune response. [Learn more about making vaccines.]

The gene vaccine approach was like a scalpel. Patients would be injected with precisely what was needed to inoculate them against a disease. Though experimental, the method showed promise. It could eliminate the risk of infection associated with some live and weakened vaccines. It could also ease production and compliance with federal regulations, the complexities of which had stymied anthrax vaccines for so long. Gene vaccines were chemical, not biological. That cut the chance of contamination and spoilage. Finally, they were also highly stable. Unlike conventional vaccines that needed refrigeration, gene vaccines could be stored dry or in solution under many conditions and temperatures, making their distribution easier.

Johnston's research was important because it sped up the identification of suitable DNA snippets, reducing the search time from a year or more down to months. And he proceeded to accelerate the process further, finding ways to mechanize it with tiny robots. His goal, which he called instant immunization, was to make a new vaccine in a day. If successful, this promised to help scientists react very quickly to attacks with designer bugs that no one had ever encountered before.

DNA processor Recent biotechnology allows the "re-shuffling" of genes to make proteins unknown in nature—and of potential use in battling germs.

Anthrax detergents and aerosol vaccines
Some of DARPA's most futuristic work was done by Maxygen, a small company in Redwood City, California, that Jones visited just after its founding. The concept was an elegant elaboration of Cohen and Boyer's discoveries. Where the pioneers of gene splicing took a gene from one organism and moved it to another, Maxygen mixed up hundreds, even thousands of genes to produce a single, new product. Nature works by a similar process of trial and error. Over millions of years, bugs mutate and a tiny number become better equipped to deal with their environment. Maxygen had found a way to fast-forward the evolutionary process by recombining genes into hundreds, even thousands of new ways.

One early project involved an enzyme used in detergents like Tide to dissolve grass stains, which researchers had been trying for years to improve. Maxygen's scientists shuffled thousands of genes in different combinations until they created a new genetic blueprint, one that had never before existed in nature which involved 26 genes, each sliced from a different kind of bacteria. The result was a much more powerful enzyme that could be used in detergents.

Man being sprayed with decontaminant Sprays are now available to decontaminate workers cleaning up hazardous materials. Someday aerosol vaccines might protect people before, or immediately after, a bioweapons attack.
Jones immediately saw the applications to biodefense. In 1998, DARPA gave Maxygen a $3.8 million contract to refine the enzyme further, making it strong enough to dissolve not only grass stains but anthrax bacteria and other germs that form hardened spores. Perhaps someday the military would have a detergent that could be sprayed over people and neutralize an anthrax attack. Another Maxygen contract, for $7.7 million in 1999, focused on developing unusually strong gene vaccines that would stimulate the human body into superimmunity against viral and bacterial invaders. The military also asked the company to develop aerosol-based vaccines that could be inhaled to safeguard people against a broad range of pathogens. A cloud of vaccine, sprayed over many square miles, was seen as potentially the simplest way to protect people and animals from epidemics.

A main goal of the research was to shuffle the genetic material that made pathogen proteins and antigens, which spur the body to make protective antibodies. By tweaking the naturally occurring antigens of, say, anthrax, the company hoped to produce a more powerful immune response. Russell J. Howard, the president of Maxygen, said the initial results were encouraging and that it appeared possible to make vaccines that were not only more powerful but, perhaps, effective against several diseases at once.

RAPID detector Defense researchers in the 1960s struggled to make devices that could rapidly detect and analyze germ attacks. Today mobile labs, such as Idaho Technology's RAPID, pinpoint germs in minutes.

Rewards of blue-sky research
At first, many of the DARPA projects were criticized because they tended to be so radical. Work on modifying red blood cells to knock out toxins and microbes was ridiculed because no one had ever tried it before, and it was judged, for the near future at least, as merely intriguing. But other projects showed quick promise, often raising commercial interest. Shapiro at Stanford, who discovered an enzyme common to many bacteria, was widely praised for advances that promised antibiotics of broad effectiveness. And Maxygen, whose claims seemed extravagant at first, was quickly proven right as rival companies rushed to exploit the shuffling technique.

A measure of the program's success, and Pentagon approval, was DARPA's expanding budget for defense against biological weapons, which included not only work on medical treatments but research on such devices as advanced germ detectors. The annual budget went from $59 million in 1998 to $162 million in 2001 and was projected to hit $205 million by 2005. Over that time, the agency was to spend $1.2 billion, making it a new power in the world of biomedical research. However, the benefits of the DARPA-funded research for biological defense, if any, would be unclear for years, even decades. And Jones acknowledged that some projects would surely be "extraordinary failures" and that the value of others would not be known until they were rigorously tested on people. After all, a promising response in a petri-dish or a mouse was no guarantee of human benefit. That kind of evaluation required the slow, painstaking, carefully regulated process of clinical trials in which doctors and volunteers took on the responsibility of searching for unexpected side effects as well as proving safety and effectiveness.

But Jones and company saw the initiative as a good insurance policy, a cheap one given the stakes.

Miller, Engelberg, and Broad
Judith Miller, a correspondent for the New York Times since 1977, has reported from throughout the world and concentrated on the Middle East and the former Soviet republics. Stephen Engelberg has reported on national security for over a decade and is now investigations editor for the Times. William Broad, a science writer for the Times since 1983, has twice shared the Pulitzer Prize.

This article was adapted with permission from the authors' book Germs: Biological Weapons and America's Secret War (Simon & Schuster, 2001).

Germs book cover

Photos: (1) Corbis Images; (2-5) WGBH/NOVA; (6) Courtesy of Idaho Technology; (7) Naum Kazhdam; (8) Jacket Design—Eric Fuentecilla for Simon and Schuster.

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