The New Defenders

An explosion of federal funding has Bay Area researchers at the forefront of America's counter-terrorism program. Will the money make us safer - or just make science a military secret?

Only months after terrorists used airliners to decimate the World Trade Center and anthrax to shut down Congress, the United States hosted the Winter Olympics in Utah. During the Games, a Bay Area team won a gold medal -- in the peace and security competition.

Before the Olympics began, about 40 people -- many of them scientists from the Lawrence Livermore National Laboratory -- took over the Utah Department of Public Health. They came armed with black boxes, each about the size of a fax machine, that had been developed at Livermore and constitute perhaps the highest achievement in American counterterrorism technology: the DNA analyzer.

These boxes (which also come in a smaller, brick-size version known as the Handheld Advanced Nucleic Acid Analyzer) use a biochemical process called polymerase chain reaction, or PCR, to analyze the genetic material of living organisms suspended in water samples. Then, via a computerized system of fluorescent tagging and matching, the machine compares those analyses with the DNA patterns of anthrax and other known agents of biological warfare or terror. (For security reasons, the Livermore lab will not say exactly what it is able to identify.)

Scientists at Lawrence Livermore National Laboratory 
were sent across the country after Sept. 11.
Paolo Vescia
Scientists at Lawrence Livermore National Laboratory were sent across the country after Sept. 11.
Page Stoutland took a particular interest in developing 
a detection system for weapons of bioterrorism.
Paolo Vescia
Page Stoutland took a particular interest in developing a detection system for weapons of bioterrorism.
Jim Marks led a group of UCSF researchers who 
discovered a drug that could be mass-produced to 
combat botulism.
Paolo Vescia
Jim Marks led a group of UCSF researchers who discovered a drug that could be mass-produced to combat botulism.
Lawrence Livermore scientists worked on purifying 
DNA so that it could be analyzed for pathogens.
Paolo Vescia
Lawrence Livermore scientists worked on purifying DNA so that it could be analyzed for pathogens.

Another, less developed machine, the Autonomous Pathogen Detection System, is designed to continuously "sniff" the air in a building or arena, much like a smoke detector, and analyze the DNA of certain pathogens that might be present.

The systems, of course, are primarily aimed at detecting biological hazards so that people can be evacuated before they're infected in a bioterror attack, or at least be treated before they're too sick. A side benefit of DNA-sniffing research is that once sniffing for bioterror agents such as anthrax, bubonic plague, botulism, and smallpox has been mastered, it's a short technological step to sniffing for other organisms. So-called sick buildings might soon be diagnosed with the same type of DNA analyzer used this winter in Salt Lake City. It should, therefore, come as no surprise that commercial rights to the handheld analyzer and its larger cousins have been licensed to private firms in Maryland and Texas.

And in exactly this way, counterterrorism appears to be on the verge of becoming a new growth industry -- one that will have a huge impact on the Bay Area science community and economy.

A handful of Bay Area laboratories are poised to receive a payload of federal money targeted at national security research in the biotechnology and information technology fields. In June, President George W. Bush signed the Public Health, Security, and Bioterrorism Preparedness Response Act, which earmarked nearly $3 billion for counterterrorism measures, including biotechnology research and development. Lawrence Livermore National Laboratory's budget for its Non-Proliferation, Arms Control, and International Security Directorate, which includes counterterrorism research, jumped $80 million in the past year. And the National Institutes of Health -- the major funding source for biological research at the University of California campuses -- have increased funding related to infectious disease by more than 16 percent.

Certainly, the federal money is being welcomed by local scientists, and research is proceeding apace. Livermore's air-sniffing systems are only a few in a host of technological gadgets that seem like science fiction but are as real as ground zero: a portable neutron detector that can examine cargo containers, from the outside, for nuclear weapons; human antibodies, manufactured in the lab, that can fight the deadly infections of biological weaponry; microbes that can seek out and neutralize bioterror agents; and information technology that can trace almost any chemical compound or recognize speech, eye, and fingerprint patterns.

But the new era of government-funded counterterror research has already begun to raise fundamental questions about control.

Many scientists are wondering whether, in an age when disease can be used as a weapon of mass destruction, biological research may soon be shrouded in the type of secrecy that characterized nuclear research efforts during the Cold War -- a secrecy that undermines the scientific openness that, many researchers feel, has led to U.S. pre-eminence in the biotechnology field.

There is also growing discomfort among researchers with a new reality: To have worked scientifically with certain biological agents is to be, like federal anthrax researcher Steven Hatfill, a suspect when terror strikes.

Regulators, meanwhile, are wrestling with entirely new paths for the approval of biological discoveries that have anti-terror applications as well as other uses that might be marketed to the public at large. For theoretical example, if and when a multipurpose anti-bioterror vaccine becomes available, who will make the profit on its sale?

The infrastructure for counterterror research is being configured as you read this story. The balance between government funding and government control of what is almost certain to become one of the nation's major growth industries is being struck -- but on an ad hoc basis, with little public debate, and almost nothing that might be called long-term planning.

By the time anthrax showed up in a Senate office building just a month after the Sept. 11 attacks, much of the Livermore lab was already operating on 24-hour, seven-day-a-week shifts. Its scientists had been deployed all over the country; at the World Trade Center collapse, they monitored the air for contamination.

Dr. Page Stoutland, deputy division leader of an area in the Livermore lab named R-Division, is very tall and thin and more easygoing than you might think for a man with his responsibility. Stoutland is in charge of projects having to do with chemical and biological national security programs, nuclear response activities, and the forensics of weapons of mass destruction.

Environmental monitoring -- particularly the detection of harmful pathogens such as anthrax -- is Stoutland's specialty. He started the project to develop a biodetection system before he left the Department of Energy's Chemical and Biological Non-Proliferation Program in 2000. Government agencies had been thinking seriously about bioterrorism since the Persian Gulf War, but even with the ability to direct research at a national laboratory, it's a long process to get from thinking about something to designing research, and then securing funding for the research, and then doing actual laboratory work that shows results.

"We knew that detection would be important," Stoutland explains. "The reason we have this is because we've been working on it for the last four years. We need to look at the next five years."

Already, scientists can analyze a sample for numerous bioterror agents within 30 minutes, but that requires getting to the infected area, grabbing a sample, and taking the sample to the lab. Biodetection devices need to be smaller, quicker, and sturdier, Stoutland says, so that they can be easily used by people who work in the streets and not in a laboratory.

"There's a real sense of urgency and relevance here," Stoutland says of the last year. "We've never had so many people working so long. The area around me hasn't stopped."

Stoutland travels across the country to Washington about three times a month to confer with colleagues, bosses, and Congress about the science of countering terrorist threats. "This country has neglected microbiology," he says. "It will become a sexier area [with the future emphasis] and more people will come into it."

University scientists have a big role to play, Stoutland adds, by advancing basic science and discovering new and better ways to manipulate genes. The end game, though, is to deliver products. "We're going to step up to whatever they want us to do," Stoutland says of his impending new role. "Stay tuned."

But even in the best-case scenario, there is a tension between open science and national defense. Some of the biggest issues in what has come to be known as homeland security center on the seemingly mundane, but scientifically vital, pursuit of academic publishing.

In the standard course of scientific progress, researchers, particularly those in academic settings, will spend years investigating the intricacies of a specific question -- and then achieve a breakthrough. They will write an article on the discovery for publication in the appropriate journal of authority on the matter, for review by scientific peers. If the discovery is confirmed by other researchers, the achievement becomes incorporated into a permanent body of knowledge, and over the course of time, scientists around the world draw upon the information to advance to the next stage, and then the next -- and so on.

Of course, open science allows other people -- including terrorists, and researchers willing to be paid by terrorists -- the same access to advanced scientific knowledge that scientists have. The defense establishment is, by nature, disposed to keep scientific information with national security implications secret, as was dramatically evidenced at the beginning of the Cold War, when nuclear physicists worked in near anonymity. In fact, early nuclear science gave birth to the Lawrence laboratories that are now moving to the center of counterterrorism research.

And the Cold War's worst nuclear experiments -- which killed people and tainted property with plutonium and other atomic poisons -- are precisely the reason that scientists who have concerns about the proliferation of weapons of mass destruction can also call for scientific openness, particularly in fields like microbiology, whose leaders have always worked in collaboration, generally toward the goal of improving overall public health.

"NIH is now empowered to classify work, where they never were before," says Barbara Rosenberg, director of the Federation of American Scientists' Biological Arms Control Project. "They haven't done it, and I hope they never do.

"But the government is starting to say journal publishers should be more cautious about what they publish."

The debate about scientific publishing involves not just the advancement of science, but the furthering of scientific careers. In the "publish or perish" world of academia, career advancement is based, at least in part, on scientific results published in major academic journals. In short, if the government greatly restricts the publication of scientific results from government-funded counterterror research, it will also greatly restrict the career prospects of any young academic who participates.

The topic of potential restrictions on publishing is so heated that the National Academies of Sciences last week devoted a two-day symposium to the debate.

"If you're in a weapons lab and you get money to do academic research, that's part of the bargain," says Dr. William Barletta, who is coordinating a new "Science for Homeland Security" program at Lawrence Berkeley National Laboratory, located on the hillside above the UC Berkeley campus. "They [the government] reserve the right to prior restraint.

"[On the other hand,] we can't put students on projects where there is a restriction on this, because this is their career. This is their ability to begin to become full-fledged scientists. This is an important piece of their training. We have to be careful about that."

Thanks to new security concerns created in part by the anthrax mailings that paralyzed Congress and much of the nation's postal system last year, tomorrow's bio-laboratories will also look different than they have in the past, says Mark Wheelis, a senior lecturer at the University of California at Davis and an expert in the history of biological weapons. Once freely accessible public university laboratories will be entered through locked doors. There will be logs -- some recorded in a central government database -- documenting who had access to which pathogens at what time of which day and what happened to each sample on the bench. There may be cameras recording every move in the laboratory and possibly "buddy systems," in which no one investigator is ever allowed to work alone with samples of particular materials.

Clearly, new security concerns are enough to give some scientists pause. Whether these concerns are enough to keep scientists and potential scientists from working on sensitive material remains to be seen. Security measures that push scientists away from the counterterrorism field would have serious implications for public safety.

"The open science community in general, and in particular the university science community, is driving exactly those pieces of science and technology that perhaps not for tomorrow, but for the day after tomorrow, are the most vital keys to assuring that when attacks happen, we are able to mitigate the consequences," says Barletta. "I believe that is what science and biotechnology and infomatics and information technology and the several physical science areas hold promise for."

For more than three decades, government scientists in a little-known, unremarkable laboratory building in Maryland called the Unites States Army Medical Research Institute of Infectious Disease (AMRIID) have been picking apart the roots of deadly illnesses that might become biological weapons. And then someone from somewhere mailed finely powdered, or "weaponized," anthrax to a Senate office building.

Within days, people who usually spend their time peering through a microscope found themselves underneath one. Virtually every scientist in the country who had ever worked with anthrax -- most of them investigating vaccinations against or treatment of the disease -- became a suspect in the criminal investigation of the terror attacks.

AMRIID scientists, in particular, had their otherwise fairly normal lives pulled apart. Even the military colonel who heads the lab was investigated. Another scientist, Steven Hatfill, remains a prime target for federal agents, who have combed through every part of his professional and personal life. Hatfill, an expert in the lethal effects of anthrax, worked at AMRIID in the late 1990s; more recently, he was a government contractor who trained people, including members of the U.S. Special Forces, in the methods of responding to a biological weapons attack.

Of course, it is absolutely the FBI's job to capture criminals. But the hunt through the nation's laboratories for an anthrax madman was enough to scare the pants off the bright minds needed to develop vaccines against such infectious agents. And that hunt has made researchers uneasy, to say the least, about a new term in the national security vernacular -- a "person of interest," who, in the public mind, becomes a "potential suspect."

"One of the things we're currently seeing is increasing attention to physical security and personnel screening," notes Wheelis, the biological weapons expert at UC Davis. "It's the kind of thing that would affect people from moving into a new area."

Similarly, increased background screening of scientists to determine who can and cannot work on newly government-funded, high-priority research would risk the disqualification of academic scientists vital to such research.

"Our national security apparatus cannot expect the open science community, the university community, to compromise exactly that environment that makes science and technology so fruitful," says Lawrence Berkeley's Barletta. As example, he adds: "If I look at the program in my division, which is developing the next generation of electronics, and I look at the students, they are from all over the world, many of whom are from sensitive countries. If we were to say that many of them were [not able to work on this for security reasons], we would cripple that very research that we need for security."

From his laboratory in the maze that is San Francisco General Hospital, Jim Marks has had a front-row seat at the government's wrestling match with countering bioterrorism. Eight years ago, he received funding from the Department of Defense to work in collaboration with AMRIID scientists on combating botulism, a Class A biological agent that is, like anthrax, considered prone to weaponization.

In July, Marks' group published the results of its discovery of a drug that can be mass-produced for the prevention and cure of botulism. The long journey toward this important milestone in biological research had an interesting evolution. The project began when the U.S. military started to take the idea of biological weapons research seriously, a few years after the Gulf War ended. The work culminated as Marks watched his colleagues at AMRIID go through the hell of federal investigations surrounding the anthrax mailings.

Marks is quick to point out, in no uncertain terms, that his lab does not possess any actual spores of botulism. His researchers have managed to do their work by collaborating with AMRIID, which does have the live agent. At some point, however, he and his colleagues are going to have to decide whether to move forward into more advanced work that would require housing actual infectious agents. Marks is not as concerned about security -- they already work behind locked doors that are behind locked doors -- as he is unenthusiastic about the risk of becoming a "person of interest" to government terrorism investigators.

Jim Marks is the exact sort of bright mind that the United States government desperately needs. A practical man with graying hair and a caterpillar mustache, Marks is at home in both the hospital and the laboratory.

In 1992, he returned to San Francisco from the Laboratory of Molecular Biology at Cambridge University in England, where he'd worked on antibody research as part of his doctoral studies in molecular biology. He resumed a place on the faculty of the University of California at San Francisco, which was familiar territory, given that Marks had learned to be a doctor at UCSF and had gone on to head the Intensive Care Unit at S.F. General, a teaching hospital for the university.

Still, Marks wanted to continue his research on antibodies -- proteins that the human body makes to fight the presence of a foreign substance -- with the idea of producing them through genetic engineering to combat diseases. So, at the suggestion of a scientist friend at UC Berkeley, Marks pursued grant money from the Department of Defense.

As is the case in most scientific discovery, the process in this research was just as important as the end result. Basically, Marks and his group used a method of introducing human antibodies directly into the patient, rather than waiting for the body to make its own. This is particularly important to fighting botulism, a fast-acting virus that can produce symptoms within two hours of infection.

The group isolated parts of the DNA of particular antibodies that mice and humans produce in response to the botulism toxin and then replicated them. They combined three antibodies in the laboratory, making sort of an antibody cocktail. Each antibody attacks a particular part of the toxin; the three together bind tighter to, and therefore attack more of, the botulinum toxin molecule. "I always thought this work was important, but I never thought it would be applicable during my lifetime," Marks says, pausing from an explanation of the intricacies of antibodies.

The Defense Department had good reason to be interested in Marks' research. Long before anthrax was sent through the mail, botulism was a biological agent sought by terrorists and Saddam Hussein. The Journal of the American Medical Association's Working Group on Civilian Defense notes that a single gram of crystalline botulinum toxin, if evenly dispersed and inhaled (a big if; such widespread dispersal is not easily achieved), would kill more than 1 million people.

Following the Gulf War, Iraq admitted to United Nations weapons inspectors that it had successfully produced and weaponized more botulinum toxin than any other biological agent. Perhaps more disturbing: Some 19,000 liters (or three times the amount needed to kill off the entire human population) remains largely unaccounted for.

The botulism threat is not entirely theoretical. Aerosol versions of botulinum toxin have been dispersed by terrorists in Japan at least three times since 1990.

And botulism is a nasty bug. Within 12 to 72 hours its victims may become violently nauseated. An infected person usually also has blurred vision and loses the ability to speak and swallow. As time progresses, the botulinum toxin begins to paralyze facial muscles, limbs, and then the rest of the body, in some cases leading to respiratory failure.

This is where Marks brings a particular perspective to the laboratory bench.

In his work at hospital bedsides, Marks saw real people suffer from botulism. (Food contamination can produce naturally occurring botulism.) This experience makes him a lot less patient than many scientists with the slow bureaucracy that moves bench science to drugs that help sick people. Even so, actual production of a drug for botulinum toxin based on Marks' research is, in the best-case scenario, three to four years away.

The ultimate San Francisco terrorism nightmare: Some sort of nuclear device is hidden inside one of the more than 1 million cargo containers that come through the Golden Gate on ships each year. The device is detonated. The blast destruction far exceeds what happened to the World Trade Center, and dangerous fallout contaminates much of the Bay Area for years, or even decades.

"We're all very acutely sensitive about airport security, but the threats of what can be brought into a cargo container are much more sensitive," says Lawrence Berkeley's Barletta.

"The amount of damage that you saw in the World Trade Center would be dwarfed, and the number of casualties that would continue to occur in the following five years would be even more," Barletta says.

Even before last September, the lab was already developing neutron tubes for use in a handheld device that scans for nuclear materials on an airplane or deep inside a cargo container. The device can detect radioactive materials virtually anywhere. After September, research on a neutron detector became a priority.

The challenge in creating such a nuclear scanner is not just scientific, but also technological. Much like the handheld DNA analyzer, a nuclear scanner needs to come in a form that can be used by nontechnical workers in the field, and that is rugged enough to work even if it is dropped repeatedly. Making state-of-the-art science that sturdy and user-friendly takes money and time for field testing.

The first such device could be available within months, Barletta says, assuming that the government decides how this sort of high-priority technology is going to be transferred to the private sector. It's the kind of decision that will have to be made, repeatedly, by the people involved in the science of counterterrorism.

Ordinarily, bringing new drugs to market is a process that hopes to balance safety with need. But counter-bioterror drugs are anything but ordinary.

Consider, for instance, the case of Marks' future botulism drug. The Food and Drug Administration has yet to approve, for any purpose, a mixture of recombinant antibodies created by mixing DNA in the laboratory. Of course, the FDA generally ensures that drugs are safe through a lengthy process of clinical trials. But you can't have clinical trials on a drug for botulism without using the drug on people infected with botulism. And no one is advocating a call for volunteer botulism victims. (The FDA is working with the National Institutes of Health on new regulations for approving drugs related to bioterrorism.)

Even when regulatory approval has been granted, there's the thorny matter of licensing and production of counterterror drugs. Typically, pharmaceutical giants buy the rights to turn something new from the academic bench into a manufactured product for sale. But, as bio-scientists point out, a pharmaceutical company might be unwilling to take on the cost and risk of producing a counterterror drug that would be profitable only in the event of a huge and successful terror attack. It is, for example, quite possible that any future drug for the prevention and cure of botulism, regardless of how effective, will never be used in the mass market, and never return a profit to its manufacturer.

Thus, government counterterror funding will likely focus on "dual use" products -- that is, products that have both anti-terror and more general uses.

For instance, Terry Hazen, co-director of the new Virtual Institute for Microbial Stress and Survival (VIMSS) at Lawrence Berkeley National Laboratory, which will study biological threats, received a $36 million, five-year grant in July for a project that studies how bacteria and fungi interact with the environment. The idea: An organism could be manipulated to seek radionuclides and, through decomposition, turn them into something less hazardous. Hazen's work is intended for use at environmental cleanup sites. But if you can make a radionuclide-stabilizing bug, it's not a big step to program a "seek-and-destroy bug" to find and decompose other substances.

"If we understood all of the genetic machinery and proteins involved in how [a bacteria] detects and moves toward a substance, we could genetically engineer a bacteria that has the ability to degrade a substance and seek it out," Hazen explains.

It's a page right out of science fiction: Researchers are on their way to creating a bacteria that would look for, say, mustard gas, and then, through biological breakdown, change it into something innocuous.

Whatever the outcome of Congress' wrestling match over the new Homeland Security Department, the agency will almost certainly dispense huge amounts of research money, and a great deal of it is likely to be targeted at, and thus likely to reconfigure, the Bay Area's scientific research community. "We see the challenge of homeland security as potentially spawning a whole new industry, or at least a whole new field of activity," says Sean Randolph, president of the Bay Area Economic Forum. "A lot of money and research is going to have to be put into this."

A recent report from the group notes that the Bay Area generates more patents, and more patents per employee, than any comparable region in the nation. In fact, the argument could be made that a national security industry already exists here, only in disconnected parts: five national security laboratories (Lawrence Livermore, Lawrence Berkeley, Sandia Livermore, NASA's Ames Research Center, and the Stanford Linear Accelerator); Stanford University and the University of California at San Francisco, both big dogs in the biological research field; the Joint Genome Institute in Walnut Creek; and the University of California at Berkeley, home to the world's largest unclassified computer system. That's not to mention the area's status as the largest hub of private biotechnology and intelligence technology in the country.

The proposed Homeland Security Department calls for "Regional Centers of Excellence" that would gather scientists from various laboratories under one roof. The centers also are likely to house the sorts of highly specialized facilities that are needed for work on particularly dangerous pathogens like the Ebola virus, which is, in a high percentage of cases, fatal and has no known cure. Conventional wisdom is that at least a regional center, if not something bigger, will be located in the Bay Area. In that scenario, of course, private researchers and university scientists would likely wind up working side by side, under the aegis of the federal government.

Such an arrangement would not be new. During World War II, the Department of Defense paid for scientific research, linking many universities together like arms of the government. That funding ended with the Mansfield Amendment in 1969, which stopped research sponsored by the military, if the research wasn't in the direct scope of military operations. The Vietnam War drove an even bigger wedge between the academic and defense communities. Counterterrorism funding could well reunite those communities, and perhaps even bring them together with private-sector researchers into a new industry.

Although it was long, World War II eventually ended. It is difficult to predict when -- or even if -- the war on terrorism might end, and all but impossible to know whether its call for advanced science and technology will create a whole new industry, or simply boost existing fields. In any case, it may be viewed by historians as an era in which the business of scientific research was dramatically, and permanently, altered. For better, or for worse.

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