Custom-Built Pathogens Raise Bioterror Fears

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Custom-Built Pathogens Raise Bioterror Fears

By Joby Warrick

Washington Post Staff Writer

Monday, July 31, 2006; A01

 

STONY BROOK, N.Y.

Eckard Wimmer knows of a shortcut terrorists could someday use to get their

hands on the lethal viruses that cause Ebola and smallpox. He knows it

exceptionally well, because he discovered it himself.

In 2002, the German-born molecular geneticist startled the scientific world by

creating the first live, fully artificial virus in the lab. It was a variation

of the bug that causes polio, yet different from any virus known to nature. And

Wimmer built it from scratch.

The virus was made wholly from nonliving parts, using equipment and chemicals on

hand in Wimmer's small laboratory at the State University of New York here on

Long Island. The most crucial part, the genetic code, was picked up for free on

the Internet. Hundreds of tiny bits of viral DNA were purchased online, with

final assembly in the lab.

Wimmer intended to sound a warning, to show that science had crossed a threshold

into an era in which genetically altered and made-from-scratch germ weapons were

feasible. But in the four years since, other scientists have made advances

faster than Wimmer imagined possible. Government officials, and scientists such

as Wimmer, are only beginning to grasp the implications.

" The future, " he said, " has already come. "

Five years ago, deadly anthrax attacks forced Americans to confront the suddenly

real prospect of bioterrorism. Since then the Bush administration has poured

billions of dollars into building a defensive wall of drugs, vaccines and

special sensors that can detect dangerous pathogens. But already, technology is

hurtling past it. While government scientists press their search for new drugs

for old foes such as classic anthrax, a revolution in biology has ushered in an

age of engineered microbes and novel ways to make them.

The new technology opens the door to new tools for defeating disease and saving

lives. But today, in hundreds of labs worldwide, it is also possible to

transform common intestinal microbes into killers. Or to make deadly strains

even more lethal. Or to resurrect bygone killers, such the 1918 influenza. Or to

manipulate a person's hormones by switching genes on or off. Or to craft cheap,

efficient delivery systems that can infect large numbers of people.

" The biological weapons threat is multiplying and will do so regardless of the

countermeasures we try to take, " said Steven M. Block, a Stanford University

biophysicist and former president of the Biophysical Society. " You can't stop

it, any more than you can stop the progress of mankind. You just have to hope

that your collective brainpower can muster more resources than your

adversaries'. "

The Bush administration has acknowledged the evolving threat, and last year it

appointed a panel of scientists to begin a years-long study of the problem. It

also is building a large and controversial lab in Frederick, where new

bioterrorism threats can be studied and tested. But overall, specific responses

have been few and slow.

The U.S. Centers for Disease Control and Prevention has declined so far to

police the booming gene-synthesis industry, which churns out made-to-order DNA

to sell to scientists. Oversight of controversial experiments remains voluntary

and sporadic in many universities and private labs in the United States, and

occurs even more rarely overseas.

Bioterrorism experts say traditional biodefense approaches, such as stockpiling

antibiotics or locking up well-known strains such as the smallpox virus, remain

important. But they are not enough.

" There's a name for fixed defenses that can easily be outflanked: They are

called Maginot lines, " said Roger Brent, a California molecular biologist and

former biodefense adviser to the Defense Department, referring to the elaborate

but short-sighted network of border fortifications built by France after World

War I to prevent future invasions by Germany.

" By themselves, " Brent said, " stockpiled defenses against specific threats will

be no more effective to the defense of the United States than the Maginot line

was to the defense of France in 1940. "

How to Make a Virus

Wimmer's artificial virus looks and behaves like its natural cousin -- but with

a far reduced ability to maim or kill -- and could be used to make a safer polio

vaccine. But it was Wimmer's techniques, not his aims, that sparked controversy

when news of his achievement hit the scientific journals.

As the creator of the world's first " de novo " virus -- a human virus, at that --

Wimmer came under attack from other scientists who said his experiment was a

dangerous stunt. He was accused of giving ideas to terrorists, or, even worse,

of inviting a backlash that could result in new laws restricting scientific

freedom.

Wimmer counters that he didn't invent the technology that made his experiment

possible. He only drew attention to it.

" To most scientists and lay people, the reality that viruses could be

synthesized was surprising, if not shocking, " he said. " We consider it

imperative to inform society of this new reality, which bears far-reaching

consequences. "

One of the world's foremost experts on poliovirus, Wimmer has made de novo

poliovirus six times since his groundbreaking experiment four years ago. Each

time, the work is a little easier and faster.

New techniques developed by other scientists allow the creation of synthetic

viruses in mere days, not weeks or months. Hardware unveiled last year by a

Harvard genetics professor can churn out synthetic genes by the thousands, for a

few pennies each.

But Wimmer continues to use methods available to any modestly funded university

biology lab. He reckons that tens of thousands of scientists worldwide already

are capable of doing what he does.

" Our paper was the starting point of the revolution, " Wimmer said. " But

eventually the process will become so automated even technicians can do it. "

Wimmer's method starts with the virus's genetic blueprint, a code of

instructions 7,441 characters long. Obtaining it is the easiest part: The entire

code for poliovirus, and those for scores of other pathogens, is available for

free on the Internet.

Armed with a printout of the code, Wimmer places an order with a U.S. company

that manufactures custom-made snippets of DNA, called oglionucleotides. The DNA

fragments arrive by mail in hundreds of tiny vials, enough to cover a lab table

in one of Wimmer's three small research suites.

Using a kind of chemical epoxy, the scientist and his crew of graduate

assistants begin the tedious task of fusing small snippets of DNA into larger

fragments. Then they splice together the larger strands until the entire

sequence is complete.

The final step is almost magical. The finished but lifeless DNA, placed in a

broth of organic " juice " from mushed-up cells, begins making proteins.

Spontaneously, it assembles the trappings of a working virus around itself.

While simple on paper, it is not a feat for amateurs, Wimmer said. There are

additional steps to making effective bioweapons besides acquiring microbes. Like

many scientists and a sizable number of biodefense experts, Wimmer believes

traditional terrorist groups such as al-Qaeda will stick with easier methods, at

least for now.

Yet al-Qaeda is known to have sought bioweapons and has recruited experts,

including microbiologists. And for any skilled microbiologist trained in modern

techniques, Wimmer acknowledged, synthetic viruses are well within reach and

getting easier.

" This, " he said, " is a wake-up call. "

From Parlor Trick to Bio-Bricks

The global biotech revolution underway is more than mere genetic engineering. It

is genetic engineering on hyperdrive. New scientific disciplines such as

synthetic biology, practiced not only in the United States but also in new

white-coat enclaves in China and Cuba, seek not to tweak biological systems but

to reinvent them.

The holy grail of synthetic biologists is the reduction of all life processes

into building blocks -- interchangeable bio-bricks that can be reassembled into

new forms. The technology envisions new species of microbes built from the

bottom up: " living machines from off-the-shelf chemicals " to suit the needs of

science, said Jonathan Tucker, a bioweapons expert with the Washington-based

Center for Non-Proliferation Studies.

" It is possible to engineer living organisms the way people now engineer

electronic circuits, " Tucker said. In the future, he said, these microbes could

produce cheap drugs, detect toxic chemicals, break down pollutants, repair

defective genes, destroy cancer cells and generate hydrogen for fuel.

In less than five years, synthetic biology has gone from a kind of scientific

parlor trick, useful for such things as creating glow-in-the-dark fish, to a

cutting-edge bioscience with enormous commercial potential, said

Choffnes, an expert on microbial threats with the National Academies' Institute

of Medicine. " Now the technology can be even done at the lab bench in high

school, " she said.

Along with synthetic biologists, a separate but equally ardent group is pursuing

DNA shuffling, a kind of directed evolution that imbues microbes with new

traits. Another faction seeks novel ways to deliver chemicals and medicines,

using ultra-fine aerosols that penetrate deeply into the lungs or new forms of

microencapsulated packaging that control how drugs are released in the body.

Still another group is discovering ways to manipulate the essential biological

circuitry of humans, using chemicals or engineered microbes to shut down

defective genes or regulate the production of hormones controlling such

functions as metabolism and mood.

Some analysts have compared the flowering of biotechnology to the start of the

nuclear age in the past century, but there are important differences. This time,

the United States holds no monopoly over the emerging science, as it did in the

early years of nuclear power. Racing to exploit each new discovery are dozens of

countries, many of them in the developing world.

There's no binding treaty or international watchdog to safeguard against abuse.

And the secrets of biology are available on the Internet for free, said Robert

L. Erwin at a recent Washington symposium pondering the new technology. He is a

geneticist and founder of the California biotech firm Large Scale Biology Corp.

" It's too cheap, it's too fast, there are too many people who know too much, "

Erwin said, " and it's too late to stop it. "

A Darker Side

In May, when 300 synthetic biologists gathered in California for the second

national conference in the history of their new field, they found protesters

waiting.

" Scientists creating new life forms cannot be allowed to act as judge and jury, "

Sue Mayer, a veterinary cell biologist and director of GeneWatch UK, said in a

statement signed by 38 organizations.

Activists are not the only ones concerned about where new technology could lead.

Numerous studies by normally staid panels of scientists and security experts

have also warned about the consequences of abuse. An unclassified CIA study in

2003 titled " The Darker Bioweapons Future " warned of a potential for a " class of

new, more virulent biological agents engineered to attack " specific targets.

" The effects of some of these engineered biological agents could be worse than

any disease known to man, " the study said.

It is not just the potential for exotic diseases that is causing concern.

Harmless bacteria can be modified to carry genetic instructions that, once

inside the body, can alter basic functions, such as immunity or hormone

production, three biodefense experts with the Defense Intelligence Agency said

in an influential report titled " Biotechnology: Impact on Biological Warfare and

Biodefense. "

As far as is publicly known, no such weapons have ever been used, although

Soviet bioweapons scientists experimented with genetically altered strains in

the final years of the Cold War. Some experts doubt terrorists would go to such

trouble when ordinary germs can achieve the same goals.

" The capability of terrorists to embark on this path in the near- to mid-term is

judged to be low, " Charles E. Allen, chief intelligence officer for the

Department of Homeland Security, said in testimony May 4 before a panel of the

House Committee on Homeland Security. " Just because the technology is available

doesn't mean terrorists can or will use it. "

A far more likely source, Allen said, is a " lone wolf " : a scientist or

biological hacker working alone or in a small group, driven by ideology or

perhaps personal demons. Many experts believe the anthrax attacks of 2001 were

the work of just such a loner.

" All it would take for advanced bioweapons development, " Allen said, " is one

skilled scientist and modest equipment -- an activity we are unlikely to detect

in advance. "

Genes for Sale

Throughout the Western world and even in developing countries such as India and

Iran, dozens of companies have entered the booming business of commercial gene

synthesis. Last fall, a British scientific journal, New Scientist, decided to

contact some of these DNA-by-mail companies to show how easy it would be to

obtain a potentially dangerous genetic sequence -- for example, DNA for a

bacterial gene that produces deadly toxins.

Only five of the 12 firms that responded said they screened customers' orders

for DNA sequences that might pose a terrorism threat. Four companies

acknowledged doing no screening at all. Under current laws, the companies are

not required to screen.

In the United States, the federal " Select Agent " rule restricts access to a few

types of deadly bacteria, viruses and toxins. But, under the CDC's

interpretation of the rule, there are few such controls on transfers of

synthetic genes that can be turned into killers. Changes are being contemplated,

but for now the gap is one example of technology's rapid advance leaving law and

policy behind.

" It would be possible -- fully legal -- for a person to produce full-length 1918

influenza virus or Ebola virus genomes, along with kits containing detailed

procedures and all other materials for reconstitution, " said Richard H. Ebright,

a biochemist and professor at Rutgers University. " It is also possible to

advertise and to sell the product, in the United States or overseas. "

While scientists tend to be deeply skeptical of government intrusion into their

laboratories, many favor closer scrutiny over which kinds of genetic coding are

being sold and to whom. Even DNA companies themselves are lobbying for better

oversight.

Blue Heron Biotechnology, a major U.S. gene-synthesis company based in suburban

Seattle, formally petitioned the federal government three years ago to expand

the Select Agent rule to require companies to screen DNA purchases. The company

began voluntarily screening after receiving suspicious requests from overseas,

including one from a Saudi customer asking for genes belonging to a virus that

causes a disease akin to smallpox.

" The request turned out to be legitimate, from a real scientist, but it made us

ask ourselves: How can we make sure that some crazy person doesn't order

something from us? " said John Mulligan, Blue Heron's founder and chief

executive. " I used to think that such a thing was improbable, but then September

11 happened. "

Some scientists also favor greater scrutiny -- or at least peer review -- of

research that could lead to the accidental or deliberate release of genetically

modified organisms.

In theory, such oversight is provided by volunteer boards known as institutional

biosafety committees. Guidelines set by the National Institutes of Health call

on federally funded schools and private labs to each appoint such a board. A

2004 National Academy of Sciences report recommended that the committees take on

a larger role in policing research that could lead to more powerful biological

weapons.

In reality, many of these boards appear to exist only on paper. In 2004, the

nonprofit Sunshine Project surveyed 390 such committees, asking for copies of

minutes or notes from any meetings convened to evaluate research projects. Only

15 institutions earned high marks for showing full compliance with NIH

guidelines, said Edward Hammond, who directed the survey. Nearly 200 others who

responded had poor or missing records or none at all, he said. Some committees

had never met.

Stockpiles Aren't Enough

New techniques that unlock the secrets of microbial life may someday lead to the

defeat of bioterrorism threats and cures for natural diseases, too. But today,

the search for new drugs of all kinds remains agonizingly slow.

Five years after the Sept. 11 attacks, the federal government budgets nearly $8

billion annually -- an 18-fold increase since 2001 -- for the defense of

civilians against biological attack. Billions have been spent to develop and

stockpile new drugs, most of them each tied to a single, well-known bioterrorism

threat, such as anthrax.

Despite efforts to streamline the system, developing one new drug could still

take up to a decade and cost hundreds of millions of dollars. If successful, the

drug is a solution for just one disease threat out of a list that is rapidly

expanding to include man-made varieties.

In a biological attack, waiting even a few weeks for new drugs may be

disastrous, said Tara O'Toole, a physician and director of the Center for

Biosecurity at the University of Pittsburgh Medical Center.

" We haven't yet absorbed the magnitude of this threat to national security, "

said O'Toole, who worries that the national commitment to biodefense is waning

over time and the rise of natural threats such as pandemic flu. " It is true that

pandemic flu is important, and we're not doing nearly enough, but I don't think

pandemic flu could take down the United States of America. A campaign of

moderate biological attacks could. "

© 2006 The Washington Post Company

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