[>Htech] developing biological weapons

[Eugen Leitl]

http://www.technologyreview.com/BioTech/wtr_16485,306,p1.html?PM=GO

The Knowledge

Biotechnologybs advance could give malefactors the ability to manipulate
life processes -- and even affect human behavior.

By Mark Williams

Editor's note: Conscious of the controversial nature of this article,
Technology Review asked Allison Macfarlane, a research associate in the
Science, Technology, and Global Security Working Group in MIT's Program in
Science, Technology, and Society, to rebut its argument: see "Assessing the
Threat." We were also careful to elide any recipes for developing a biological
weapon. Such details as do appear have been published before, mainly in
scientific journals.

Last year, a likable and accomplished scientist named Serguei Popov, who for
nearly two decades developed genetically engineered biological weapons for the
Soviet Union, crossed the Potomac River to speak at a conference on
bioterrorism in Washington, DC.

Popov, now a professor at the National Center for Biodefense and Infectious
Diseases at George Mason University, is tallish, with peaked eyebrows and
Slavic cheekbones, and, at 55, has hair somewhere between sandy and faded
ginger. He has an open, lucid gaze, and he is courteously soft-spoken. His
career has been unusual by any standards. As a student in his native city of
Novosibirsk, Siberia's capital, preparing his thesis on DNA synthesis, he read
the latest English-language publications on the new molecular biology. After
submitting his doctorate in 1976, he joined Biopreparat, the Soviet
pharmaceutical agency that secretly developed biological weapons. There, he
rose to become a department head in a comprehensive program to genetically
engineer biological weapons. When the program was founded in the 1970s, its
goal was to enhance classical agents of biological warfare for heightened
pathogenicity and resistance to antibiotics; by the 1980s, it was creating new
species of designer pathogens that would induce entirely novel symptoms in
their victims.

In 1979, Popov spent six months in Cambridge, England, studying the
technologies of automated DNA sequencing and synthesis that were emerging in
the West. That English visit, Popov recently told me, needed some arranging:
"I possessed state secrets, so I could not travel abroad without a special
decision of the Central Committee of the Communist Party. A special legend,
essentially, that I was an ordinary scientist, was developed for me." The
cover "legend" Popov's superiors provided proved useful in 1992, after the
U.S.S.R. fell. When the Russian state stopped paying salaries, among those
affected were the 30,000 scientists of Biopreparat. Broke, with a family to
feed, Popov contacted his British friends, who arranged funding from the Royal
Society, so he could do research in the United Kingdom. The KGB (whose control
was in any case limited by then) let him leave Russia. Popov never returned.
In England, he studied HIV for six months. In 1993, he moved to the University
of Texas Southwestern Medical Center, whence he sent money so that his wife
and children could join him. He remained in Texas until 2000, attracting
little interest.

"When I came to Texas, I decided to forget everything," Popov told me. "For
seven years I did that. Now it's different. It's not because I like talking
about it. But I see every day in publications that nobody knows what was done
in the Soviet Union and how important that work was."

Yet if Popov's appearance last year at the Washington conference is any
indication, it will be difficult to convince policymakers and scientists of
the relevance of the Soviet bioweaponeers' achievements. It wasn't only that
Popov's audience in the high-ceilinged chamber of a Senate office building
found the Soviets' ingenious applications of biological science morally
repugnant and technically abstruse. Rather, what Popov said lay so far outside
current arguments about biodefense that he sounded as if he had come from
another planet.

The conference's other speakers focused on the boom in U.S. biodefense
spending since the attacks of September 11, 2001, and the anthrax scare that
same year. The bacteriologist Richard Ebright, a professor of chemistry and
chemical biology at Rutgers University, fretted that the enormous increase in
grants to study three of the category A bacterial agents (that is, anthrax,
plague, and tularemia) drained money from basic research to fight existing
epidemics. Ebright (who'd persuaded 758 other scientists to sign a letter of
protest to Elias Zerhouni, the director of the National Institutes of Health)
also charged that by promiscuously disseminating bioweaponeering knowledge and
pathogen specimens to newly minted biodefense labs around the United States,
"the NIH was funding a research and development arm of al-Qaeda." Another
speaker, Milton Leitenberg, introduced as one of the grand old men of weapons
control, was more splenetic. The current obsession with bioterrorism, the
rumpled, grandfatherly Leitenberg insisted, was nonsense; the record showed
that almost all bioweaponeering had been done by state governments and
militaries.

Such arguments are not without merit. So why do Serguei Popov's accounts of
what the Russians assayed in the esoteric realm of genetically engineered
bioweapons, using pre-genomic biotech, matter now?

They matter because the Russians' achievements tell us what is possible. At
least some of what the Soviet bioweaponeers did with difficulty and expense
can now be done easily and cheaply. And all of what they accomplished can be
duplicated with time and money. We live in a world where gene-sequencing
equipment bought secondhand on eBay and unregulated biological material
delivered in a FedEx package provide the means to create biological weapons.

Build or Buy?
There is growing scientific consensus that biotechnology -- especially, the
technology to synthesize ever larger DNA sequences -- has advanced to the
point that terrorists and rogue states could engineer dangerous novel
pathogens.

In February, a report by the Institute of Medicine and National Research
Council of the National Academies entitled "Globalization, Biosecurity, and
the Future of the Life Sciences" argued, "In the future, genetic engineering
and other technologies may lead to the development of pathogenic organisms
with unique, unpredictable characteristics." Pondering the possibility of
these recombinant pathogens, the authors note, "It is not at all unreasonable
to anticipate that [these] biological threats will be increasingly sought
after...and used for warfare, terrorism, and criminal purposes, and by
increasingly less sophisticated and resourced individuals, groups, or
nations." The report concludes, "Sooner or later, it is reasonable to expect
the appearance of "bio-hackers.'"

Malefactors would have more trouble stealing or buying the classical agents of
biological warfare than synthesizing new ones. In 2002, after all, a group of
researchers built a functioning polio virus, using a genetic sequence off the
Internet and mail-order oligonucleotides (machine-synthesized DNA molecules no
longer than about 140 bases each) from commercial synthesis companies. At the
time, the group leader, Eckard Wimmer of the State University of New York at
Stony Brook, warned that the technology to synthesize the much larger genome
of variola major -- that is, the deadly smallpox virus -- would come within 15
years. In fact, it arrived sooner: December 2004, with the announcement of a
high-throughput DNA synthesizer that could reproduce smallpox's 186,000-odd
bases in 13 runs.

The possibility of terrorists' gaining access to such high-end technology is
worrisome. But few have publicly stated that engineering certain types of
recombinant microC6rganisms using older equipment -- nowadays cheaply
available from eBay and online marketplaces for scientific equipment like LabX
-- is already feasible. The biomedical community's reaction to all this has
been a general flinching. (The signatories to the National Academies report
are an exception.) Caution, denial, and a lack of knowledge about
bioweaponeering seem to be in equal parts responsible. Jens Kuhn, a virologist
at Harvard Medical School, told me, "The Russians did a lot in their
bioweapons program. But most of that isn't published, so we don't know what
they know."

On a winter's afternoon last year, in the hope of discovering just what the
Russians had done, I set out along Highway 15 in Virginia to visit Serguei
Popov at the Manassas campus of George Mason University. Popov came to the
National Center for Biodefense after buying a book called Biohazard in 2000.
This was the autobiography of Ken Alibek, Biopreparat's former deputy chief,
its leading scientist, and Popov's ultimate superior. One of its passages
described how, in 1989, Alibek and other Soviet bosses had attended a
presentation by an unnamed "young scientist" from Biopreparat's
bacterial-research complex at Obolensk, south of Moscow. Following this
presentation, Alibek wrote, "the room was absolutely silent. We all recognized
the implications of what the scientist had achieved. A new class of weapons
had been found. For the first time, we would be capable of producing weapons
based on chemical substances produced naturally by the human body. They could
damage the nervous system, alter moods, trigger psychological changes, and
even kill."

When Popov read that, I asked him, had he recognized the "young scientist?"
"Yes," he replied. "That was me."

After reading Biohazard, Popov contacted Alibek and told him that he, too, had
reached America. Popov moved to Virginia to work for Alibek's company,
Advanced Biosystems, and was debriefed by U.S. intelligence. In 2004 he took
up his current position at the National Center for Biodefense, where Alibek is
a distinguished professor.

Regarding the progress of biotechnology, Popov told me, "It seems to most
people like something that happens in a few places, a few biological labs. Yet
now it is becoming widespread knowledge." Furthermore, he stressed, it is
knowledge that is Janus-faced in its potential applications. "When I prepare
my lectures on genetic engineering, whatever I open, I see the possibilities
to make harm or to use the same things for good -- to make a biological weapon
or to create a treatment against disease."

The "new class of weapons" that Alibek describes Popov's creating in Biohazard
is a case in point. Into a relatively innocuous bacterium responsible for a
low-mortality pneumonia, Legionella pneumophila, Popov and his researchers
spliced mammalian DNA that expressed fragments of myelin protein, the
electrically insulating fatty layer that sheathes our neurons. In test
animals, the pneumonia infection came and went, but the myelin fragments borne
by the recombinant Legionella goaded the animals' immune systems to read their
own natural myelin as pathogenic and to attack it. Brain damage, paralysis,
and nearly 100 percent mortality resulted: Popov had created a biological
weapon that in effect triggered rapid multiple sclerosis. (Popov's claims can
be corroborated: in recent years, scientists researching treatments for MS
have employed similar methods on test animals with similar results.)

When I asked about the prospects for creating bioweapons through synthetic
biology, Popov mentioned the polio virus synthesized in 2002. "Very prominent
people like [Anthony] Fauci at the NIH said, "Now we know it can be done.'"
Popov paused. "You know, that's...naC/ve. In 1981, I described how to carry
out a project to synthesize small but biologically active viruses. Nobody at
Biopreparat had even a little doubt it could be done. We had no DNA
synthesizers then. I had 50 people doing DNA synthesis manually, step by step.
One step was about three hours, where today, with the synthesizer, it could be
a few minutes -- it could be less than a minute. Nevertheless, already the
idea was that we would produce one virus a month."

Effectively, Popov said, Biopreparat had few restrictions on manpower. "If you
wanted a hundred people involved, it was a hundred. If a thousand, a
thousand." It is a startling picture: an industrial program that consumed tons
of chemicals and marshalled large numbers of biologists to construct, over
months, a few hundred bases of a gene that coded for a single protein.

Though some dismiss Biopreparat's pioneering efforts because the Russians
relied on technology that is now antiquated, this is what makes them a good
guide to what could be done today with cheap, widely available biotechnology.
Splicing into pathogens synthesized mammalian genes coding for the short
chains of amino acids called peptides (that is, genes just a few hundred bases
long) was handily within reach of Biopreparat's DNA synthesis capabilities.
Efforts on this scale are easily reproducible with today's tools.

What the Russians Did
The Soviet bioweapons program was vast and labyrinthine; not even Ken Alibek,
its top scientific manager, knew everything. In assessing the extent of its
accomplishment -- and thus the danger posed by small groups armed with modern
technology -- we are to some degree dependent on Serguei Popov's version of
things. Since his claims are so controversial, a question must be answered:
Many (perhaps most) people would prefer to believe that Popov is lying. Is
he?

Popov's affiliation with Alibek is a strike against him at the U.S. Army
Medical Research Institute of Infectious Diseases (Usamriid) at Fort Detrick,
MD, where Biopreparat's former top scientist has his critics. Alibek, one
knowledgeable person told me, effectively "entered the storytelling business
when he came to America." Alibek's critics charge that because he received
consulting fees while briefing U.S. scientists and officials, he exaggerated
Soviet bioweaponeering achievements. In particular, some critics reject
Alibek's claims that the U.S.S.R. had combined Ebola and other viruses -- in
order to create what Alibek calls "chimeras." The necessary technology, they
insist, didn't yet exist. When I interviewed Alibek in 2003, however, he was
adamant that Biopreparat had weaponized Ebola.

Alibek and Popov obviously have an interest in talking up Russia's bioweapons.
But neither I, nor others with whom I've compared notes, have ever caught
Popov in a false statement. One must listen to him carefully, however.
Regarding Ebola chimeras, he told me when I first interviewed him in 2003,
"You can speculate about a plague-Ebola combination. I know that those who ran
the Soviet bioweapons program studied that possibility. I can talk with
certainty about a synthesis of plague and Venezuelan equine encephalitis,
because I knew the guy who did that." Popov then described a Soviet strategy
for hiding deadly viral genes inside some milder bacterium's genome, so that
medical treatment of a victim's initial symptoms from one microbe would
trigger a second microbe's growth. "The first symptom could be plague, and a
victim's fever would get treated with something as simple as tetracycline.
That tetracycline would itself be the factor inducing expression of a second
set of genes, which could be a whole virus or a combination of viral genes."

In short, Popov indicated that a plague-Ebola combination was theoretically
possible and that Soviet scientists had studied that possibility. Next, he
made another turn of the screw: Biopreparat had researched recombinants that
would effectively turn their victims into walking Ebola bombs. I had asked
Popov for a picture of some worst-case scenarios, so I cannot complain that he
was misleading me -- but the Russians almost certainly never created the
plague-Ebola combination.

One further testimonial to Popov: the man himself is all of a piece. Recalling
his youth in Siberia, he told me, "I believed in the future, the whole idea of
socialism, equity, and social justice. I was deeply afraid of the United
States, the aggressive American military, capitalism -- all that was deeply
scary." He added, "It's difficult to communicate how people in the Soviet
Union thought then about themselves and how much excitement we young people
had about science." Biological-weapons development was a profession into which
Popov was recruited in his 20s and which informed his life and thinking for
years. To ask him questions about biological weapons is to elicit a cascade of
analysis of the specific cell-signaling pathways and receptors that could be
targeted to induce particular effects, and how that targeting might be
achieved via the genetic manipulation of pathogens. Popov is not explicable
unless he is what he claims to be.

Popov's research in Russia is powerfully suggestive of the strangeness of
recombinant biological weapons. Because genetics and molecular biology were
banned as "bourgeois science" in the U.S.S.R. until the early 1960s, Popov was
among the first generation of Soviet university graduates to grow up with the
new biology. When he first joined Vector, or the State Research Center of
Virology and Biotechnology, Biopreparat's premier viral research facility near
Novosibirsk, he didn't immediately understand that he had entered the
bioweaponeering business. "Nobody talked about biological weapons," he told
me. "Simply, it was supposed to be peaceful research, which would transition
from pure science to a new microbiological industry." Matters proceeded,
however. "Your boss says, "We'd like you to join a very interesting project.'
If you say no, that's the end of your career. Since I was ambitious then, I
went further and further. Initially, I had a dozen people working under me.
But the next year I got the whole department of fifty people."

In 1979, Popov received orders to start research in which small, synthesized
genes coding for production of beta-endorphins -- the opioid neurotransmitters
produced in response to pain, exercise, and other stress -- were to be spliced
into viruses. Ostensibly, this work aimed to enhance the pathogens' virulence.
Popov shrugged, recalling this. "How could we increase virulence with
endorphins? Still, if some general tells you, you do it." Popov noted that the
particular general who ordered the project, Igor Ashmarin, was also a
molecular biologist and, later, an academician on Moscow State University's
biology faculty. "Ashmarin's project sounded unrealistic but not impossible.
The peptides he suggested were short, and we knew how to synthesize the DNA."

Peptides, such as beta-endorphins, are the constituent parts of proteins and
are no longer than 50 amino acids. Nature exploits their compactness in
contexts where cell signaling takes place often and rapidly -- for instance,
in the central nervous system, where peptides serve as neurotransmitters. With
10 to 20 times fewer amino acids than an average protein, peptides are
produced by correspondingly smaller DNA sequences, which made them good
candidates for synthesis using Biopreparat's limited means. Popov set a
research team to splicing synthetic endorphin-expressing genes into various
viruses, then infecting test animals.

Yet the animals were unaffected. "We had huge pressure to produce these more
lethal weapons," Popov said. "I was in charge of new projects. Often, it was
my responsibility to develop the project, and if I couldn't, that would be my
problem. I couldn't say, "No, I won't do it.' Because, then, what about your
children? What about your family?" To appease their military bosses, Popov and
his researchers shifted to peptides other than beta-endorphins and discovered
that, indeed, microbes bearing genes that expressed myelin protein could
provoke animals' immune systems to attack their own nervous systems. While the
Vector team used this technique to increase the virulence of vaccinia, with
the ultimate goal of applying it to smallpox, Popov was sent to Obolensk to
develop the same approach with bacteria. Still, he told me, "We now know that
if we'd continued the original approach with beta-endorphins, we would have
seen their effect."

This vision of subtle bioweapons that modified behavior by targeting the
nervous system -- inducing effects like temporary schizophrenia, memory loss,
heightened aggression, immobilizing depression, or fear -- was irresistibly
attractive to Biopreparat's senior military scientists. After Popov's
defection, the research continued. In 1993 and 1994, two papers, copublished
in Russian science journals by Ashmarin and some of Popov's former colleagues,
described experiments in which vaccines of recombinant tularemia successfully
produced beta-endorphins in test animals and thereby increased their
thresholds of pain sensitivity. These apparently small claims amount to a
proof of concept: bioweapons can be created that target the central nervous
system, changing perception and behavior.

I asked Popov whether bioweaponeers could design pathogens that induced the
type of effects usually associated with psychopharmaceuticals.

"Essentially, a pathogen is only a vehicle," Popov replied. "Those vehicles
are available -- a huge number of pathogens you could use for different jobs.
If the drug is a peptide like endorphin, that's simple. If you're talking
about triggering the release of serotonin and dopamine -- absolutely possible.
To cause amnesia, schizophrenia -- yes, it's theoretically possible with
pathogens. If you talk about pacification of a subject population -- yes, it's
possible. The beta-endorphin was proposed as potentially a pacification agent.
For more complex chemicals, you'd need the whole biological pathways that
produce them. Constructing those would be enormously difficult. But any drug
stimulates specific receptors, and that is doable in different ways. So
instead of producing the drug, you induce the consequences. Pathogens could do
that, in principle."

Psychotropic recombinant pathogens may sound science fictional, but sober
biologists support Popov's analysis. Harvard University professor of molecular
biology Matthew Meselson is, with Frank Stahl, responsible for the historic
Meselson-Stahl experiment of 1957, which proved that DNA replicated
semiconservatively, as Watson and Crick had proposed. Meselson has devoted
much effort to preventing biological and chemical weapons. In 2001, warning
that biotechnology's advance was transforming the possibilities of
bioweaponeering, he wrote in the New York Review of Books, "As our ability to
modify life processes continues its rapid advance, we will not only be able to
devise additional ways to destroy life but will also become able to manipulate
it -- including the fundamental biological processes of cognition,
development, reproduction, and inheritance."

I asked Meselson if he still stood by this. "Yes," he said. After telling him
of Popov's accounts of Russian efforts to engineer neuromodulating pathogens,
I said I was dubious that biological weapons could achieve such specific
effects. "Why?" Meselson bluntly asked. He didn't believe such agents had been
created yet -- but they were possible.

No one knows when such hypothetical weapons will be real. But since Popov left
Russia, the range and power of biotechnological tools for manipulating genetic
control circuits have grown. A burgeoning revolution in "targeting
specificity" (targeting is the process of engineering molecules to recognize
and bind to particular types of cells) is creating new opportunities in
pharmaceuticals; simultaneously, it is advancing the prospects for chemical
and biological weapons. Current research is investigating agents that target
the distinct biochemical pathways in the central nervous system and that could
render people sedate, calm, or otherwise incapacitated. All that targeting
specificity could, in principle, also be applied to biological weapons.

The disturbing scope of the resulting possibilities was alluded to by George
Poste, former chief scientist at SmithKline Beecham and the sometime chairman
of a task force on bioterrorism at the U.S. Defense Department, in a speech he
gave to the National Academies and the Center for Strategic and International
Studies in Washington, DC, in January 2003. According to the transcript of the
speech, Poste recalled that at a recent biotech conference he had attended a
presentation on agents that augment memory: "A series of aged rats were
paraded with augmented memory functions.... And some very elegant structural
chemistry was placed onto the board.... Then with the most casual wave of the
hand the presenter said, "Of course, modification of the methyl group at C7
completely eliminates memory. Next slide, please.'"

Basement Biotech
The age of bioweaponeering is just dawning: almost all of the field's
potential development lies ahead.

The recent report by the National Academies described many unpleasant
scenarios: in addition to psychotropic pathogens, the academicians imagine the
misuse of "RNA interference" to perturb gene expression, of nanotechnology to
deliver toxins, and of viruses to deliver antibodies that could target ethnic
groups.

This last is by no means ridiculous. Microbiologist Mark Wheelis at the
University of California, Davis, who works with the Washington-based Center
for Arms Control and Non-Proliferation, notes in an article for Arms Control
Today, "Engineering an ethnic-specific weapon targeting humans is...difficult,
as human genetic variability is very high both within and between ethnic
groups...but there is no reason to believe that it will not eventually be
possible."

But commentators have focused on speculative perils for decades. While the
threats they describe are plausible, dire forecasts have become a ritual -- a
way to avoid more immediate problems. Already, in 2006, much could be done.

Popov's myelin autoimmunity weapon could be replicated by bioterrorists. It
would be no easy feat: while the technological requirements are relatively
slight, the scientific knowledge required is considerable. At the very least,
terrorists would have to employ a real scientist as well as lab technicians
trained to manage DNA synthesizers and tend pathogens. They would also have to
find some way to disperse their pathogens. The Soviet Union "weaponized"
biological agents by transforming them into fine aerosols that could be
sprayed over large areas. This presents engineering problems of an industrial
kind, possibly beyond the ability of any substate actor. But bioterrorists
might be willing to infect themselves and walk through crowded airports and
train stations: their coughs and sniffles would be the bombs of their terror
campaign.

Difficult as it may still be, garage-lab bioengineering is getting easier
every year. In the vanguard of those who are calling attention to
biotechnology's potential for abuse is George Church, Harvard Medical School
Professor of Genetics. It was Church who announced in December 2004 that his
research team had developed a new high-throughput synthesizer capable of
constructing in one pass a DNA molecule 14,500 bases long.

Church says his DNA synthesizer could make vaccine and pharmaceutical
production vastly more efficient. But it could also enable the manufacture of
the genomes of all the viruses on the U.S. government's "select agents" list
of bioweapons. Church fears that starting with only the constituent chemical
reagents and the DNA sequence of one of the select agents, someone with
sufficient knowledge might construct a lethal virus. The smallpox virus
variola, for instance, is approximately 186,000 bases long -- just 13 smaller
DNA molecules to be synthesized with Church's technology and bound together
into one viral genome. To generate infectious particles, the synthetic variola
would then need to be "booted" into operation in a host cell. None of this is
trivial; nevertheless, with the requisite knowledge, it could be done.

I suggested to Church that someone with the requisite knowledge might not need
his cutting-edge technology to do harm. A secondhand machine could be
purchased from a website like eBay or LabX.com for around $5,000.
Alternatively, the components -- mostly off-the-shelf electronics and plumbing
-- could be assembled with a little more effort for a similar cost.
Construction of a DNA synthesizer in this fashion would be undetectable by
intelligence agencies.

The older-generation machine would construct only oligonucleotides, which
would then have to be stitched together to function as a complete gene, so
only small genes could be synthesized. But small genes can be used to kill
people.

"People have trouble maintaining the necessary ultrapure approach even with
commercial devices -- but you definitely could do some things," Church
acknowledged.

What things? Again, Serguei Popov's experience at Biopreparat is instructive.
In 1981, Popov was ordered by Lev Sandakhchiev, Vector's chief, to synthesize
fragments of smallpox. "I was against this project," Popov told me. "I thought
it was an extremely blunt, stupid approach." It amounted to a pointlessly
difficult stunt, he explained, to impress the Soviet military; when his
researchers acquired real smallpox samples in 1983, the program was
suspended.

A closely related program that Popov had started, however, continued after he
departed Vector for Biopreparat's Oblensk facility in the mid-1980s. This
project used the poxvirus vaccinia, the relatively harmless relative of
variola used as a vaccine against smallpox. Not only was vaccinia -- whose
genome is very similar to variola's -- a convenient experimental stand-in for
smallpox, but its giant size (by viral standards) also made it a congenial
candidate to carry extra genes. In short, it was a useful model for
bioweapons.

For at least a decade, therefore, a team of Biopreparat scientists
systematically inserted into vaccinia a variety of genes that coded for
certain toxins and for peptides that act as signaling mechanisms in the immune
system. Though Popov had directed that the recombinant-vaccinia program should
proceed through the genes coding for immune system-modulating peptides, he
left before the researchers finished with the interleukin genes. But it would
be surprising if the Vector researchers did not reach the gene for
interleukin-4 (IL-4), an immune-system peptide that coaxes white blood cells
to increase their production of antibodies and then releases them.

There is some evidence that the Russians discovered the effects of inserting
the IL-4 gene into a poxvirus. Those effects are deadly. In 2001, Ian Ramshaw
and a team of virologists from the Australian National University in Canberra
spliced IL-4 into ectromelia, a mousepox virus, and learned that the resulting
recombinant mousepox triggered massive overproduction of the IL-4 peptide.
Even the immune systems of mice vaccinated against mousepox could not control
the growth of the virus: a 60 percent mortality rate resulted. Other
experiments have confirmed the lethality of the recombinant pathogen. The
American poxvirus expert Mark Buller, of Saint Louis University in Missouri,
engineered various versions of the recombinant, one of which maintained the
mousepox virus's full virulence while generating excessive interleukin-4. All
the mice infected with this recombinant died. The BBC reported that when asked
about the Australian experiment, Sandakhchiev, Vector's director, remarked,
"Of course, this is not a surprise."

Because vaccinia is universally available, it is fortunate that a
vaccinia-IL-4 hybrid would not be an effective biological weapon: vaccinia has
limited transmissibility between humans. Still, there are other viruses that
are transmissible. Smallpox, the most infamous, is nearly impossible for
aspiring bioterrorists to acquire. But a herpesvirus named varicella-zoster,
or common chickenpox, is easily acquired and even more infectious than
smallpox.*

What would happen if bioterrorists spliced IL-4 into chickenpox and released
the hybrid into the general population? Perhaps nothing. Very often, the
Soviet bioweaponeers successfully spliced new genes into pathogens, only to
find that infected test animals showed no symptoms. One reason was that the
genetically engineered microbes were often "environmentally unstable" -- that
is, they did not retain the added genes. Engineering recombinant pathogens can
be ineffective for other reasons, too: the foreign gene might be expressed in
the "wrong" organ. But according to several virologists with knowledge of
biological weapons, the result of splicing IL-4 into chickenpox might be to
suppress the immune response to the disease. According to these virologists,
the effect would be similar to what happens to cancer patients when they catch
chickenpox. They often die -- even when treated with antiviral therapiesis
companies altogether. Conveniently, without its junk DNA, IL-4 is only about
462 base pairs long. It's possible to download IL-4's genetic sequence from
the Internet, use a basic synthesizer to construct it in five segments, and
then assemble those segments "manually," as Popov's scientists did. The other
principal tools needed would be a centrifuge -- like the $5,000 DNA
synthesizer, cheaply available via Internet sites -- and a transfection kit, a
small bottle filled with reagent that costs less than $200 and which would be
necessary to introduce the IL-4 gene into chickenpox. Finally, the terrorists
would also require an incubator and the media in which to grow the resulting
cells. The total costs, including the DNA synthesizer: probably less than
$10,000.

*Correction: an earlier version of this story misidentified varicella-zoster,
a herpesvirus, as an orthopoxvirus.

Be Afraid. But of What?
In the public debate about how to defend ourselves against biological weapons,
the advance of biotechnology has been little discussed. Instead, most
biologists and security analysts have debated the merits and shortcomings of
Project BioShield, the Bush administration's $5.6 billion plan to protect the
U.S. population from biological, chemical, radiological, or nuclear attack.
After last year's bioterrorism conference in DC, I called on Richard Ebright,
whose Rutgers laboratory researches transcription initiation (the first step
in gene expression), to hear why he so opposes the biodefense boom (in its
current form) and why he doesn't worry about terrorists' synthesizing
biological weapons.

"There are now more than 300 U.S. institutions with access to live bioweapons
agents and 16,500 individuals approved to handle them," Ebright told me. While
all of those people have undergone some form of background check -- to verify,
for instance, that they aren't named on a terrorist watch list and aren't
illegal aliens -- it's also true, Ebright noted, that "Mohammed Atta would
have passed those tests without difficulty."

Furthermore, Ebright told me, at the time of our interview, 97 percent of the
researchers receiving funds from the National Institute of Allergy and
Infectious Diseases to study bioweapon agents had never been funded for such
work before. Few of them, therefore, had any prior experience handling these
pathogens; multiple incidents of accidental release had occurred during the
previous two years.

s-level pathogens is scary enough, I conceded. But isn't the proliferation of
bioweaponeering expertise, I asked, more worrisome? After all, what reliable
means do we have of determining whether somebody set out to be a molecular
biologist with the aim of developing bioweapons?

"That's the most significant concern," Ebright agreed. "If al-Qaeda wished to
carry out a bioweapons attack in the U.S., their simplest means of acquiring
access to the materials and the knowledge would be to send individuals to
train within programs involved in biodefense research." Ebright paused. "And
today, every university and corporate press office is trumpeting its success
in securing research funding as part of this biodefense expansion, describing
exactly what's available and where."

As for the threat of next-generation bioweapons agents, Ebright was
dismissive: "To make an antibiotic-resistant bacterial strain is frighteningly
straightforward, within reach of anyone with access to the material and
knowledge of how to grow it." However, he continued, further engineering -- to
increase virulence, to provide escape from vaccines, to increase environmental
stability -- requires considerable skill and a far greater investment of
effort and time. "It's clearly possible to engineer next-generation enhanced
pathogens, as the former Soviet Union did. That there's been no bioweapons
attack in the United States except for the 2001 anthrax attacks -- which bore
the earmarks of a U.S. biodefense community insider -- means ipso facto that
no substate adversary of the U.S. has access to the basic means of carrying it
out. If al-Qaeda had biological weapons, they would release them."

Milton Leitenberg, the arms control specialist, goes a step further: he says
because substate groups have not used biological weapons in the past, they are
unlikely to do so in the near future. Such arguments are common in security
circles. Yet for many contemplating the onrush of the life sciences and
biotechnology, they have limited persuasiveness.

I suggested to Ebright that synthetic biology offered low-hanging fruit for a
knowledgeable bioterrorist. He granted that there were scenarios with sinister
potential. He allowed that biotechnology could make BioShield, which focuses
on conventional select agents such as smallpox, anthrax, andill, he
maintained, "a conventional bioweapons agent can potentially be massively
disruptive in economic costs, fear, panic, and casualties. The need to go to
the next level is outside the incentive structure of any substate
organization."

Even those who are intimately involved with biodefense often support this
view. For an insider's perspective, I contacted Jens Kuhn, the Harvard Medical
School virologist. The German-born Kuhn has worked not only at Usamriid, and
at the Centers for Disease Control in Atlanta, but also -- uniquely for a
Westerner -- at Vector.

Kuhn, like Ebright, is no fan of how the biodefense boom is unfolding. "When I
was at Usamriid, it exemplified how a biodefense facility should be," he told
me. "That's why I'm worried -- because the system worked, and the experts were
concentrated at the right places, Fort Detrick and the CDC. Now this expertise
gets diluted, which isn't smart."

Kuhn believes, nevertheless, that some kind of national biodefense program is
needed. He just doesn't think we are preparing for the right things.
"Everybody makes this connection with bioterrorism, anthrax attacks, and
al-Qaeda. That's completely wrong." Kuhn recalled his time at Vector and that
facility's grand scale. "When you look at what the Russians did, those kinds
of huge state programs with billions of dollars flowing into very
sophisticated research carried on over decades -- they're the problem. If
nation-states start a Manhattan Project to build the perfect biological
weapon, we're in deep shit."

But doesn't modern biotechnology, I asked, allow small groups to do
unprecedented things in garage laboratories?

Kuhn conceded, "There are a few things out there" with the potential to kill
people. But weighing the probabilities, he saw the threat in these terms:
"Definitely more biowarfare than bioterrorism. Definitely more the
sophisticated bioweapons coming in the future than the stuff now. There's
danger coming towards us and we're focusing on concerns like BioShield. I
don't think that's the stuff that will save us."

Is Help on the Way?
The 21st century will see a biological revolution analogous to the industrial
revolution of the 19th. But both its benefits and its threats will be more
profound and more disruptivem threat is that genes could be hacked outside of
large laboratories. This means that terrorists could create recombinant
biological weapons. But the leading edge of bioweapon research has always been
the work of government labs. The longer-term threat is what it always has
been: national militaries. Biotechnology will furnish them with weapons of
unprecedented power and specificity. George Poste, in his 2003 speech to the
National Academies, warned his audience that in coming decades the life
sciences would loom ever larger in national-security matters and international
affairs. Poste noted, "If you actually look at the history of the assimilation
of technological advance into the calculus of military affairs, you cannot
find a historical precedent in which dramatic new technologies that redress
military inferiority are not deployed."

Harvard's Matthew Meselson has said the same and added that a world in which
the new biotechnology was deployed militarily "would be a world in which the
very nature of conflict had radically changed. Therein could lie unprecedented
opportunities for violence, coercion, repression, or subjugation." Meselson
adds, "Governments might have the objective of controlling very large numbers
of people. If you have a situation of permanent conflict, people begin
contemplating things that the ordinary rules of conflict don't allow. They
begin to view the enemy as subhuman. Eventually, this leads to viewing people
in your own culture as tools."

What measures could mitigate both the near and the more distant threats of
bioweaponry? BioShield, as it is now constituted, will not protect us from
genetically engineered pathogens. A number of radical solutions (like somehow
boosting the human immune system through generic immunomodifiers) have been
proposed, but even if pursued, they might take years or decades to develop.

More immediately, no one has a good idea about what should be done. Some
scientists hope to arrest the spread of bioweapons knowledge. Rutgers's
Richard Ebright wants to reverse what he believes to be countg guns, where you
just give people a license and let them do whatever they want," he says.
"Along with the license would come responsibilities for reporting."
Furthermore, Church believes that just as all DNA synthesizers should be
registered, so should any molecular biologists researching the select agents
or the human immune system response to pathogens. "Nobody's forced to do
research in those areas. If someone does, then they should be willing to have
a very transparent, spotlighted research career," Church says.

But enactment of Church's proposals would represent an unprecedented
regulation of science. Worse, not all nations would comply. For instance,
Russian biologists, some of whom are known to have worked at Biopreparat, have
reportedly trained molecular-biology students at the Pasteur Institute in
Tehran.

More fundamentally, arresting the progress of biological-weapons research is
probably impractical. Biological knowledge is all one, and therapies cannot be
easily distinguished from weapons. For example, a general trend in biomedicine
is to use viral vectors in gene therapy.

Robert Carlson, senior scientist in the Genomation Lab and the Microscale Life
Sciences Center in the Department of Electrical Engineering at the University
of Washington, believes there are two options. On the one hand, we can clamp
down on biodefense research, stunting our ability to respond to biological
threats. Alternatively, we can continue to push the boundaries of what is
known about how pathogens can be manipulated -- spreading expertise in
building biological systems, for better and for worse, through experiments
like Buller's assembly of a mousepox-IL4 recombinant -- so we are not at a
mortal disadvantage. One day, we must hope, technology will suggest an
answer.

Serguei Popov has lived with these questions longer than most. When I asked
him what could be done, he told me, "I don't know what kind of behavior or
scientific or political measures would guarantee that the new biology won't
hurt us." But the vital first step, Popov said, was for scientists to overcome
their reluctance to discuss biological weapons. "Public awareness is very
important. I can't say it's a solution to this problem. Frankly, I don't see
any solution right now. Yet first we have to be aware."

Mark Williams is a contributing writer to Technology Review.

--
Eugen* Leitl <a href="http://leitl.org">leitl</a> http://leitl.org
______________________________________________________________
ICBM: 48.07100, 11.36820            http://www.ativel.com
8B29F6BE: 099D 78BA 2FD3 B014 B08A  7779 75B0 2443 8B29 F6BE



----- End forwarded message -----
--
Eugen* Leitl <a href="http://leitl.org">leitl</a> http://leitl.org
______________________________________________________________
ICBM: 48.07100, 11.36820            http://www.ativel.com
8B29F6BE: 099D 78BA 2FD3 B014 B08A  7779 75B0 2443 8B29 F6BE

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