March/April 2006
The Knowledge

Biotechnology’s 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 microörganisms 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...naïve. 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 therapies. For healthy
children or adults, chickenpox is usually a superficial disease that mainly
affects the skin; but depending on the immunosuppressive state of an
infected cancer patient, chickenpox lesions can be slow to heal, and the
viscera -- that is, the lungs, the liver, and the central nervous system --
become progressively diseased.

Bioterrorists could create a varicella-IL-4 recombinant virus more easily
than they could acquire or manufacture the pathogens that top the
select-agents list. IL-4 is one of the standard genes used in medical
research; a plasmid of human IL-4 could be ordered from one of the DNA
synthesis jobbing companies and delivered via FedEx for $350. If our
hypothetical bioterrorists were worried about detection, they might avoid
the DNA synthesis 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.

Slipshod handling of bioweapons-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, and
Ebola, less relevant. Still, 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 disruptive.

The near-term 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 counterproductive
in the funding of biodefense. More dramatically, Harvard's George Church is
calling for all DNA synthesizers to be registered internationally. "This
wouldn't be like regulating 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.


Ivan Handler
Networking for Democracy
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