by Mark Williams
Technology Review, vol. 109, no. 1
Mark Williams is a
contributing writer to Technology Review.
According to the author,
biotechnology's advance could give malefactors the
ability to manipulate life processes -- and even affect
human behavior. Williams tells the story through
interviews with Sergei Popov, who for nearly 20
years developed genetically engineered biological
weapons for the Soviet Union and is now working in the
U.S. Popov's accounts of what the Russians accomplished
in producing genetically engineered bioweapons are
important now, Williams says, because the achievements
show what is possible, and all can be accomplished today
with time and money.
The growing scientific
consensus is 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. He
describes the Soviet bioweapons program, which involved
plague, Ebola virus, and even concepts of subtle
bioweapons that modified behavior by targeting the
nervous system, inducing effects like temporary
schizophrenia, memory loss, heightened aggression,
immobilizing depression, or fear, or pacification of a
Just as a 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, it is advancing the prospects for
chemical and biological weapons.
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
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
After submitting his doctorate in 1976,
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.
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.
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
Ebright (who'd persuaded 758 other
scientists to sign a letter of protest to Elias Zerhouni, the
director of the National Institutes of Health - NIH) 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
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
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
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 micro-organisms 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
Following this presentation, Alibek
"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
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
"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
"Very prominent people like [Anthony] Fauci at the NIH said,
'Now we know it can be done.'"
"You know, that's... naive. 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 marshaled 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.
this scale are easily reproducible with today's tools.
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.
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
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
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
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
"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
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
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
"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
experiment of 1957, which proved that DNA replicated
semi-conservatively, 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
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
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.'"
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.
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
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
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.
BBC reported that when asked about the Australian experiment, Sandakhchiev, Vector's director, remarked,
"Of course, this is not a
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
Correction: an earlier version of this story misidentified varicella-zoster,
a herpesvirus, as an orthopoxvirus.
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
Be Afraid. But of
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.
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
"Mohammed Atta would have passed those tests without
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
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
"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
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
But doesn't modern biotechnology, I
asked, allow small groups to do unprecedented things in garage
Kuhn conceded, "There are a few things out there" with the potential
to kill people. But weighing the probabilities, he saw the threat in
"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
don't think that's the stuff that will save us."
Is Help on the
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.
"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,
"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
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
"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
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
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
Robert Carlson, senior scientist in the
Genomation Lab and
Microscale Life Sciences Center in the
Department of Electrical
Engineering at the University of Washington, believes there are two
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
"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."