MIT Technology
Insider
Technology Review
Monday, March 13, 2006
The
Knowledge -- Part 1
Soviet scientists
were developing plague-like bioweapons in the 1980s. Why aren't we listening
more to a key defector?
By Mark Williams
This article -- the cover story
in Technology Review's March/April 2006 print issue -- has been divided
into three parts for presentation online. This is part 1; part 2 will appear
on March 14, and part 3 on March 15.
Our editor in chief, Jason
Pontin, dedicated his column in the most recent TR issue ("The Loss of
Biological Innocence") to the pros and cons of publishing a story on such
a dark and controversial issue.
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.'"
This is part 1 of a three-part
article. Part 2 will appear on March 14.
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.
Mark Williams is
a contributing writer to Technology Review.
Tuesday,
March 14, 2006
The
Knowledge -- Part 2
Terrorists could
buy reagents on the Web, build a DNA synthesizer, and create a deadly virus.
But it would be no easy feat.
By Mark Williams
This article -- the cover story
in Technology Review's March/April 2006 print issue -- has been divided
into three parts for presentation online. This is part 2; part 1 appeared
on March 13, and part 3 will run on March 15.
In part 1, Russian-born scientist
Serguie Popov, now a professor at the National Center for Biodefense and
Infectious Diseases at George Mason University, spoke about his work developing
bioweapons in the Soviet Union in the 1980s -- and correspondent Mark Williams
explained why it matters to us today.
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 poxviruses 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.
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.
Mark Williams is
a contributing writer to Technology Review.
Wednesday,
March 15, 2006
The
Knowledge -- Part 3
The current revolution
in biotechnology is more likely to be exploited by national militaries
than by terrorists.
By Mark Williams
This article -- the cover story
in Technology Review's March/April 2006 print issue -- has been divided
into three parts for presentation online. This is part 3; part 1 appeared
on March 13, and part 2 on March 14.
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."
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.
Mark Williams is
a contributing writer to Technology Review. |