Biowar for dummies

Eugen Leitl eugen at
Mon Feb 20 23:45:23 PST 2006$1439

Biowar for Dummies

    How hard is it to build your own weapon of mass destruction? We take a
crash course in supervirus engineering to find out.

Anthrax. Smallpox. Ebola. For thriller writers and policy crusaders,
biological warfare was a standard what-if scenario long before anyone mailed
anthrax to government and media offices in 2001. Pentagon war games like Dark
Winter, held just before 9/11, and this yearbs Atlantic Storm suggested that
terrorists could unleash germs with the killing power of a nuclear weapon.

Scientists, though, have always been skeptical. Only massive, state-sponsored
programsbnot terrorist cells or lone kooksbpose a plausible threat, they
say. As the head of the Federation of American Scientists working group on
bioweapons put it in a 2002 Los Angeles Times op-ed: b
A significant
bioterror attack today would require the support of a national program to

Or not. A few months ago, Roger Brent, a geneticist who runs a California
biotech firm, sent me an unpublished paper in which he wrote that genetically
engineered bioweapons developed by small teams are a bigger threat than
suitcase nukes.

Brent is one of a growing number of researchers who believe that a
bioterrorist wouldnbt need a team of virologists and state funding. He says
advances in DNA-hacking technology have reached the point where an evil lab
assistant with the right resources could do the job.

    Gene hackers could make artificial smallpoxbor worsebfrom standard lab

I decided to call him on it. I hadnbt set foot in a lab since high school.
Could I learn to build a bioweapon? What would I need? What would it cost?
Could I set up shop without raising suspicions? And, most important, would it

An advanced grad student could do it.b
bRoger Brent, head of the
Molecular Sciences Institute in Berkeley, California.

To find out, I meet with Brent at the Molecular Sciences Institute, his
company in Berkeley. The 49-year-old researcher has a few million dollars a
year in government funding and a staff of 25. Hebs the co-author of the
must-read lab manual Current Protocols in Molecular Biology, and hardly seems
like someone in the grip of apocalyptic fervor. As he shows me around the
labba few quiet rooms of workbenches, pipette stands, pinky-sized test tubes
and the odd PowerBookbwe plan our attack.

Experts used to think that distributing a killer germ would require a few vats
and a crop duster. Brent and I have a different idea. Webll infect a
suicidal patient zero and hand him a round-the-world plane ticket. But we need
a dangerous virusbsmallpox, maybe. We wonbt be able to steal a sample;
webll have to make our own.

Too dangerous, Brent says. He gives me a proxy mission: Modify something
mundane into something strange. In this case, rejigger standard brewerbs
yeast to manufacture a glowing cyan-colored protein usually found in

Great. I wanted to make something as lethal as an A-bomb, and instead Ibm
brewing ultraviolet beer.

Brent smiles and shrugs at my disappointment. b
All life is one,b
 he says,
and hebs not just being Zen. All over the world, laboratories like Brentbs
splice genesbthe techniques are as common as the Pyrex beaker, and getting
easier every day. Getting yeast to sport blue genes takes the same skills and
gear as adding the genes for something toxic. DNA is just the stuff that tells
cells what proteins to makebthe only real difference between being able to
insert a single gene and inserting all the genes that make a virus is

I start my to-do list: I have to acquire the right equipment. I have to track
down the genetic sequence I want, then learn how to make the gene. Then I have
to get it into the yeast. Brent offers me lab space and staff advice, but
insists that I do the work myself. And not everyone has the knack, he says.
Some people are natural-born labsters, some arenbt.b
 I know what he
means. I used to be a software engineer, and in that field, procedures are
well documented and the source code is readily available, but some people just
arenbt hackers.

Itbs time to find out what kind of genetic engineer I am.

Making DNA turns out to be easy if you have the right hardware. The critical
piece of gear is a DNA synthesizer. Brent already has one, a yellowing plastic
machine the size of an office printer, called an ABI 394. b
So, what kind of
authorization do I need to buy this equipment?b
 I ask.

I suggest you start by typing bused DNA synthesizerb into Google,b

Brent says.

I hit eBay first, where ABI 394s go for about $5,000. Anything I canbt score
at an auction is available for a small markup at sites like
Two days later I have a total: $29,700btaxes and shipping not included.
Nucleosides (the A, C, T, G genetic building blocks) and other chemicals for
the synthesizer cost more than the hardwarebin the end, a single base pair
of DNA runs about a buck to make. Enough raw material to build, say, the
smallpox genome would take just over $200,000.

    The ABI 394 synthesizer. Think of it as an inkjet printer for DNA. (click
photo to enlarge)

The real cost of villainy is in overhead. Even with the ready availability of
equipment, you still need space, staff, and time. Brent guesses he would need
a couple million dollars to whip up a batch of smallpox from scratch. No need
for state sponsors or stolen top-secret germ samples. b
An advanced grad
student could do it,b
 Brent says. Especially with the help of some high
schoolers who actually went to lab classes.

But how would I find the gene sequence? Simple. I went to the Web site of the
National Center for Biotechnology Information (no password required) and
downloaded the DNA sequence for a 770-base pair gene called the Enhanced Cyan
Fluorescent Protein. Thatbs what Brent wanted me to program into my yeast.
It took me about 15 minutes to find. Far easier to track down was the
200,000-base pair sequence for smallpox. Only two known samples of smallpox
exist; the blueprints are free online.

    It's glowing. Is that good?

I load my nucleosides into the ABI 394, and itbs as easy as replacing a
toner cartridge. I transmit a test sequence from my Mac and go to lunch. When
I come back, I have a custom strand of genetic material waiting for me. This
is the anyone-on-Slashdot-can-do-it part of the job.

These days, many labs donbt even bother synthesizing their own genes. They
order nucleotide chains online. Thatbs right: mail-order genes. Just to test
this out, I buy a sequence from MWG Biotech in High Point, North Carolina, and
have it shipped to my house. Three days later, Ibm sitting on the train to
Berkeley holding a FedEx box. MWG didn't do anything wrong, but not long ago
New Scientist magazine approached sixteen other custom DNA shops to find out
if they scan incoming orders. Could a terrorist order a killer virus piece by
piece? Only five of the sixteen said they screen every sequence.

Still, mail-order is cheating. If you were a smart terrorist, youbd make the
thing yourself to avoid suspicion. You can't order smallpox, but anyonebs
allowed to buy raw genetic material and lab equipmentbthe government only
monitors certain radioactive, toxic, or otherwise scary substances.

Getting living cells to absorb synthetic genes is where biotech stops looking
like IT and turns into French cooking. The process, called transformation,
happens in nature only rarely; itbs part of the way microorganisms evolve.
In the lab, you can improve the odds itbll work by softening up the host
cells with chemicals and removing sections of their DNA with tailor-made
enzymes. Douse the hosts with synthetic DNA and some fraction of them slurp it
up. And some fraction of those start making the protein that the gene codes
for. It doesnbt matter if itbs jellyfish fluorescence or smallpox (though
obviously smallpox is more complicated).

It sounds like submicroscopic surgery, but all you do is squirt chemicals into
a culture dish and let it all soak overnight. In the morning you come back to
see if it worked or, more likely, didnbt. My first batch flops. My second,
too. One of the MSI researchers offers to break Brentbs rules and do it for
me while I watch. It doesnbt work for him, either.

Eventually, we fumble our way to a plastic dish full of translucent goop. If
Ibd been working on smallpoxband really committed to my causebthis would
have been the part where Ibd inject a lab animal with the stuff to see if it
got sick. Then Ibd give myself a dose and head off on a days-long,
multi-airport, transnational suicide run. But it was just yeast. Set on top of
a black light, it glowed an eerie bright blue, like a Jimi Hendrix poster. My
creation ... lived.

    Biotech's growth curves leave Moore's Law in the dust.

Would the nations of the world kneel before my awesome power? I asked an
expert. Three years ago, Eckard Wimmer headed a team of researchers at SUNY
Stony Brook that made live polio virus from scratch, part of a Defense
Department project to prove the threat of synthetic bioweapons. So how much of
a leap is that from cyan-tinged yeast?

A simple laboratory technician would have trouble,b
 he says. With
smallpox, b
the virus is very large and brings with it enzymes that it needs
to proliferate. If you just made the genome and put it into a cell, nothing
would happen.b

In the wild, viruses hijack host cells and turn them into virus replication
factories. Wimmer was sure any one of the 2,847 members of the American
Society for Virology could figure out how to do the same.

Soon, though, I might not even need that expertise. DNA synthesis is following
a kind of accelerated Moorebs lawbthe faster and easier it gets, the
faster and easier it gets. Last year, a group of researchers synthesized DNA
strands of more than 300,000 base pairsblonger than the smallpox
genomebusing a method that eliminates most of the shake-and-bake lab steps
Ibd spent weeks learning.

The rush toward DIY genetics is reflected in so-called Carlson curves, plotted
by Rob Carlson, a physicist-turned-biologist (and Brentbs former lab partner
at MSI) who worked them out in 2003. b
Within a decade,b
 Carlson wrote in
the journal Biosecurity and Bioterrorism, b
a single person could sequence or
synthesize all the DNA describing all the people on the planet many times over
in an eight-hour day.b

Today, when hebs not tinkering with cellular-scale measurement gadgets at
the University of Washington, Carlson designs custom proteins on a computer in
his Seattle home. According to his calculations, if the current pace of
biotech proceeds for another decade, cooking up a lethal bug will be as easy
and cheap as building a Web site. b
You donbt need a national program,b

Carlson says. b
The technologybs changing fast, and therebs nothing we
can do about it.b

Even if hebs wrong about the timeframe, if someone solves the problem of
synthesizing RNA (the single-stranded adjunct to DNA), it would open the door
to modifying retroviruses like influenza and HIVband in 1918 the flu managed
to kill 20 million people without any help from bioterrorists.

If we do what we need to for biodefense ... We could, as a planet,
eliminate large lethal epidemics.b
bTara O'Toole, Center for Biosecurity

Bolstered by what scientists like Carlson and Brent are saying, bioweapon
policy wonks are calling for an all-out biodefense program. Worried about
bacteria and viruses of mass destruction, the federal government pushes nearly
$6 billion a year toward research. Tara ObToole, director of the University
of Pittsburghbs Center for Biosecurity, says after-the-fact vaccines wonbt
stop a plague; they take months to develop and deploy. She believes the only
option is a general-purpose virus detector and destroyer, which has yet to be
invented. The cost would be enormous, but donbt think of it as just an
antiterror tool. b
If we do what we need to for biodefense, webre going to
do an enormous amount of good for routine health care and global disease,b

says ObToole. b
We could, as a planet, eliminate large lethal epidemics of
infectious disease in our lifetime.b

Brent agrees. Hebs been tinkering on a general virus detector as a side
project. b
Of course Ibd be thrilled to see a huge expenditure on
 he says. b
But the truth is, itbll probably take an attack to
get us there.b

We might not have long to wait. Every hands-on gene hacker I polled during my
project estimated they could synthesize smallpox in a month or two. I remember
that game from my engineering days, so I mentally scale their estimates using
the old software managerbs formula: Double the length, then move up to the
next increment of time. That gives us two to four yearsbassuming no one has
already started working.b

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

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