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ICG Risk Blog - [ Designer bioagents: Why a potential Iranian, or existing Pakistani or DPRK, nuclear weapon does not overly excite me ]

Designer bioagents: Why a potential Iranian, or existing Pakistani or DPRK, nuclear weapon does not overly excite me


Watching the countdown to highly dispersed, easily achieved asymmetrical use of designed bioagents, even "de novo" or newly created biological agents, by multiple actors working independently or in concert tempers my risk calculus of one or a few nuclear events. It is not infeasible to envision high value metropolitan areas bearing the brunt of multiple agent attacks by unrelated protagonists. We are on the cusp, arguably within the decade, of a diversified 'beneath the radar' capacity to cheaply produce designer bioagents for which the defense community has acknowledged that there is no current workable defense, no means of designing and distributing an appropriate vaccine. (Forget stockpiling as a designer agent may well demand a designed vaccine.) Worse, our labyrinthine bureaucracies will most likely hobble us in attempting to interdict these many agile actors driven by a widening range of grievances.

The threat of designer bioagents exceeds that of organophosphate (nerve agent) production via miniaturized microfactories, but I expect to see the chemical attacks first as components are already commercially available. See my earlier Manufacturing efficiency gives rise to a new arms race: convergence of legitimate pharma-chemical, illicit drug, and CW/BW agent.

The Long War (extended 4GW of indefinite duration), or the Wide War (many simultaneous locations), which has morphed from the GWOT, contains an unrealistic timeframe, i.e., we do not have the time implied to defeat our adversaries using current methods and tools. Consider the asymmetrical victory that Hezbollah inflicted on Israel using conventional, even simplistic means; a major regional power possessing excellent air dominance, tactical air and artillery - including counter-battery fire, mechanized infantry and armor capacity was beaten by anti-tank missiles, IEDs, snipers, simple rockets (RPGs, Qassams and Katyushas), local knowledge, bunkers, weapons dispersal and motivation.

The impact of designer bioagents is so great that it satisfies a characteristic of emerging Fifth Generation War, that of superempowerment:

Superempowerment: The range of effect for each individual soldier ( or terrorist) will be vastly increased even as the economic costs are driven down by market forces and proliferation of dual-use technology to the civilian consumer.

I agree with John Robb's assertion that "we are in a phase transition from classic 4GW guerrilla warfare to something worse. In my view, that something worse is ultimately going to be the super-empowered individual that can use the technologies of self-replication to collapse/kill on a grand scale. That is, in a nutshell, is what 5GW is all about. It is the end game in human conflict."

Push conventional means to even simple biologic means in the hands of asymmetrical attackers and any group can take on a larger opponent at multiple points simultaneously, even with multiple agents. Abu Musab al-Zarqawi's successor in Iraq, Abu Hamza al-Muhajir Abu Ayyub al-Masri) has publicly initiated the effort in earnest, calling to those skilled in "chemistry, physics, electronics, media and all other sciences — especially nuclear scientists and explosives experts":

We are in dire need of you… The field of jihad can satisfy your scientific ambitions, and the large American bases (in Iraq) are good places to test your unconventional weapons, whether biological or dirty, as they call them.

The historical restraints placed on the use of biological weapons by nation states does not apply to many asymmetrical attackers or lone individuals. Proliferation will be increasingly difficult to constrain within the same groups as they acquire personnel with the needed skills or steal product from a widening supply of biologic investigators.

For those readers in recoil, saying that it can't happen, that it is propaganda, consider how rapidly the technology moved in the past five years and how time and cost to produce has plummeted. And it has plummeted most quickly with viruses:

2001: Hope and reality at the annual meeting of the American Association for the Advancement of Science (AAAS)

"This isn't trivial to do and no-one has yet reported doing it" [Eckard Wimmer is already halfway through the project and will report it in 2002.]… "There's enough bad stuff out there now. So far, there is no reason to believe that this technology is going to make things any worse."

"Am I worried about a synthesised virus? No, you only worry about it if someone does it out of malicious motives."

"You don't have to synthesise a genome from scratch to be able to make a version of smallpox… You could get a close relative and use standard genetic engineering. You could probably do that right now."

2002: First synthetic virus (poliovirus) made from a chemical map available on the web, with existing technology, with chemical supply mail-order materials, and without cellular material. Over two years required.

Viruses are a good place to start:

Viruses are unusual because they have characteristics of living and nonliving entities. Poliovirus, which the researchers call a "chemical with a life cycle," has a mere 7,500 nucleotide bases in its entire genome. (A typical bacterial genome has millions.) The virus invades cells, where its RNA genome is translated into various proteins. Simultaneously, it replicates the genome thousands of times. The new RNA can be combined with proteins inside a viral coat and then released for invasion of other cells.

Eckard Wimmer showed that "it is possible to synthesize an infectious agent by in vitro chemical-biochemical means solely by following instructions from a written sequence."

Simple but time consuming:

Trained as a chemist, Wimmer was convinced long before bioterrorism became an issue that viruses are chemicals with a life cycle and, thus, viruses could be synthesized. Wimmer [focused] on poliovirus, an agent that he has investigated for more than 35 years. The key was to chemically string together a sequence of nucleotides, the building blocks of nucleic acid. This was done through the assembly of oligonucleotides (sets of nucleotides about 60 units long), all simply bought from a biotechnology company. The resulting synthetic nucleic acid corresponded to a copy of double-stranded DNA of the viral genome, roughly 7500 base pairs long. Since poliovirus is an RNA virus, the synthetic DNA was transcribed into genomic RNA that, in turn, produced authentic virus in a cell-free system.

The synthetic virus was "almost indistinguishable" from its natural counterpart; mice injected with it were paralyzed, lapsing into death.


Driven by "an urgent need to understand, prevent and cure viral disease;" financed by DoD as part of a biowarfare response program:

Wimmer wanted to [show] hypothesis of viral synthesis was viable. One axiom of biology holds that proliferation of cellular organisms or viruses depends on the presence of a functional genome that instructs the replication process, he said. "Of course, in our case, we didn't need a viral genome. All we needed was the Internet; no natural template was necessary. The virus was made from information, available in the public domain—that is, from the known nucleotide sequence of its genome. This presents a proof of principle that is applicable to the synthesis of all viruses."

Wimmer notes that "it was possible that viruses like Ebola could be assembled in laboratories, but there were only a few people in the world with that skill."


The stitching took "more than 2 years of painstaking work" to complete.


Any virus thought eradicated in the wild, and for which vaccination has largely ceased (think polio and smallpox), could be reconstituted from its genetic map. So much for fixated protection of US and Russian specimen stockpiles.

2003 Second synthetic produced (PhiX174, harmless to humans). Accomplished in two weeks.

Smith and Venter's team was able to synthesize the bacteriophage's genome with a technique to "assemble large pieces of DNA with relative ease and unprecedented speed. The technique, which will not be patented, allowed the complete genome of a small virus to be synthesised in just 14 days." At some 6000 DNA bases, the PhiX 174 genome is similar in size as the poliovirus synthesized by Wimmer in 2002. Wimmer said, "I'm impressed. If I had to do it again I'd use their method."

Smith et al, were able to assemble up to 130 pieces of synthetic DNA into one long double-helical molecule over 5,000 nucleotides in length. Purification of the initial DNA mixture reduced the error rate and, therefore, also the number of needed repairs to the sequence. The final assembly of 5386 base pairs matched the natural virus genome and was accomplished in only 14 days.

They "modified a common laboratory technique known as PCR so they could paste together hundreds of oligonucleotides in one test tube. The molecules then self-assembled into the right sequence. The resulting DNA was placed into bacterial cells where it replicated, creating new and infectious viral particles. [The] method is not yet suitable to make [an] artificial chromosome [as] the viruses produced were not perfect, it turns out. They had mutations most probably introduced by initial errors in the original oligonucleotides, so the technique will have to be coupled with others designed to correct those errors."

The ultimate aim of the project, funded by the US Department of Energy, is to create microbes with special properties, such as the ability to sequester carbon dioxide or consume toxic waste. The speed of the technique means it could also help accelerate any research in which large sections of DNA are used, for example gene therapy, vaccine research or agricultural biotechnology. But the method equally makes it much simpler to manufacture a deadly virus for use as a bioweapon. The simple precursors needed would be impossible for governments to keep out of the hands of would-be biowarriors.

Late 2004

Short stretches of DNA (50-100 nucleotides in length) can be chemically synthesized automatically, and, in a series of relatively simple steps, joined end to end to make a single long DNA molecule. The challenge to making these long DNA molecules (5,000 to 10,000 nucleotides) is to achieve accuracy with longer and longer molecules, but this challenge is being met through the development of methods for repairing mistakes. Several [firms] assemble long (up to 18,000 nucleotides) double-stranded DNA sequences with essentially no errors at costs as low as $2.35 per base-pair…

[New] technology is now also making it easier to "write" DNA, or create it from scratch using chemical building blocks… Today, customized strings of DNA can be ordered from several companies. A single gene can still cost $4,000 or more. But costs are dropping rapidly. "If you look at the curve, it's headed to about zero in 2006."

Terrorism and inadvertence

We take it as an axiom that, on average, each generation of technology takes half the time of its predecessor as tools, knowledge and practice diffuse into the industry. In the biologic sciences it may be even faster. Put the progressions noted above into the context of inadvertent or deliberate destructive applications of biology:

Any individual or organization dedicated to destruction but only capable of undertaking small-scale operations might plausibly choose advanced biology as the instrument of choice… [An] attack with an especially virulent pathogen might in principle induce a disease epidemic sufficient to disorganize an entire society or degrade an entire economy. Otherwise a clandestine operation could only accomplish genuinely massive social destruction by the use of nuclear explosives, and the fissile material required is currently much more elaborately protected than are pathogens. Biotechnology is one of only two technologies that truly deserve the label "agent of mass destruction" and it is by far the more accessible of the two.

Basic knowledge required for bio-terrorism can be extracted from legitimate global research:

The relevant biomedical research community is very extensive and globally distributed. More than a million scientific articles are published every year and seminal results are generated in all parts of the world. Information flows rapidly among leading-edge scientists and knowledge of fundamental developments also transfers rapidly to those in training. [Yet] current regulation of advanced biology is conducted primarily by national governments and is principally concerned with the localized containment of dangerous pathogens, the safety of research personnel, the treatment of research animals, and the preparation of distributed products such as drugs and vaccines…

Since compelling good and appalling harm cannot be disentangled at the level of fundamental science, a burden of management is being imposed that human institutions are not currently prepared to handle [yet] efforts to devise an effective response are still at an embryonic stage…

All of which makes the US position difficult as:

Within the current administration, especially, the largely implicit but powerfully entrenched assumptions are that the danger derives mainly from hostile foreign sources and that it can be managed primarily by controlling access to dangerous pathogens themselves. Understandable and perhaps inevitable as that reaction may be in political and emotional terms, it is highly dysfunctional in terms of scientific reality and will almost certainly intensify the underlying peril…

The limits of ethics

The problem is that the ethics embodied in Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma, the work of the expert panel chaired by Gerald R. Fink and now commonly abbreviated as the Fink Report, designed to prevent malicious applications of "dual-use" research in the life sciences, or more frankly put "to prevent the life sciences from becoming the death sciences through bioterrorism or biowarfare," do not apply outside the community that submits to voluntary oversight and regulation.

In the near to medium term, the Fink Committee considered microbial pathogens and toxins as the primary threat, and proceeded to identify seven process-based rather than organism-based "experiments of concern" that "will require review and discussion by informed members of the scientific and medical community before they are undertaken or, if carried out, before they are published in full detail":

  • Demonstrate how to render a vaccine ineffective
  • Confer resistance to therapeutically useful antibiotics or antiviral agents
  • Enhance the virulence of a pathogen or render a nonpathogen virulent
  • Increase transmissibility of a pathogen
  • Alter the host range of a pathogen
  • Enable evasion of diagnostic and detection modalities
  • Enable the weaponization of a biological agent or toxin

All seven classes will be targeted by asymmetrical bioengineers wherever they operate.

Part 2 to follow, Specific US actions, bureaucratic and biological, to contain bioterrorism

Al-Qaida in Iraq leader recruiting scientists
Jihad an opportunity to test weapons, tape says
David Rising
September 29, 2006
Columbus Dispatch

Tactics that have kept the Middle East's most powerful army at bay
From Nicholas Blanford in Tyre, Daniel McGrory in Beirut and Stephen Farrell in Haifa
The Times
August 10, 2006

In the fight against terrorism, the long war is the wrong war
Sooner or later, terrorists will get, and use, WMD
John Arquilla
San Francisco Chronicle
July 16, 2006

Losing the Long War
Tom Porteous
Agence Global
May 28, 2006

Defining the Long War: Tony Corn's 4GW
posted by Draconian Observations
February 12, 2006

Commentary on:
World War IV As Fourth-Generation Warfare
By Tony Corn
Policy Review
January 2006

Controlling Dangerous Pathogens: A Prototype Protective Oversight System
John Steinbruner, Elisa D. Harris, Nancy Gallagher, Stacy Okutani
Center for International and Security Studies at Maryland (CISSM)
December 2005

Francis Collins Interview
The Stuff of Life
By Robert Krulwich
October 2005

By Mark
Sunday, July 17, 2005

Biologist Venter aims to create life from scratch
By Antonio Regalado
The Wall Street Journal
Wednesday, June 29, 2005
Mirror at Post Gazette

Biological Weapons: From the Invention of State-Sponsored Programs to Contemporary Bioterrorism
By Jeanne Guillemin
Columbia University Press
ISBN 0231129424
Jan 17, 2005
Synopsis, Google book search, Amazon

Synthetic Genomes: Technologies and Impact
Biological and Environmental Research (BER)
U.S. Department of Energy (DOE)
December 2004

Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma
Committee on Research Standards and Practices to Prevent the Destructive Application of Biotechnology
National Research Council
The National Academies Press: 2004

Fifth Generation Warfare?
On War #53
By William S. Lind

Biotechnology in the Age of Terrorism: Confronting the Dual Use Dilemma
Presenter: Ronald Atlas, PhD
What are the Boundaries?
National Security & Biological Research
The New York Academy of Sciences
November 11, 2003
posted Jan 12, 2004

Synthesis of Poliovirus in the Absence of a Natural Template
Eckard Wimmer, PhD
What are the Boundaries?
National Security & Biological Research
The New York Academy of Sciences
November 11, 2003
posted Jan 12, 2004

Generating a synthetic genome by whole genome assembly: phiX174 bacteriophage from synthetic oligonucleotides.
Smith HO, Hutchison CA 3rd, Pfannkoch C, Venter JC.
Institute for Biological Energy Alternatives, 1901 Research Boulevard, Suite 600, Rockville, MD 20850, USA.
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15440-5. Epub 2003 Dec 2.
PMID: 14657399 [PubMed - indexed for MEDLINE]

Virus synthesised in a fortnight
Sylvia Pagán Westphal news service
12:31 14 November 2003

Chemical synthesis of poliovirus cDNA: generation of infectious virus in the absence of natural template.
Cello J, Paul AV, Wimmer E.
Department of Molecular Genetics and Microbiology, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY 11794-5222, USA.
Science. 2002 Aug 9;297(5583):1016-8. Epub 2002 Jul 11.
PMID: 12114528 [PubMed - indexed for MEDLINE]
Abstract, Full Text, PDF, Supporting Online Material

For the first time, scientists create a virus using only its genome sequence
By Sarah Post
Genome News Network (GNN)
July 23, 2002

Q&A: First synthetic virus
12 July, 2002, 09:18 GMT 10:18 UK

First synthetic virus created
By Dr David Whitehouse
BBC News Online science editor
11 July, 2002, 23:28 GMT 00:28 UK

Synthetic virus nearing reality
By BBC News Online's Jonathan Amos in San Francisco
BBC News
21 February, 2001, 04:15 GMT

Gordon Housworth

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