ISBI Conference on de novo Synthesis of Smallpox, Washington DC

On June 29-30, 2009, ISBI and the Defense Threat Reduction Agency convened a workshop in Washington, DC of the world’s premier bioviolence experts to identify how security policies can more effectively meet dangers associated with synthetic production of pox viruses.

Dedicated to Bioviolence Prevention and Preparedness
Policy Implications of Laboratory Synthesis of Smallpox –
Workshop Lessons

              The communities of experts and officials who focus on bioviolence (the intentional infliction of disease) have long considered smallpox (variola major) to be among the most terrifying bio-agents.  It is exceptionally lethal; up to 30 percent of its victims die.  It need not be weaponized or delivered by advanced dispersal devices but would spread through inhalation of droplets exhaled by victims.

              The reason to be not so concerned about smallpox is that it has been eradicated from nature.  Smallpox is unique to humans; there is no other animal or insect vector.  Except for specialized laboratory conditions, it can survive only briefly outside the human body.  An effective vaccine was discovered centuries ago.  After World War II, the World Health Organization (WHO) successfully coordinated 120,000 doctors and health care personnel to identify smallpox victims and vaccinate everyone around them – ring vaccination.  The disease had nowhere to go, and it eventually died out for lack of a host.  The last reported case of smallpox occurred in the late 1970s, and the WHO declared its eradication in 1980.

              With that declaration, WHO recommended that every seed stock of smallpox be destroyed except for two viral stocks, tightly secured in the Centers for Disease Control and Prevention (CDC) in Atlanta and VEKTOR, a research laboratory outside of Novosibirsk, Russia.  It is conceivable that the virus might continue to exist in victims’ corpses and could escape.  Also, rumors circulate that the Russians diverted strains before their consolidation at VEKTOR or that laboratories having samples might not have complied with the recommendation to destroy them, whether due to negligence or other motive.

Following eradication, the WHO recommended cessation of vaccination, believing that the risks associated with vaccination far outweigh the risks of the disease’s natural recurrence:  for every million persons vaccinated, 14 – 52 will experience life-threatening adverse reactions; one or two may die; persons who are immune-compromised will suffer far higher mortality rates.

Security policy from smallpox bioviolence have been based on denial:  policies have been developed to prevent wrongful access to the known strains of variola major.  These policies have, so far, worked.  Increasingly, however, experts are concerned that smallpox can be synthesized; that is, a malevolent (or just very curious) scientist might be able to reincarnate the virus by stringing together segments of its DNA.  If so, and if that newly synthesized virus were to be released, it would confront a population with remarkably low immunity.

To analyze the policy implications of this possibility, the Defense Threat Reduction Agency (DTRA) Advanced Systems and Concepts Office (ASCO) produced an unclassified workshop; the Northrop Grumman Corporation organized the workshop, and the International Security & Biopolicy Institute (ISBI) helped to identify key issues, the agenda, and potential discussants.  Approximately forty experts participated including senior officials representing various departments and agencies throughout the U.S. government as well as prominent non-governmental persons.

The workshop expressly stayed away from questions of whether laboratory synthesis of smallpox is scientifically realistic at this time or when such capability might be available to persons having malevolent intentions.  The workshop presumed a positive answer to these questions.  Instead, the workshop asked whether laboratory synthesis is a gamechanger and, if the technological feasibility of laboratory synthesis of smallpox exists, are we ready to address the dangers inherent in that capability? This brief report is intended to summarize the workshop’s treatment of that issue.

Is Laboratory Synthesis of Smallpox a Gamechanger?

What is the risk that emerging technological capacities might enable a terrorist, criminal, or State to re-introduce the scourge of smallpox to humanity?  The majority of the workshop’s participants offered that, viewed exclusively as a scientific question, laboratory synthesis of smallpox is not a gamechanger.  Regardless of whether the precise genome of variola major can now or very soon will be synthesized, it is certainly possible to manipulate various orthopox viruses (e.g., monkeypox or camelpox) to create an extremely dangerous pathogen.  Indeed, such capabilities have been possible for a while – there is no gamechanger here.

What might be a gamechanger is not the scientific reality of capabilities for synthesizing a dangerous orthopox genome but the spreading availability of such capabilities.  Until recently, capabilities for manipulating orthopox viruses into something usable as a weapon have been confined to a very few select, world-class laboratories accessible by only a small number of the world’s elite scientists.  That such technology and expertise might be spreading and more scientists can take advantage of this capability might be the gamechanger, not as a scientific capacity but as a policy challenge.

              In this sense, the answer to the gamechanger question is that it really does not matter whether smallpox synthesis is a new phenomenon or something that scientists have long been able to accomplish.  Similar policy implications arise regardless.  More simply and without debate, it may be asserted that if someone wants to manipulate orthopox viruses to commit grievous harm, they probably can do so, and with each passing day that challenge becomes easier.  Thus, the objective of reducing that risk is paramount.  Whether laboratory synthesis of smallpox is a gamechanger or is nothing radically new, we must address the non-zero risk that the technological capacity for synthesizing smallpox could be misused.

Should Capabilities for Laboratory Synthesis Be Controlled?

If capacities for synthesizing smallpox or a comparably dangerous orthopox virus carry such threatening ramifications, then it makes sense to ask if those capacities should be controlled.  Perhaps some regulatory regime could be envisioned that would permit scientists to work with such viruses but where the scope of that research could be curtailed and the pathogens themselves could be contained.

Many of the workshop participants propounded the view that regulations to deny malefactors access to synthesizing capabilities are pointless.  The knowledge is too widespread, the equipment is too available, and the DNA material is too fungible for regulation to be effective in stopping a malevolent actor from synthesizing a dangerous pathogen.  Moreover, imposition of regulatory control on scientific activity could alienate bioscientists, leading them either to abandon beneficial research on viruses or dissuading them from cooperating with security officials in identifying misconduct.  It would be more effective to engage the scientific community by enhancing ethical commitments to exercise care in handling dangerous pathogens and to understand the potential for misuse of bioscience.

Other participants, while agreeing that regulation of bioscience is not likely to establish a substantial bulwark against the potential for bioviolence, asserted that some regulatory oversight and reporting mechanisms could usefully support tracking the movement of pathogen strains wherever they might be misused and following post-attack clues to hold perpetrators accountable.  That is, even if regulation would not likely obstruct someone who is absolutely committed to wrongful behavior, regulation might strengthen deterrence as well as contribute to successful prosecution of wrongdoers.

In this view, regulatory burdens must be sharply tailored to the risks and to a realistic assessment of what benefits these burdens might convey.  Certainly, there is consensus against regulation of research in this field merely for the sake of complicating the scientific undertaking.  Moreover, discussion of regulation in connection with intentional infliction of smallpox necessarily implicates the role of law enforcers who must apprehend the culprit and hold him/her accountable.  How closely to link regulation against smallpox to law enforcement raises unsettling questions about the need for and efficacy of enabling police and other security officials to gather information about scientific activities involving, for example, orthopox viruses.  Is this danger sufficient to justify diverting scarce law enforcement resources away from core missions (e.g., drug trafficking, homicide)?

How To Distinguish Legitimate from Illegitimate Bioscience?

Imposition of regulatory burdens would be easier if those burdens apply only to illegitimate bioscientists without imposing substantial burdens on legitimate scientists.  The workshop’s scientist participants offered that drawing this distinction is troubling from their perspective because there are not precise scientific criteria of legitimacy.  It is difficult to identify what information about bioscience could be usefully reported and what mechanisms to track people, pathogens, and equipment could be implemented.  Information about bioscience could be manipulated in countless ways either to cloak illicit behavior (to create a false negative) or to wrongly accuse someone else of illicit behavior (to create a false positive).  Information that is so readily distortable is, from this perspective, not worth the bother of collecting.

Other workshop participants, reflecting a legal or law enforcement perspective, disagreed.  In their view, legitimacy is less about the quality or intention of science than whether that science is reasonably overt.  Science undertaken in secret, accordingly, should be illegal without further evidence of motive or harmful consequence.  The more dangerous the potential implications of the science, the more reasonable it is to insist that authorized government officials have some knowledge of who the scientist is and what is the purpose of the research.  And for rare research that poses uniquely severe dangers, there should be minimally intrusive bases for rapid identification and accurate accountability of misconduct.  In extreme contexts, any potential for misconduct should be examinable.

From such a legal perspective, it is reasonable to ask whether collection of information in connection with uniquely dangerous activities can contribute to detection of clearly malevolent behavior, can increase the chances that such malevolence will fail, and can increase the potential for apprehending an attack perpetrator especially if there are multiple attacks in a series.  If information collection can contribute in these ways, then it is reasonable to try to identify cost-effective collection mechanisms that, at minimum, can incrementally add to deterrence by raising a perpetrator’s concern of being detected before the attack is committed.  

With regard to the threat of smallpox violence, these capacities should be supplemented with relevant intelligence, timely threat assessments, and strategies for anticipating future threats.  Finally, there must be an explicit process for providing information about emerging dangers to key stakeholders for purposes of attribution and interdiction.  Certainly, these mechanisms should be global because bioviolence is an inherently global danger.  Whether currently existing mechanisms are optimal from this perspective is a question that could be usefully studied.

Finally on this point, there was some disagreement as to whether collection, analysis, and sharing of information really is so difficult and error prone and imposes such grievous burdens on the conduct of bioscience.  Again, scientist participants posited that the obstacles to precisely accurate management of information gathering systems undercut the potential value of such systems.  Legal participants, by contrast, suggested that confrontation of those challenges could offer opportunities for multi-beneficial systems that simultaneously reduce dangers and facilitate accomplishment of other priorities.

A microcosm of this disagreement concerned the fact that systems for information collection, analysis, and sharing must rationalize different sources of data that employ terminology very differently than other sources.  Unquestionably, these terminological variations compound institutional resistance among diverse stakeholders; ultimately valuable information about manifest threats may be subject to significant classification barriers to its sharing.  The question here is whether this should be seen as a problem or an opportunity.  Does the existence of different terminology argue against trying to build harmonized collection mechanisms, or is it more reasonable to suggest that development of harmonized mechanisms that overcome barriers can usefully contribute economic, health, law enforcement, or educational benefits?  Ultimately on this question, the workshop reached an agreement to disagree.

Prevention or Preparedness?

              Prevention refers to policies for blocking or disabling malevolent actors who might undertake bioviolence.  Preparedness refers to policies for enabling populations to optimally withstand a bio-attack.  The question that arose at this point in the workshop was whether one set of policies should predominate or, if not, how should both sets of policies be balanced?.

The workshop identified a subtle point of distinction that appears merely semantic but actually carries substantial meaning.  Are risks of bioviolence a problem of emerging disease with the add-on of intentionality, or are these risks a problem of malevolence with disease as merely the weapon of choice?  Are the risks associated with development and spreading of exceptionally dangerous pathogens essentially a public health concern calling for, perhaps, subtle adjustments to address the potential for intentional infliction, or are these risks essentially a security concern calling for, perhaps, subtle adjustments of intelligence-law enforcement policies to address the unique implications of enemies choosing to weaponize disease?

              This distinction is important in answering what should be the focus of policies to address these risks.  If the former view is dominant, then we should ask whether vaccine and other medical countermeasure (MCM) readiness is efficient.  If the latter view is dominant, then we should ask whether our intelligence and law enforcement prevention capacities are sufficient.  If neither is dominant – if both views deserve attention – then an interesting question arises as to whether there currently is optimal synergy among public health preparedness policies and anti-terrorism-crime policies.  As to these two sets of policies calling for action by different communities, if attention to both is better than attention to either, would we be better off if all these communities work more effectively together?

What Should Be The Emphasis on Preparedness?

Workshop participants expressed a widespread consensus that it is unreasonable to believe that prevention efforts, no matter how rigorous, will be foolproof; some attention must be devoted to preparedness measures.  That is, as there can be no guarantee that a malevolent actor will be stopped, it is imperative to have capabilities for treating victims and staunching the spread of infection.   Moreover, preparedness measures have multiple public health benefits.

Workshop participants expressed appreciation of the value of optimizing situational awareness and threat/hazard evaluation through more adroit use of biosurveillance techniques.  These techniques include refinements of long-employed disease reporting mechanisms for purposes of early attack warning, disease diagnosis, identification, and discernment of unusual patterns of disease.  Also, resources can effectively be dedicated to build epidemiological capacity to enable determinations of the extent and cause of the outbreak and laboratory testing to confirm the disease agent.

More centrally and somewhat more controversially, is whether we have sufficient capacity to respond to a smallpox outbreak if it occurs:  are there adequate MCMs (e.g., vaccines) stockpiled and linked to rapid delivery networks?

The answer to this question turns on another seemingly semantic question:  who is we?  If we refers to the United States, then it is arguable that we have sufficient capacity to respond effectively.  The situation can always be improved, of course; enabling effective response among health, law enforcement, and other sectors is problematic, even more so due to our federal system that assigns vast authority to local officials.  Certainly, more training could be useful.  Yet, on the whole, United States policy makers understand the need both to be prepared for a catastrophic attack by having sufficient medicine on hand and to focus considerable security attention on stopping all types of catastrophic violence, including bioviolence.

The rest of the world, however, is not comparably prepared.  Global stockpiles of smallpox vaccine are less than 800 million doses – enough for at best 12% of the world’s population assuming ideal distribution.  Over 80% of these doses are stockpiled in 6 countries.  Ten countries have appreciable stockpiles of vaccine (relative to their population size).  Only four of these countries are outside NATO + G-8:   Israel, Singapore, South Africa, and Malaysia. Nearly all other countries have little or no vaccine. These deficiencies were demonstrated in the 2005 Atlantic Storm exercise on smallpox response:

Although some countries had enough to vaccinate their entire population, others had only enough of the vaccine for one percent of their citizens, or even less. “When I saw the list [of vaccine stocks], that was a shock to me, how little prepared many countries are, even rich Western countries,” said Klaas de Vries, who played the Dutch Prime Minister.[1]

Is The United States Secure Amid Global Unpreparedness?

At this point, the workshop picked up perhaps the most central policy question:  is the United States secure from a catastrophic smallpox attack even if its people and territory are largely protected from the disease’s worst ravages?  Or, would the consequences of a foreign intentional smallpox outbreak be so widely and deeply traumatic that we Americans cannot insulate ourselves; in this context we must include persons and institutions outside U.S. jurisdiction?

Many participants asserted that it is not exactly newsworthy that we live in a globalized world and that human existence in the United States is interconnected with at least some people elsewhere.  Also worth noting is a humanitarian concern:  perhaps the United States should take action to minimize risks associated with foreign victims of a bio-attack even if American interests are not catastrophically implicated.  Certainly, if the answer here is “yes”, then preparedness is deficient.  If global preparedness is important, there can be no serious debate that, in fact, a lot of needed work is not being done.  Thus, if the technological capacity for making smallpox exists, the world is vulnerable to a catastrophic rupture.

Some participants, offering a different perspective, suggested just because a technological capacity to do something horrific exists, that doesn’t mean someone will successfully commit that horrific act.  If the chances of intentionally-inflicted smallpox are low, perhaps it is reasonable to protect our nation (or perhaps our small group of nations) while making every effort to strengthen global recovery capacities but without advocating a global system of medical countermeasure stockpiling and distribution.  Is the “cure” of building a global system for stockpiling and distribution of medical countermeasures against intentionally-inflicted smallpox worse than the disease, diverting key resources away from where they could be more effectively and beneficially applied?    

There are many layers to this question, not each of which was sufficiently explored in the workshop.  At its base, the argument in favor of the current uneven distribution of smallpox MCMs rests on a low threat assessment.  Although a number of workshop participants challenged that assessment, the workshop reached no definitive conclusion other than to observe that threat assessment might not be able to produce an unequivocal and broadly agreed weighting of the probability of smallpox-violence.  The entire discussion of what to do about these dangers rests, therefore, on an ambiguity:  how high are the chances that someone would actually commit such an attack?   

Yet, some workshop participants expressed an intuitive discomfort about living in a world where someone – anyone – could aspire to commit an attack that would surely have cataclysmic consequences yet capacities to limit those consequences are concentrated in just a few nations.   While carrying out the attack no doubt entails complexities, the mere fact that it is doable implies an intolerable risk that compels preparatory action.  Obviously, because smallpox is extremely contagious, it would spread throughout unvaccinated populations regardless of where it is released, putting virtually everyone outside the United States and a few developed allies in extreme peril.

These workshop participants looked at this question from the perspective of post-attack recovery:  would it be reasonable for any policymaker to argue – in the wake of an intentionally inflicted smallpox attack outside the United States – that the likelihood of such an attack had been so small as to justify a lack of a global system for smallpox MCM preparedness?

Moreover, these participants asked if the purported costs of developing such a global biopreparedness system are so daunting as to dissuade us from the effort.  Such a system entails weaving a worldwide network to identify a bioviolence attack (at least an attack involving smallpox), to have medicines for treating victims and containing the damage, to have the logistical capacities to rapidly move those medicines to wherever they are needed, and the lawful authority to do all this efficiently.  Admittedly, there are substantial difficulties inherent in setting up such a system in a global environment afflicted by conflict and corruption.  Yet, these workshop participants suggested that if a global biopreparedness system is designed intelligently, perhaps it could actually contribute to accomplishment of corollary priorities.  Such a system could serve less to divert key resources than to multiply the efficacy of those resources.

The attribute of “designed intelligently” is not a simple matter.  There are huge challenges in building anything as complex as a global biopreparedness system:  How to agree on what MCMs should be procured? How and from whom should they be procured?  Where should they be stockpiled and with what logistical capacities to ensure their effective use when needed?  In the event of a demand for MCMs, who decides on their distribution?  What if there are multiple demands for distribution of MCMs in response to a multiple-location series of smallpox attacks?  What are the licensing requirements among various jurisdictions, and are these requirements optimally framed to deal with the unique challenges of smallpox violence?  Might necessary action be delayed by controversies about who might be liable for any alleged consequences of their actions or lack of actions?

In the context of smallpox violence, a mantra that we all need to coordinate together leaves many issues unaddressed about how diverse disciplines that all must be engaged in biopreparedness – law enforcement, public health, science, humanitarian communities – can integrate their efforts into networks that have effective command and control capabilities to cope with a security crisis.  The workshop could only begin the process of thinking about how these challenges might be introduced into policy discourse by asking, again, do emerging technological capacities earlier referred to as “laboratory synthesis of smallpox” constitute a sufficient gamechanging phenomenon as to justify accelerating focus on how to resolve these challenges?

How Should Authority for Global Preparedness Be Allocated?

The world is not well organized to address emerging bioviolence challenges – no workshop was needed for that understanding.  The workshop turned to a discussion of what would be the most appropriate forum for directing an accelerated focus on progressive policies:  the United Nations (whether via the Biological Weapons Convention or otherwise), the WHO, NATO, the Global Health Security Action Group (GHSAG), the G-20, something else.  Each of these institutions has useful capacities, but none so far has demonstrated clear leadership in this context.  WHO is ill-suited and seemingly unwilling to coordinate the smallpox violence response dimensions that are not directly related to WHO’s core public health mission; the BWC currently lacks institutional capacity to sustain policy progress.  Worldwide, law enforcers remain widely untrained and unauthorized to investigate, apprehend, and hold perpetrators of such an attack accountable; there is reason to be concerned that they might not be capable of carrying out trans-national aspects of sustaining order and controlling movement of populations during a smallpox violence crisis.

Perhaps the most positive recent development has been the GHSAG’s agreement “to enhance preparedness for CBRN threats and pandemic influenza by collaborating in moving towards a sustainable global infrastructure, including research and development, for medical countermeasures.” GHSAG includes ministerial level participation from the US, Canada, France, Germany, Italy, Japan, Mexico, and the United Kingdom as well as leadership of the European Commission and the World Health Organization.  It has no de jure authority, but its high level participants can coordinate and commit to devoting substantial resources to advance common health objectives.

The GHSAG agreement suggests an unprecedented seriousness of purpose in this context.  A great virtue of the GHSAG is that, as a club of powerful nations, it can undertake positive activity with fewer impediments than can more formally established international organizations.  Yet, it is precisely the narrowness of its membership that could conceivably undercut the effort becoming truly global.  These nations are hardly representative of the world:  six are involved in both NATO and the United Nations Western European and Others Group (the U.S. is a partial member).  China and India which together represent one-third of the world’s population and are among the fastest growing economies are not included.  GHSAG includes no Islamic, African, South American, or former Soviet Union nations, and only one Asian nation (Japan).

There is an important tactical question here:  should the first steps toward a global biopreparedness system be pursued by a small group of trustworthy, capable nations, or should those steps engage a wider group of potential allies, even if might be premature to consider a truly universal effort?  While GHSAG’s limited membership no doubt contributes to its ability to advance initiatives, a useful mid-ground between its very narrow membership and something truly global (perhaps engagement at the level of the G-20) might offer benefits in terms of engagement and resources that would be worth the difficulties of reaching consensus among a larger group.  Perhaps there are useful configurations here that are more inclusive than the current GHSAG structure.

How Can Optimal Policy and Diplomatic Linkages Be Established?

The possibility for institutional leadership to develop a global MCM preparedness system for addressing dangers of smallpox violence raises important questions of linkage – to what should such a system be linked and, perhaps more important, not linked?  It makes sense to establish linkages between such a system and the emergence of global public health capacities for surveillance, diagnostics, and treatment – the same logistical capacities that could carry smallpox medicines could carry any type of medication to address any type of pandemic.  There is a dual benefit here of policies to promote global biopreparedness:  even if the feared attack does not take place (and we hope that preparedness deflates some of the incentive for committing such an attack), the money spent on such preparedness has practical benefits in addressing far more likely, albeit perhaps less devastating, outbreaks.

The more difficult questions of linkage pertain to what makes smallpox violence different from natural pandemics:  an act of smallpox violence would threaten international peace and security.  Here is why the semantic distinction mentioned above is important:  if smallpox violence is viewed as predominantly a security threat involving the weaponization of disease, then the commitment to being prepared against that threat should be prioritized vis-a-vis other security threats including, for example, threats from inter-continental missiles.  Moreover, from an institutional perspective, if smallpox violence is viewed as predominantly a security threat, then the United Nations Security Council should be engaged in threat reduction efforts.

A final matter concerning development of a global biopreparedness system has to do with the diplomatic virtues of proposing such a system.  It is true, of course, that the United States has an active and integrated biopreparedness system; the disparity between the United States and much of the rest of the world is impossible to ignore.  Does that disparity have diplomatic consequences, perhaps weakening U.S. efforts to promote various improvements for, as examples, laboratory security or diagnostic capacities?  That is, when the United States seeks to encourage other countries to take even modest steps to reduce dangers associated with intentionally inflicted disease, do those foreign officials cite the enormous disparity of biopreparedness as a reason to object to bearing their share of “global” danger reduction efforts?  Put in reverse, would the diplomatic elevation of global biopreparedness to a central pillar of international policy encourage a broad array of progressive policies?


              Although no workshop can definitively answer these questions associated with laboratory synthesis of smallpox, three conclusions are indisputable.  First, the stakes are enormous.  Release of smallpox or a modified orthopox virus could be cataclysmic, resulting in perhaps millions of casualties.  Smallpox killed hundreds of millions in the 20th Century before its eradication.  Intentional release of it today could be just as grave.  Second, the world is horribly unprepared for a smallpox pandemic.  For years, policy has relied on the virus’ unavailability, not preparedness.  If the virus becomes available, then preparedness must be improved.

Third, there should be far broader efforts to impel many stakeholders worldwide to assess and defend the implications of their perspectives in connection with a topic as inherently compelling as smallpox violence.  Only by raising awareness among diverse communities and bringing the vast capacities of many international and national organizations can meaningful progress be sustained.


[1] See Hamilton, Daniel S. & Bradley T. Smith, Atlantic Storm: A Simulated Bioterrorist Attack Demonstrated the Weakness of International Public Health and Security Systems When Dealing with a Sudden Outbreak of Highly Infectious Diseases EMBO reports Vol. 7 No. 1 (2006) available at