Between Publishing and Perishing? H5N1 Research Unleashes Unprecedented Dual-Use Research Controversy

Between Publishing and Perishing? H5N1 Research Unleashes Unprecedented Dual-Use Research Controversy

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Michael Tu

Research Associate, The James Martin Center for Nonproliferation Studies


On April 13, 2012, reports of epidemic bird flu on chicken farms in northwestern China caused the Chinese government to kill more than 95,000 chickens as a precautionary measure against the possible transmission of the virus to humans.[1] While H5N1 most typically only infects a small fraction of people working in very close contact with sick birds, the virus elicits particular alarm because of its high human mortality rate. To date, of the 602 human cases reported to the World Health Organization (WHO), roughly 60% have resulted in death.[2] Although originally predominantly a concern in Southeast Asia, H5N1 began a dramatic worldwide spread in 2003, with increases observed both in total cases and geographic range from 2003 to 2007.[3][4]

H5N1's high mortality rate and the possibility that it might mutate to become easily transmissible from human-to-human make it a high priority research topic for public health preparedness and pandemic prevention efforts. However, these same factors mean research involving the virus poses public health and biosecurity risks. Nine years after the virus first began spreading from Southeast Asia, many questions remain about the magnitude of the threat actually posed by H5N1.[5] The scientific community still does not understand many fundamental aspects of the virus and why it is so deadly.[6] Scientists worldwide therefore continue to study H5N1 for insights into the virus's behavior, its potential to evolve into a pandemic-suitable strain, and how to contain it if it does mutate. Recently, researchers in the Netherlands and the United States identified genetic mutations that could also enable H5N1 to become easily transmissible from one human to another.[7] In the United States and abroad, controversy has emerged about whether the details of these two particularly sensitive H5N1 studies should be openly published to aid global pandemic preparedness or withheld in the interests of national security.

Findings of this kind simultaneously provide insight into global health questions while carrying the potential for costly and deadly laboratory accidents and/or intentional misuse by bioterrorists.[8] The debate that has ensued exemplifies the so-called "dual-use" dilemma, whereby research and technological innovations pursued for peaceful purposes could also be used in warfare or terrorism. Where these two characteristics exist simultaneously, as in the H5N1 research, a wide spectrum of policy recommendations emerge. On one end lie those who believe that the threats created by dual-use H5N1 research are unacceptable, that access to the products and findings of any such research should be restricted, and even that all such research should be discontinued.[9] Others believe that the virus in nature already constitutes a very serious menace, that greater insights into the virulence factors central to H5N1's pathology should be studied, and that discussion of this research would contribute positively to global biosecurity.[10]

Devising policy initiatives that would minimize both the natural public health risks and the weapons proliferation risks posed by H5N1 thus requires creativity and ingenuity. Because similar trade-offs will emerge frequently in the field of biotechnology, and because new and powerful technological advancements continue to broaden the scope of what is possible in an unclassified civilian laboratory, the task of devising effective management strategies for so-called "dual-use research of concern" will continue to increase in both complexity and importance. The high-profile controversy generated by the H5N1 papers may leave a lasting impression on both the popular outlook and regulatory management of dual-use research of concern.

Federal strategies for managing dual-use research of concern

A mere week following the September 11, 2001 attacks, a country already sensitized to the threat of terrorism looked on in increasing panic as a series of anthrax-laced letters were found to have been sent through the U.S. mail to the offices of Senators Tom Daschle and Patrick Leahy and several news agencies.[11] The ensuing alarm about the bioterrorism threat rallied Congress behind passage of the USA PATRIOT Act of 2001, which established criminal penalties for the unauthorized possession or use of sensitive biological agents and toxins.[12]

To better comprehend the appropriateness of strong regulatory approaches such as the USA PATRIOT Act and to suggest policy initiatives that support the interests of both national security and scientific freedom, the National Academies of Sciences in 2001 issued Biotechnology Research in an Age of Terrorism (known alternatively as the "Fink Report," after Dr. Gerald Fink, who chaired the authoring committee). Following one recommendation of the Fink report, the Department of Health and Human Services (HHS) established a National Science Advisory Board for Biodefense (NSABB) in summer 2005 "to provide advice and assessments to the government and the scientific community" on issues such as dual-use life science research.[13]

Within months, the HHS asked the NSABB to perform its first review of "contentious" research. In October 2005, scientists had recreated the 1918 influenza virus in the laboratory in an effort to understand, at a genetic level, why it was so deadly, and to shed insights into how to better prepare for and treat influenza viruses as a whole.[14] The re-creation of such a disease caused significant alarm in certain quarters, as some scientists felt that it was irresponsible to re-create an extinct but devastating virus.[15] However, the NSABB unanimously recommended full publication of the 1918 influenza research, asserting that the benefits outweighed the risks.[16]

Several other life science publications have become notorious for the complex risk-benefit tradeoffs they presented. As early as 2001, before the NSABB was established, scientists genetically engineered deadlier strains of existing diseases. For example, researchers in Australia accidentally produced a strain of mousepox (Ectromelia virus) with a 100% case fatality rate that killed even vaccinated mice.[17] Scientists have also identified ways to create antibiotic-resistant strains of diseases. In 2006, scientists located genes that made plague bacteria (Yersinia pestis) resistant to standard antibiotic treatments.[18] While such research sheds insights into the design of more powerful antibiotics, a field of particular importance in an era of antibiotic-resistant diseases such as MRSA and multi-drug resistant tuberculosis, the publication of information that could be useful for anyone wishing to produce antibiotic-resistant plague raised serious weapons proliferation concerns.

In June 2007 the NSABB identified seven types of "dual-use research of concern," all of which variously involved enhancing the ability of a pathogen to overcome the human immune system or other barriers to infection.[19] The recent H5N1 research qualifies under at least two of the seven categories because it could increase the transmissibility or the ability to disseminate H5N1, and it also generates a novel strain of H5N1.

Bird flu: An unknown risk

What would compel a scientist to create a more dangerous virus? Drs. Ron Fouchier and Yoshihiro Kawaoka, who in independent research projects produced the mutant H5N1 viruses at Erasmus Medical Center in Rotterdam and the University of Wisconsin at Madison, respectively, believe that ignorance about the threat posed by H5N1 presents a baseline global health time bomb that must be addressed. In a series of letters published in late January 2012, Fouchier and Kawaoka urged readers to remember that highly virulent influenzas can emerge suddenly, and that understanding their make-up is the essential first step towards effectively monitoring for new viruses and efficiently developing new vaccines.

Thus far H5N1 has exhibited high lethality, killing roughly 60% of infected humans. However, H5N1 cannot easily move from one human to another. [20] This characteristic of naturally occurring H5N1 strains may have prevented a devastating global H5N1 pandemic to-date. Why the virus lacks this ability remains unknown, and "H5N1 continues to challenge our understanding of interspecies transmission of influenza viruses."[21] Because the molecular basis for H5N1's virulence factors remains poorly understood, Drs. Fouchier and Kawaoka seek to determine the seriousness of the threat posed by H5N1, recently cautioning that "there is no scientific evidence to support" prevailing assumptions about its likelihood to cause a global flu pandemic.[22]

Two central questions that cannot be rigorously answered at this time are how close H5N1 is to achieving efficient human-to-human transmission, and whether the virus will remain as deadly if it does mutate in this fashion. Although the WHO continues to monitor the virus's evolution, it does not know which mutations could increase H5N1's pandemic potential. If human-to-human transmissibility were combined successfully with H5N1's observed high lethality, however, the mutated virus could produce a catastrophic pandemic. Drs. Fouchier and Kawaoka argue that creating infectious H5N1 strains and studying their behavior in mammals is essential to determining if a genetic mutation exists that could make H5N1 both highly communicable and highly lethal.

Policy responses and implications

Not all scientists agree that researching dangerous new strains of H5N1 is justifiable. The U.S. National Science Advisory Board for Biosecurity (NSABB) announced on 20 December 2011 that the benefits to science of such research did not outweigh the risks.[23] The NSABB also issued an unprecedented recommendation that Science and Nature, two of the most influential journals in the field, withhold publication of several key methodologies used in the research.[24] Drs. Fouchier and Kawaoka initially accepted this recommendation, and on 20 January 2012 voluntarily agreed, along with a group of 39 additional H5N1 researchers, to suspend all research for 60 days.

However, in late February 2012 the WHO convened a group of prominent virologists and one bioethicist. Disagreeing with the NSABB finding, the WHO study group argued that the H5N1 research holds significant public health importance, and urged full publication of the research including all methodological details. Further, the WHO study group announced that the voluntary research moratorium on lab-modified H5N1 viruses would be extended past the original 60-day period.[25] Several days later, the U.S. National Security Council (NSC) announced plans to issue more restrictive guidelines for research on highly lethal diseases and toxins.[26] On 29 February 2012 the HHS asked the NSABB to re-convene. Upon doing so, the NSABB reversed its earlier decision, and on 30 March 2012 recommended that the papers be published.[27] One board member, however, alleged that the National Institutes of Health (NIH), which manages the NSABB and its operations, selected speakers and briefings that advocated this reversal and biased the NSABB in favor of publication.[28] Nevertheless, on 20 April 2012 the HHS formally accepted the NSABB's new recommendation to permit full publication of the H5N1 findings.[29]

Opposed to this decision, U.S. Representative Jim Sensenbrenner, Vice Chairman of the House Committee on Science, Space, and Technology, wrote to John Holdren, President Obama's senior science and technology advisor, to criticize the Obama administration's handling of the papers as "ad hoc, delayed, and inadequate."[30] In response, Holdren replied, several days after the NSABB reversed its recommendation, that "The circumstances surrounding the recent review of H5N1 manuscripts are unprecedented. While the NSABB and other groups have examined the issue of [dual-use research of concern] for years, this is the first instance in which there has been an NSABB recommendation to refrain from publishing information from a research paper. Thus, the [United States government] until now has not needed to have a system in place specifically for restricting dissemination of the results of [dual-use research of concern]."[31] Although Holdren also announced the Obama administration's plans to implement mandatory screening of all dual-use research proposals involving fifteen high-risk pathogens, a still-dissatisfied Rep. Sensenbrenner sent a second letter to the NIH.[32]

Adding further complexity to the situation, in early April 2012 the Dutch government informed Dr. Fouchier that publication of his H5N1 research would violate Dutch export control laws.[33] Dutch laws consider knowledge, and not just physical goods, to be protected under export control laws. Thus the transfer of controlled information to a foreign national, in the absence of a government-issued license, constitutes an export violation even if no physical item ever leaves Dutch territory. While Dutch regulations usually exempt fundamental research from such laws (research not intended to produce a commercial product), Dutch authorities dropped this exemption and invoked export control restrictions on Dr. Fouchier's work.[34] Accordingly, Dutch authorities informed Dr. Fouchier that he might have already violated export control regulations and that he would need to obtain a license before publishing his work or face up to 6 years in jail and a $102,000 fine.[35] The Dutch government also barred Dr. Fouchier from talking about his work with any foreign nationals without a license. Dr. Fouchier, incensed, first declared his intention to ignore the export licensing requirement but later applied for and was granted an export permit.[36]

While Nature published Dr. Kawaoka's work in full on 2 May 2012, and while Dr. Fouchier's work appears likewise headed for full publication in Science, the underlying issues that inspired the controversy remain unresolved, posing continuing challenges for the management of high-risk dual-use life science research.[37]

Who has the authority to regulate life science research?

Interestingly, only limited discussion has occurred in the United States about the role of the Fundamental Research Exemption (National Security Decision Directive-189, or NSDD-189).[38] Established by a 1985 Reagan administration executive order, NSDD-189 establishes national policy for dealing with the findings of fundamental research, or research that is not intended to produce a commercial product.[39] Specifically, NSDD-189 declares that for all fundamental research, "to the maximum extent possible, the products of fundamental research remain unrestricted," and in cases where security concerns make this unadvisable, then the research should be secured by formally classifying it."[40] NSDD-189 goes on to stipulate that any necessary controls should occur under the laws that give the government the right to classify information and limit its distribution to authorized individuals. While NSDD-189 does not specifically or exclusively address biotechnology, the Bush administration reaffirmed NSDD-189 in 2001 following the anthrax letter attacks.[41] The 2004 Fink Report also unambiguously urged that NSDD-189 remain the foundation for handling the publication of "contentious" research.

Under NSDD-189, the H5N1 publications should be either openly published or classified.[42] NSDD-189 instructs policymakers, by executive order, to review research findings, perform risk analysis, and either allow free dissemination of research or classify the findings. NSDD-189 implicitly instructs policymakers to avoid fumbling through ad-hoc and vague designations falling somewhere between classification and publication. Over the years, observers have continued to reaffirm that NSDD-189 serves the best interests of both national security and scientific progress.[43] However, rather than abiding by NSDD-189, the NSABB originally recommended a third alternative—restricted access that stopped short of classification.[44] Thus the NSABB's first recommendation moved outside of NSDD-189's provisions by creating a new category of research lying in an undefined space between open dissemination and classification, where the standardized rules for securing classified information and the principles of scientific freedom could both be violated.

Interestingly, the Fink Report, which inspired the NSABB's creation, warned that the establishment of a "sensitive but unclassified" category, with its vagaries and costs, would discourage talented scientists from pursuing controversial research and thus have a "chilling effect on biodefense research vital to U.S. national security."[45] Indeed, "for all the serious concerns that can arise over whether information is properly classified … far more problematic is the interest in designating certain areas of research …. as ‘sensitive but unclassified.'"[46] Dr. Bruce Alberts, editor-in-chief of Science, and Dr. Philip Campbell, editor-in-chief of Nature, noted that their journals remain confused over how to make sensitive information available to legitimate scientists but not to anyone else, indicating the lack of an obvious mechanism for instituting such a system. Thus theoretical concerns about the soundness of sensitive but unclassified types of controls have been augmented by the observation that they are impractical to implement.[47]

Moreover, creating a system of restricted access, and one where research is neither freely discussed nor secured by the laws that govern access to classified information, would not only impose significant bureaucratic burdens on biodefense research, but might also create a false sense of security. Under the NSABB approach, hundreds of scientists in the United States and abroad would be authorized to receive limited-distribution information. Moreover, many have noted that "scientists becoming terrorists" represents a far greater bioterrorism threat than "terrorists becoming scientists."[48] The NSABB's recommendation specifically promised to ensure "access to the information to those with a legitimate need" to access it. However, if a hypothetical bioterrorist is also someone who is well-versed in the latest methods and research, then this hypothetical bioterrorist may very well be able, at least on paper, to claim a legitimate need to access restricted information and ultimately gain access to it even if he or she does not possess a United States security clearance. Ambiguity also exists as to who would exercise the authority to decide who does and does not legitimately need to access sensitive but unclassified information.

The biosecurity community should therefore consider whether an information control system of this type would have stopped Dr. Bruce Ivins, who spent decades performing anthrax research in U.S. government laboratories, and who the FBI identified as the perpetrator of the 2001 anthrax attacks, from accessing the latest anthrax research. The biosecurity community should also consider whether a restricted system that stops short of classification would inhibit national laboratories in foreign countries. If a clandestine biological weapons program exists under the veil of a national laboratory or research center, then this program may also be able to claim a legitimate need to access sensitive information. Would any security benefits derived from such a system justify the costs of its operationalization and the burden it imposes on international public health and biodefense research?

Can life scientists self-regulate?

The 2004 Fink Report noted the impracticality of using mandatory controls to guard sensitive life science research. The Fink Committee instead recommended a voluntary system of self-governance whereby scientific journals would identify potentially problematic publications.[49] The proposal to defer such decisions to the same experts who regularly review the merits of scientific publications gained significant momentum. However, if the treatment of the H5N1 research represents the current review structure, the peer-regulation paradigm may actually be under threat. Rather than the editorial boards of the journals reviewing the papers for their dual-use risks, the NSABB and the WHO issued recommendations that researchers and the journals quickly accepted. Given the substantial financial clout of the NIH (which house NSABB) vis-à-vis funding opportunities for life science research, researchers and journals may have very little leverage in rejecting NSABB recommendations. The biosecurity community must deliberate on whether or not the handling of the H5N1 publication preserved the spirit of peer regulation.

Another important issue that should be addressed is what phase of the research process presents the best opportunity for interventions such as the NSABB recommendation. Almost immediately after the NSABB decision, many scientists noted that it might not effectively control information flow in a way that reflects the realities of laboratory research. As the 2004 Fink Report noted, scientists collaborate during the process of performing research, and many scientists outside of Drs. Fouchier and Kawaoka's labs had already become familiar with their methods and results.[50] Dr. Richard H. Ebright of Rutgers University, who would like to see all such research discontinued, described publication controls as "utterly futile."[51] The biosecurity community should scrutinize whether the publication stage is the appropriate level at which to restrict activity, and if not, how to manage intervention at an earlier stage. Improved institutional coordination between organizations responsible for research review at these phases would help build their capacity to contribute towards dual-use research management. Further, clarification from NSABB about what research they would deem unacceptable for publication would also empower earlier and more effective management of research of concern, and hopefully enable measures to be taken before the methods and results have already been discussed by research scientists.

Can international norms be developed?

The conflicting recommendations issued by the NSABB and the WHO also shed light on the need for international norms to manage dual-use research of concern. The 2004 Fink Report specifically recommended the development of international norms for identifying and managing "experiments of concern," as well as for disseminating "sensitive" life science information.[52] The NSABB's December 2011 recommendation clearly failed to precipitate international consensus, and perhaps even damaged the NSABB's ability to establish itself as an effective international arbiter. In an era of globalized science and technology, the United States does not hold a monopoly on biotechnology, and is one of several countries contributing cutting-edge and sometimes dual-use research of concern. The NSABB thus cannot assume that it will play an authoritative role in the establishment of international norms on dual-use life science research.

Many scientists have spoken of the H5N1 debate in similar terms to the Asilomar Conference on Recombinant DNA, where in 1975 140 leading biologists and related professionals drafted voluntary guidelines to ensure that research involving recombinant DNA would be conducted responsibly.[53] A similar conference to continue this discussion in light of new emerging technology may be warranted. Whether the current WHO conference will expand its activities to a similar scope remains to be seen. Important distinctions between such a scenario and the Asilomar Conference exist. First, Asilomar was convened by concerned scientists, thus constructing immediate buy-in. Public outcry, on the other hand, motivated the WHO conference. Second, Asilomar in fact pre-dated the maturation of contentious recombinant DNA research, whereas the current WHO conference of virology experts occurred in response to completed research. Nevertheless, many anticipate that a more comprehensive and consensus-building review may occur in the near future. Such steps could represent significant progress towards building public confidence on laboratory responsibility.

A situation unresolved

Should an Asilomar-like conference occur, among the most difficult questions it will need to grapple with is how to manage two very different kinds of risks that are both high-magnitude and of unknown probability. Making policy judgments about dual-use research when risk analysis is hampered by this intractable reality lies at the discursive fulcrum of such debates. There is certainly risk involved in continuing to pursue the research on pandemic H5N1. Malevolent duplication of the research; utilization of its techniques for weaponization; laboratory accidents with consequences that could dwarf the 1979 Sverdlovsk incident (in which the release of anthrax spores in April 1979 from a Soviet military facility resulted in roughly 100 deaths); theft of the deadly virus from the laboratory; and unsecure transport or reconstruction of the virus all represent foreseeable scenarios of severe consequence. Continued questions about the strength of physical security and personnel accountability at laboratories both in the United States and abroad will also inspire trepidation about the conduct of this and other sensitive life science research.

The importance of finding a workable solution and continuing to gain knowledge on H5N1 cannot be overstated. By some estimates, a pandemic form of the virus could kill up to 1 billion people globally.[54] As Dr. Palese vigorously argued, scientific ignorance about the virus presents a different but also very serious menace. The Obama administration's National Strategy for Countering Biological Threats therefore identifies "timely and accurate insight on current and emerging risks" as one of seven objectives, and also describes the key role that scientific research plays in protecting the nation against a biological attack.[55] Public health officials worldwide still do not have any empirical and rigorous basis upon which to identify monitoring priorities and offer recommendations about the risk of a pandemic H5N1 outbreak.

Devising an optimal policy strategy will not be easy, but challenges involving the management of sensitive life science research will only grow in importance as time passes. Leading experts on dual-use research of concern note that all life science is dual-use.[56] Moreover, this dynamic does not limit itself to the life sciences. Leading experts note that "every major technology – metallurgy, explosives, internal combustion, aviation, electronics, nuclear energy – has been intensively exploited, not only for peaceful purposes but also for hostile ones"[57]

Nature ultimately published Dr. Kawaoka's paper after six months of international controversy.[58] As of this writing, Dr. Fouchier's paper remains under review by Science, but also appears headed for full publication. Some, however, have commented that the policy response to these papers was nothing more than to "kick the can down the road" and wait for the next piece of "contentious" research to appear.[59] Such a policy, of course, is unsustainable. Nevertheless, the controversy set forth by the H5N1 papers and the questions detailed in this issue brief will continue to vex the life sciences community for many years to come. As noted by the NSABB in its report to the U.S. Government, "the Board's discussions underscored the risks associated with not sharing the information, which could jeopardize pandemic influenza preparedness efforts. Specifically, there was concern that the United States would be perceived as redacting information with potential public health benefits and that this could undermine valuable international collaborations."[60]

Given the continuing discord and the record of conflicting and reversed recommendations, it would be difficult to consider the recent H5N1 publication controversy to be a verdict on what is and is not acceptable scientific inquiry. Nevertheless, the recent controversy provides a unique opportunity to more thoroughly study and refine the regulations that manage dual-use research of concern. The H5N1 papers thus represent an important case study of the various policy structures that govern the intersection of the life sciences and security, and offer an opportunity to identify the mechanisms that worked well and those that could be more appropriately designed to serve both basic research and security needs.

[1] "Bird Flu Reported at Chinese Farms," UPI, 18 April 2012,
[2] World Health Organization, "Cumulative Number of Confirmed Cases of Avian Influenza A(H5N1) Reported to WHO, 2003-2012,", 12 April 2012.
[3] World Health Organization, "Cumulative Number of Confirmed Cases of Avian Influenza A(H5N1) Reported to WHO, 2003-2012,", 12 April 2012.
[4] J.S. Malik Peiris, Menno D. de Jong, and Yi Guan, "Avian Influenza Virus (H5N1): A Threat to Human Health," Clinical Microbiology Reviews, Vol. 20, No. 2, April 2007, pp. 243-267.
[5] Ron Fouchier and A.B. Osterhaus, "Globalize the Discussion," in "Preventing Pandemics: The Fight Over Flu," Nature, vol. 481, Issue 7381, pp. 257-259, 19 January 2012; Institute of Medicine of the National Academies, The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health, Workshop Summary, (Washington, DC: National Academies Press, 2002).
[6] Ron Fouchier and AB Osterhaus,"Globalize the Discussion," in "Preventing Pandemics: The Fight Over Flu," Nature, Vol. 481, Issue 7381, pp. 257-259, 19 January 2012; Institute of Medicine of the National Academies, The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health, Workshop Summary, (Washington, DC National Academies Press, 2002).
[7] Martin Enserink, "Scientists Brace for Media Storm Around Controversial Flu Studies," Science Insider, 23 November 2011,; Masaki Imai et al, "Experimental Adaptation of an Influenza H5 HA Confers Respiratory Droplet Transmission to a Reassortant H5 HA/H1N1 Virus in Ferrets," Nature, 2 May 2012.
[8] Lynn Klotz and Ed Sylvester, "Worry about Lab Infections," in "Preventing Pandemics: The Fight Over Flu," Nature, vol. 481, Issue 7381, pp. 257-259, 19 January 2012; D.A. Henderson, "The Ultimate Biological Threat," in "Preventing Pandemics: The Fight Over Flu," Nature, vol. 481, Issue 7381, pp. 257-259, 19 January 2012.
[9] See, for example: "An Engineering Doomsday," The New York Times (New York), 7 January 2012.
[10] See, for example, an op-ed published by the Directors of the National Institute of Allergy and Infectious Disease, the NIH Vaccine Research Center, and the National Institutes of Health: Anthony S. Fauci, Gary J. Nabel and Francis S. Collins, "A Flu Virus Risk Worth Taking," The Washington Post, 30 December 2011.
[11] Julie E. Fischer, Stewardship or Censorship? Balancing Biosecurity, the Public's Health, and the Benefits of Scientific Openness," (Washington, DC: The Henry L. Stimson Center, 2006).
[12] Julie E. Fischer, Stewardship or Censorship? Balancing Biosecurity, the Public's Health, and the Benefits of Scientific Openness," (Washington, DC: The Henry L. Stimson Center, 2006).
[13] National Research Council, Biotechnology Research in an Age of Terrorism (Washington, DC: National Academies Press, 2004), pp. 110-111.
[14] TM Tumpey, CF Basler, PV Aguilar, H. Zeng, A Solorzano, DE Swayne, NJ Cox, JM Katz, JK Taubenberger, P. Palese, A. Garcia-Sastre, "Characterization of the Reconstructed 1918 Spanish Pandemic Virus." Science. (2005) 310, pp. 77-80; JK Taubenberger, AH Reid, RM Lourens, R. Wang, G. Jin, TG Fanning, "Characterization of the 1918 Influenza Virus Polymerase Genes," Nature (2005) Vol. 437, pp. 889-893; and Eckard Wimmer, "The Test-tube Synthesis of a Chemical Called Poliovirus; The Simple Synthesis of a Virus has Far-reaching Societal Implications," EMBO Reports, Vol. 7, Special Issue, July 2006, pp. S3-S9; Jocelyn Kaiser, "Resurrected Influenza Virus Yields Secrets of Deadly 1918 Pandemic." Science (2005) 310, pp. 28-29; Andrew Pollack, "Traces of Terror: The Science; Scientists Create a Live Polio Virus," The New York Times, 12 July 2002.
[15] Debora MacKenzie, "Experts Fear Escape of 1918 Flu from Lab," The New Scientist, 21 October 2004.
[16] Eckard Wimmer, "The Test-tube Synthesis of a Chemical Called Poliovirus; The Simple Synthesis of a Virus has Far-reaching Societal Implications," European Molecular Biology Orginaziation, Vol. 7, Special Issue, July 2006, pp. S3-S9; Phillip A. Sharp, "1918 Flu and Responsible Science." Science. (2005) 310: 195; Dana A. Shea, Oversight of Dual-Use Biological Research: The National Science Advisory Board for Biosecurity, CRS Report for Congress RL33342, (Washington, DC: Library of Congress, Updated April 27, 2007).
[17] RJ Jackson, AJ Ramsay, CD Christensen, S. Beaton, DF Hall, IA Ramshaw, "Expression of Mouse Interleukin-4 by a Recombinant Ectromelia Virus Suppresses Cytolytic Lymphocyte Responses and Overcomes Genetic Resistance to Mousepox," Journal of Virology, Vol 75, No. 3, February 2001, pp. 1205-1210; Michael J. Selgelid, "The Mousepox Experience: An Interview with Ronald Jackson and Ian Ramshaw on Dual-use Research," EMBO Reports, Vol. 11, No. 1, January 2010, pp. 18-24.
[18] Rupa A. Udani and Stuart B. Levy, "MarA-Like Regulator of Multidrug Resistance in Yersinia pestis," Antimicrobial Agents and Chemotherapy, Vol. 50, No. 9, September 2006, pp. 2971-2975.
[19] National Science Advisory Board for Biosecurity, Proposed Framework for the Oversight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of Research Information (Washington, DC: National Institutes of Health, June 2007), pp. 18-21.
[20] Masaki Imai et al, "Experimental Adaptation of an Influenza H5 HA Confers Respiratory Droplet Transmission to a Reassortant H5 HA/H1N1 virus in ferrets," Nature, 2 May 2012. While a very small number of cases of "probable" human-to-human transmission may have occurred, no sustained human-to-human transmission of H5N1s has ever been observed. From an epidemiological standpoint, while such cases invite further inquiry, natural H5N1s are generally still not considered a human-to-human transmission risk, and a more infectious strain has yet to have been observed in, or harvested from, naturally occurring H5N1. See: Kumnuan Ungchusak, et al., "Probable Person-to-Person Transmission of Avian Influenza A (H5N1)," New England Journal of Medicine, Vol. 352, No. 4, 27 January 2005, pp. 333-340.
[21] J.S. Malik Peiris, Menno D. de Jong, and Yi Guan, "Avian Influenza Virus (H5N1): a Threat to Human Health," Clinical Microbiology Reviews, Vol. 20, No. 2, April 2007, pp. 243-267.
[22] Ron A.M. Fouchier, Sander Herfst, Albert D.M.E. Ostehaus, "Restricted Data on Influenza H5N1 Virus Transmission," Science, 19 January 2012.
[23] Kenneth I. Berns et al, "Policy: Adaptations of Avian Flu Virus Are a Cause for Concern," Nature, published online 31 January 2012.
[24] For data on the impact factor of the journals Nature and Science, see: "Ranks for Nature and Science by Citation Impact, 2000-2010," Thomson Reuters, 3 April 2011,
[25] Debora MacKenzie, "Bird Flu Research to be Published in Full," New Scientist, 17 February 2012.
[26] Neela Banerjee, "NSC Wants Rules on Research that Could Lead to Biological Weapons," Los Angeles Times, 18 February 2012.
[27] National Institutes of Health, "National Science Advisory Board for Biosecurity Findings and Recommendations March 29-30, 2012," 20 April 2012.
[28] Michael T. Ostehrolm, Letter to Amy P. Patterson, 12 April 2012,
[29] National Institutes of Health, "Statement by NIH Director Francis Collins, MD, PhD on the NSABB Review of Revised H5N1 Manuscripts," 20 April 2012.
[30] F. James Sensenbrenner, Jr., "Letter to The Honorable John P. Holdren," Congress of the United States, House of Representatives, 1 March 2012.
[31] John P. Holdren, "Letter to The Honorable F. James Sensenbrenner, Jr.," Executive Office of the President, Office of Science and Technology Policy, 9 April 2012.
[32] John P. Holdren, "Letter to The Honorable F. James Sensenbrenner, Jr.," Executive Office of the President, Office of Science and Technology Policy, 9 April 2012; National Institutes of Health, "United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern," F. James Sensenbrenner, Jr., "Letter to Dr. Francis Collins, M.D., Ph.D., Director, National Institute of Health," Congress of the United States, House of Representatives, 23 April 2012.
[33] Nell Greenfieldboyce, "Bird Flu Studies Mired in Export Control Law Limbo," Morning Edition, National Public Radio, Washington, DC, 10 April 2012.
[34] Martin Enserink, "Will Dutch Allow ‘Export' of Controversial Flu Study?" Science, Vol. 336, no. 6079, 20 April 2012, p. 285.
[35] Jim Wappes and Lisa Schnirring, "Fouchier Plans to Flout Dutch Export Law, Publish H5N1 Study," CIDRAP News, 17 April 2012.
[36] Nell Greenfieldboyce, "Dutch Government Set to Reconsider Restrictions on Bird Flu Study," Shots: NPR Health Blog,, 20 April 2012; Nell Greenfieldboyce, "Bird Flu Scientist Has Applied For Permit To Export Research," Shots: NPR Health Blog,, 24 April 2012.
[37] Masaki Imai et al, "Experimental Adaptation of an Influenza H5 HA Confers Respiratory Droplet Transmission to a Reassortant H5 HA/H1N1 Virus in Ferrets," Nature, 2 May 2012; Robert Roos, "Dutch Officials Approve Publication of Fouchier's H5N1 Study," CIDRAP News, 27 April 2012.
[38] No discussion of H5N1 and NSDD-189 seems to have appeared in news outlets. A search of LexisNexis Academic Universe and Google News using search term ("H5N1" AND "NSDD-189") returned zero results. Limited discussions appeared following the second NSABB recommendation in academic literature and include: Gerald L. Epstein, "Preventing Biological Weapon Development Through the Governance of Research," Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science, Volume 10, Issue 1, 28 March 2012; and David Malakoff, "U.S. Agencies to Start Screening Biomedical Proposals for Dual Use," Science, Volume 336, No. 6077, 6 April 2012.
[39] White House Press Office, "National Policy on the Transfer of Scientific, Technical and Engineering Information," NSDD 189, 21 September 1985.
[40] White House Press Office, "National Policy on the Transfer of Scientific, Technical and Engineering Information," NSDD 189, 21 September 1985.
[41] The White House, "Letter from Dr. Condeleezza Rice to Dr. Harold Brown, co-chairman, Center for Strategic and International Studies," 1 November 2001.
[42] In October 2001, President Bush signed an executive order granting classification authority to the NIH. See: "The White House, Executive Order for Department of Health and Human Services: Further Amendment to Executive Order 10789, as Amended, to Authorize the Department of Health and Human Services to Exercise Certain Contracting Authority in Connection with National Defense Functions," 20 October 2001.
[43] National Research Council, Science and Security in a Post-9/11 World (Washington, DC: National Academies Press, 2007), pp. 27-48.
[44] National Institutes of Health, "Press Statement on the NSABB Review of H5N1 Research," U.S. Department of Health and Human Services, 20 December 2011.
[45] National Research Council, Biotechnology Research in an Age of Terrorism (Washington, DC: National Academies Press, 2004), pp. 92-104.
[46] National Research Council, Biotechnology Research in an Age of Terrorism (Washington, DC: National Academies Press, 2004), p. 93.
[47] American Association for the Advancement of Science, "Statement by Science Editor-in-Chief Dr. Bruce Alberts Regarding Publication of the H5N1 Avian Influenza Research," 20 December 2011.
[48] See, for example: Gerald Epstein, "Big off: Taking the Bioterrorism Threat Seriously," The National Strategy Forum Review, Vol. 17, Issue 1, Winter 2007; "The Future of Terrorism," Discover July 2006, "Statement of Senator Bob Graham, Chairman of the Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism Before a Hearing of the Senate Subcommittee on Oversight of Government Management, the Federal Workforce and the District of Columbia," 30 April 2009; Yanzhong Huang, "Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science," Vol. 9, Issue 1, 11 March 2011; Carnegie Corporation of New York, "Crafting Strategies to Control Biological Weapons," Carnegie Review, 2009; BioWeapons Prevention Project, "How do countering bioterrorism and the BWC relate to each other?" BWPP Online Discussions, 6 December 2011,
[49] National Research Council, Biotechnology Research in an Age of Terrorism (Washington, DC: National Academies Press, 2004).
[50] Dr. William Schaffner, Chair of Preventive Medicine at Vanderbilt University School of Medicine, noted that "we already have a growing pyramid of people who know all these data, and that pyramid will grow over time. See: Troy Brown,"Scientists Asked Not to Publish H5N1 Flu Research Details," Medscape Medical News, 22 December 2011.
[51] Dr. Ebright goes on to suggest that preventing such work from being done at all is the only solution to preventing people from learning its methodological basis. See: Declan Butler, "Fears Grow Over Lab-bred Flu: Scientists Call for Stricter Biosafety Measures for Dangerous Avian-Influenza Variants," Nature, Vol. 480, Issue 7378, 20 December 2011.
[52] National Research Council, Biotechnology Research in an Age of Terrorism (Washington, DC: National Academies Press, 2004), p. 125.
[53] Paul Berg, David Baltimore, Sydney Brenner, Richard O. Roblin III, and Maxine F. Singer, "Summary Statement of the Asilomar Conference on Recombinant DNA Molecules," Proceedings of the National Academy of Sciences, Vol. 72, No. 5, pp. 1981-1984 (June 1975).
[54] Peter Christian Hall, "As a Biological Weapon, H5N1 is for the Birds," Reuters, 9 January 2012.
[55] National Security Council, National Strategy for Countering Biological Threats (Washington, DC: The White House, 2009).
[56] Ronald M. Atlas, "Responsible Conduct by Life Scientists in an Age of Terrorism," Science and Engineering Ethics, Vol. 15, No. 3, September 2009, pp. 293-301.
[57] Matthew Meselson, "The Problem of Biological Weapons," Symposium on Biological Weapons and Bioterrorism, National Academy of Sciences, Washington, DC, 2 May 2000.
[58] Masaki Imai et al, "Experimental Adaptation of an Influenza H5 HA Confers Respiratory Droplet Transmission to a Reassortant H5 HA/H1N1 Virus in Ferrets," Nature, 2 May 2012.
[59] Robert Roos, "NSABB Member Says Officials Stacked Deck for Board's H5N1 Decision," CIDRAP News, 13 April 2012.
[60] "U.S. Security Advisors Urge Limits for Data," The Associated Press, 14 February 2012,

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