Is there a Role for the States Parties to the BWC in Oversight of Lab-created Potential Pandemic Pathogens?
by Lynn C. Klotz, PhD
Senior Science Fellow
Center for Arms Control and Non-proliferation
Scientists Working Group on Biological and Chemical Security http://armscontrolcenter.org/issue-cent ... l-weapons/
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Summary
Research by Ron Fouchier and Yoshihiro Kawaoka marked the beginning of a “Research Enterprise” creating mammalian-airborne-transmissible highly-pathogenic avian-influenza viruses. For the sake of brevity, they will be called matHPAI. At present, likely more than ten laboratories are creating or researching matHPAI live viruses. While most of our concern has focused on matHPAI, the recent de novo creation of horsepox virus, an orthopoxvirus related to smallpox virus, is also of highly worrisome.
Both these viruses are examples of lab-created potential pandemic pathogens (PPPs), which bring up questions reflecting our concerns: Should details of this dual use research be published? Could lab-created PPPs be accidentally released from a laboratory and seed a human pandemic? Could they be employed as biological weapons?
The probability of accidental release into the community from one of the laboratories in the matHPAI Research Enterprise is uncomfortably high. For these and other lab-created PPPs, just one or a few laboratory-infected researchers could seed an outbreak or a pandemic. Concern over a pandemic from a Research Enterprise laboratory release should rival our grave concern over a natural pandemic as the likelihood of both are similar. Furthermore, a laboratory worker with hostile intent could introduce a PPP into the community.
This is not a problem for future consideration, it is upon us now. There is urgent need for international oversight and regulation of this research.
The BWC States Parties may not believe it to be within the BWC mandate to oversee academic research whose goal is public health. However, if the Parties decide this is within its mandate under Article XII of the BWC, it could speed up the enactment of guidelines and regulations. At the very least, the BWC Parties could and should be the catalyst to launch discussions for a different international treaty on oversight and regulation of this dangerous research, perhaps even banning some research. In the meantime, since enacting new treaties is an uncertain and long process, the BWC Parties should work to pass legislation in their own nations.
Background and Commentary
In 2012, Fouchier published1 the creation of mammalian aerosol-transmissible H5N1 avian influenza virus (matH5N1). This virus is responsible for bird flu outbreaks in Asia, and it kills 60% of poultry workers who become infected through close contact with infected poultry.
The Fouchier research along with that of Kawaoka2 marked the beginning of the “Research Enterprise” for creating matPPPs in the laboratory. Subsequently in 2013, letters to the journals Science and Nature, 3,4 ...
Gain-of-function experiments on H7N9
by Ron A. M. Fouchier, Yoshihiro Kawaoka & 20 co-authors
Nature volume 500, pages 150–151(2013)
August 7, 2013
Since the end of March 2013, avian influenza A viruses of the H7N9 subtype have caused more than 130 human cases of infection in China, many of which were severe, resulting in 43 fatalities. Although this A(H7N9) outbreak is now under control, the virus (or one with similar properties) could re-emerge as winter approaches.
To better assess the pandemic threat posed by A(H7N9) viruses, investigators from the NIAID Centers of Excellence in Influenza Research and Surveillance and other expert laboratories in China and elsewhere have characterized the wild-type avian A(H7N9) viruses in terms of host range, virulence and transmission, and are evaluating the effectiveness of antiviral drugs and vaccine candidates. However, to fully assess the potential risk associated with these novel viruses, there is a need for further research, including experiments that may be classified as 'gain of function' (GOF).
Here we outline the aspects of the current situation that most urgently require additional research, our proposed studies, and risk-mitigation strategies.
The A(H7N9) virus haemagglutinin protein has several motifs that are characteristic of mammalian-adapted and human influenza viruses, including mutations that confer human-type receptor binding and enhanced virus replication in mammals. The pandemic risk rises exponentially should these viruses acquire the ability to transmit readily among humans.
Reports indicate that several A(H7N9) viruses from patients who were undergoing antiviral treatment acquired resistance to the primary medical countermeasure — neuraminidase inhibitors (such as oseltamivir, peramivir and zanamivir). Acquisition of resistance to these inhibitors by A(H7N9) viruses could increase the risk of serious outcomes of A(H7N9) virus infections.
The haemagglutinin proteins of A(H7N9) viruses have a cleavage site that is consistent with a low-pathogenic phenotype in birds. In the past, highly pathogenic H7 variants (with basic amino-acid insertions at the cleavage site that enable the spread of the virus to internal organs) have emerged from populations of low-pathogenic strains circulating in domestic gallinaceous poultry.
Normally, epidemiological studies and characterization of viruses from field isolates are used to inform policy decisions regarding public-health responses to a potential pandemic. However, classical epidemiological tracking does not give public-health authorities the time they need to mount an effective response to mitigate the effects of a pandemic virus. To provide information that can assist surveillance activities — thus enabling appropriate public-health preparations to be initiated before a pandemic — experiments that may result in GOF are critical.
Therefore, after review and approval, we propose to perform experiments that may result in GOF (see 'Proposed gain-of-function experiments').
All experiments proposed by influenza investigators are subject to review by institutional biosafety committees. The committees include experts in the fields of infectious disease, immunology, biosafety, molecular biology and public health; also, members of the public represent views from outside the research community. Risk-mitigation plans for working with potentially dangerous influenza viruses, including the 1918 virus and highly pathogenic avian H5N1 viruses, will be applied to conduct GOF experiments with A(H7N9) viruses (see Supplementary Information). Additional reviews may be required by the funding agencies for proposed studies of A(H7N9) viruses.
The recent H5N1 virus-transmission controversy focused on the balance of risks and benefits of conducting research that proved the ability of the H5N1 virus to become transmissible in mammals (see http://www.nature.com/mutantflu). These findings demonstrated the pandemic potential of H5N1 viruses and reinforced the need for continued optimization of pandemic-preparedness measures. Key mutations associated with adaptation to mammals, included in an annotated inventory for mutations in H5N1 viruses developed by the US Centers for Disease Control and Prevention, were identified in human isolates of A(H7N9) viruses. Scientific evidence of the pandemic threat posed by A(H7N9) viruses, based on H5N1 GOF studies, factored in risk assessments by public-health officials in China, the United States and other countries.
Since the H5 transmission papers were published, follow-up scientific studies have contributed to our understanding of host adaptation by influenza viruses, the development of vaccines and therapeutics, and improved surveillance.
Finally, a benefit of the H5N1 controversy has been the increased dialogue regarding laboratory biosafety and dual-use research. The World Health Organization issued laboratory biosafety guidelines for conducting research on H5N1 transmission and, in the United States, additional oversight policies and risk-mitigation practices have been put in place or proposed. Some journals now encourage authors to include biosafety and biosecurity descriptions in their papers, thereby raising the awareness of researchers intending to replicate experiments.
The risk of a pandemic caused by an avian influenza virus exists in nature. As members of the influenza research community, we believe that the avian A(H7N9) virus outbreak requires focused fundamental and applied research conducted by responsible investigators with appropriate facilities and risk-mitigation plans in place. To answer key questions important to public health, research that may result in GOF is necessary and should be done.Box 1: Proposed gain-of-function experiments
• Immunogenicity. To develop more effective vaccines and determine whether genetic changes that confer altered virulence, host range or transmissibility also change antigenicity.
• Adaptation. To assist with risk assessment of the pandemic potential of field strains and evaluate the potential of A(H7N9) viruses to become better adapted to mammals, including determining the ability of these viruses to reassort with other circulating influenza strains.
• Drug resistance. To assess the potential for drug resistance to emerge in circulating viruses, evaluate the genetic stability of mutations conferring drug resistance, and evaluate the efficacy of combination therapy with antiviral therapeutics. Also, to determine whether A(H7N9) viruses could become resistant to available antiviral drugs, and to identify potential resistance mutations that should be monitored during antiviral treatment.
• Transmission. To assess the pandemic potential of circulating strains and perform transmission studies to identify mutations and gene combinations that confer enhanced transmissibility in mammalian models (such as ferrets and guinea pigs).
• Pathogenicity. To aid risk assessment and identify mechanisms, including reassortment and changes to the haemagglutinin cleavage site, that would enable circulating A(H7N9) viruses to become more pathogenic.
Author information
Affiliations
Erasmus Medical Center, Rotterdam, the Netherlands
Ron A. M. Fouchier
University of Wisconsin-Madison, Wisconsin, USA
Yoshihiro Kawaoka
Consortia
20 co-authors
Corresponding authors
Correspondence to Ron A. M. Fouchier or Yoshihiro Kawaoka.
Supplementary Information
Including a full list of co-authors (PDF 820 kb)
Related links
Related links in Nature Research
Limited airborne transmission of H7N9 influenza A virus between ferrets
Avian flu: Extra oversight for H7N9 experiments
H5N1 virus: Transmission studies resume for avian flu
Pause on avian flu transmission studies
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Fouchier, R., Kawaoka, Y. Gain-of-function experiments on H7N9. Nature 500, 150–151 (2013). https://doi.org/10.1038/500150a
Published: 07 August 2013
Issue Date: 08 August 2013
DOI: https://doi.org/10.1038/500150a
twenty-two virologists notified the research community of their interest in creating airborne-transmissible strains of the also deadly H7N9 Asian influenza virus.
A 2015 commentary5 submitted to the U. S. National Science Advisory Board for Biosecurity (NSABB) identified at least 35 publications from laboratories, mostly in Asia, where matHPAI and other influenza viruses were created or researched. Now, there is likely more published research, and many unpublished research projects are likely underway.
(1) Should details of this dual use research be published?
The methods to create these airborne-transmissible viruses are straight-forward and could be reproduced by researchers not highly skilled in molecular virology. Furthermore, skilled molecular virologists could re-create these viruses by directly making the genetic modifications in the laboratory. Re-creating matHPAI and other PPPs brings up the serious biosecurity concern of their use for hostile purposes.
Criteria6, established in 1982, for making decisions about publication of dual use research,...
Scientific Communication and National Security: A report prepared by the Panel on Scientific Communication and National Security Committee on Science, Engineering, and Public Policy
National Academy of Sciences
National Academy of Engineering
Institute of Medicine
NATIONAL ACADEMY PRESS
Washington, D.C. 1982
PREFACE
The use of American science and technology in the rapid increase in Soviet military strength over the past decade has aroused substantial concern in the current administration. This concern has been expressed frequently in recent months by high-ranking officials, who have called for tighter controls on all forms of technology transfer, including communication among scientists by such means as the publication of papers in scientific journals and by face-to-face meetings. In addition, federal agencies have already taken steps to control the flow of data and information from scientific research. These statements and actions have led to rising concern in the U.S. scientific community that such controls might impede scientific progress and its contribution to the national welfare.
In March 1982, discussions among officials of the Academy complex and the Department of Defense led to the creation of the Panel on Scientific Communication and National Security under the aegis of the Committee on Science, Engineering, and Public Policy, a standing committee, to study the question. The charge to the Panel was, generally, to examine the relation between scientific communication1 and national security in light of the growing concern that foreign nations2 are gaining military advantage from such research. It states four major elements, as follows:
• An examination of the national security interests and the interests in free communication in two or three specific fields of science and technology (e.g., cryptology, very high speed integrated circuits, artificial intelligence) to be selected by the study panel in consultation with the Department of Defense. This analysis will include an examination of the extent to which American research has been used in Soviet military programs and, if possible, a consideration of how such information was transferred. In addition, the Panel will assess and compare the contribution to Soviet military strength from the transfer of research information with that arising from other means of technology transfer, such as the Soviet acquisition of American hardware.
• A review—with an emphasis on the International Traffic in Arms Regulations (ITAR) and the Export Administration Regulations (EAR), and a proposed executive order on the classification system—of the principal policy and operational concerns of the respective government agencies, universities, scientific societies, and researchers. (The proprietary concerns of industry will not be considered.) The goal is to identify issues where common agreement exists, to expose those where apparent disagreements are based on misperceptions and misunderstandings, and, perhaps, to narrow and sharpen the issues on which genuine differences exist.
• A rigorous evaluation of critical issues concerning the application of controls on the flow of research information.
• The development of recommendations and conclusions concerning: (i) the intended and proper reach of controls vis-à-vis various categories of science and technology; (ii) areas of science and technology that are or should be outside the operation of controls; (iii) approaches that might provide more certainty and predictability to the regulatory system; and (iv) alternative procedures that might prove acceptable to all of the concerned sectors.
This study has been sponsored by the Department of Defense, the National Science Foundation, the American Association for the Advancement of Science, the American Chemical Society, the American Geophysical Union, and the National Academy of Sciences.3 The Panel, composed of 19 members, includes senior members of university faculties and administrations, former federal agency officials, and leaders in high-technology industrial firms.
At the time the Panel was created, conversations among the Panel chairman, the President of the National Academy of Sciences, and the Under Secretary of Defense for Research and Engineering led to a decision that Panel members would be given security clearance (if they did not already possess it) so that it would be possible for them to receive classified information about technology transfers to other countries. The Panel was subsequently given three secret-level briefings by members of the intelligence community. In addition, a subpanel, comprising six members of the Panel who hold clearance at the highest level, was briefed at two additional meetings.
The Panel has examined the evidence provided at the intelligence briefings and has sought to deal with this information in a way that would eliminate the need to classify this report. The main thrust of the Panel’s findings is completely reflected in this document. However, the Panel has also produced a classified version of the subpanel report based on the secret intelligence information it was given; this statement is available at the Academy to those with the appropriate security clearance.
The Panel invited as participants in its sessions liaison representatives from all the study’s sponsors as well as from the departments of State and Commerce, the Office of Science and Technology Policy, the intelligence community, the Association of American Universities, the Institute of Electrical and Electronics Engineers, and the American Physical Society. Liaison members participated in the Panel’s open sessions and those with the appropriate security clearance attended the Panel’s classified briefings. A list of all those who participated in the Panel’s deliberations is included (see pages 72–76).LIST OF BRIEFERS, CONTRIBUTORS, AND LIAISON REPRESENTATIVES
Briefers
ARTHUR J.ALEXANDER, Associate Head, Economics Department, The Rand Corporation
BETSY ANDERSON, Consular Officer, Bureau of Consular Affairs, Department of State
LEWIS M.BRANSCOMB, Chief Scientist, IBM Corporation
STEPHEN D.BRYEN, Deputy Assistant Secretary, International Economic, Trade and Security Policy, Department of Defense
WILLIAM D.CAREY, Executive Officer, American Association for the Advancement of Science
MICHAEL CIFRINO, Attorney Advisor, Office of the Assistant General Counsel, Department of Defense
W.DONALD COOKE, Vice President for Research, Cornell University
JOHN C.CROWLEY, Director, Federal Relations for Science and Research, Association of American Universities
JAMES DEARLOVE, Chairman, Committee on Exchanges, Technology Transfer Branch; Defense Intelligence Agency, Department of Defense
BOHDAN DENYSYK, Deputy Assistant Secretary, Export Administration, Department of Commerce
ERWIN FRIEDLANDER, Staff Physicist, Lawrence Berkeley Laboratory
ALBERT GORE, JR., Chairman, Investigations and Oversight Subcommittee, Committee on Science and Technology, House of Representatives
WALTER GRANT, Chief, Technology Transfer Branch of the Nuclear Energy and Applied Science Division, Defense Intelligence Agency, Department of Defense
C.DAVID HARTMANN, Executive Secretary, Technology Transfer Intelligence Committee
MARTIN HELLMAN, Professor, Department of Electrical Engineering, Stanford University
CHARLES HORNER, Deputy Assistant Secretary for Science and Technology, Bureau of Oceans and International Environmental and Scientific Affairs, Department of State
BOBBY RAY INMAN, Deputy Director, Central Intelligence Agency
ERNEST B.JOHNSTON, Senior Deputy Assistant Secretary, Bureau of Economic and Business Affairs, Department of State
FRANCIS B.KAPPER, Director, Military Technology Sharing, International Programs and Technology, Office of the Under Secretary of Defense for Research and Engineering, Department of Defense
MICHAEL LORENZO, Deputy Under Secretary of Defense for Research and Engineering (International Programs and Technology), Department of Defense
MICHAEL B.MARKS, Special Assistant to the Under Secretary, Office of the Under Secretary for Security Assistance, Science and Technology, Department of State
RICHARD F.POST, Deputy Associate Director for Physics, Magnetic Fusion Division, Lawrence Livermore National Laboratory
FRANK H.T.RHODES, President, Cornell University
RONALD RIVEST, Professor, Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology
HOWARD E.ROSENBLUM, Deputy Director for Communications Security, National Security Agency
JOSEPH P.SMALDONE, Chief, Arms Licensing Division, Office of Munitions Contol, Department of State
RICHARD SPICER, Intelligence Analyst, Soviet Section, Intelligence Division, Federal Bureau of Investigation
STEPHEN UNGER, Professor, Department of Computer Science, Columbia University
JACK VORONA, Assistant Vice Director for Scientific and Technical Intelligence (International), Defense Intelligence Agency, Department of Defense
DAVID A.WILSON, President’s Executive Assistant, University of California
LEO YOUNG, Director for Research and Technical Information, Office of the Under Secretary of Defense for Research and Engineering, Department of Defense
Contributors
LAURENCE J.ADAMS, Senior Vice President, Martin Marietta Corporation
WAYNE BERT, Munitions Policy Analyst, International Economic, Trade and Security Policy, Department of Defense
JENNIFER SUE BOND, Program Analyst, National Science Foundation
J.FRED BUCY, President, Texas Instruments, Inc.
ALAN M.CAMPBELL, Executive Secretary, U.S.-U.S.S.R. Committee on Cooperation in Physics, Office of International Affairs, National Academy of Sciences
ROSEMARY CHALK, Program Head for Scientific Freedom and Responsibility, American Association for the Advancement of Science
JOHN C.CROWLEY, Director, Federal Relations for Science and Research, Association of American Universities
EDWARD E.DAVID, JR., President, Exxon Research and Engineering Company
CAROLE A.GANZ, International Science Analyst, National Science Foundation
RICHARD L.GARWIN, IBM Fellow, T.J.Watson Research Center, IBM Corporation
S.E.GOODMAN, Professor, Department of Information Systems and Decision Sciences, University of Arizona
RUTH GREENSTEIN, Associate General Counsel, Policy, National Science Foundation
WILLIAM C.HITTINGER, Executive Vice President, RCA Corporation
JEANNE E.HUDSON, Special Assistant, Office of the Director, National Science Foundation
JOHN W.KISER III, Kiser Research, Inc.
RICHARD KRASNOW, Congressional Science Fellow
LAWRENCE C.MITCHELL, Staff Director, Office of International Affairs, National Academy of Sciences
MARTIN E.PACKARD, Assistant to the Board Chairman, Varian Associates
THOMAS O.PAINE, Thomas Paine Associates
HAROLD RELYEA, Analyst, Government Division, Congressional Research Service
LEONARD M.RIESER, Chairperson, Committee on Scientific Freedom and Responsibility, American Association for the Advancement of Science
IAN M.ROSS, President, Bell Laboratories
ROBERT D.SCHMIDT, Vice Chairman of the Board, Control Data Corporation
ROLAND W.SCHMITT, Vice President, Corporate Research and Development, General Electric Company
MICHAEL A.STROSCIO, Special Assistant to the Director of Research and Technical Information, Office of the Under Secretary of Defense for Research and Engineering, Department of Defense
Liaison Representatives
American Academy of Arts and Sciences
HERMAN FESHBACH, Professor, Department of Physics, Massachusetts Institute of Technology
American Association for the Advancement of Science
J.THOMAS RATCHFORD, Associate Executive Officer, American Association for the Advancement of Science
American Chemical Society
RAYMOND P.MARIELLA, Executive Director, American Chemical Society
American Geophysical Union
FRED SPILHAUS, Executive Director, American Geophysical Union
American Physical Society
MELVIN B.GOTTLIEB, Science and Public Policy Fellow, The Brookings Institution
THOMAS A.BARTLETT, President, Association of American Universities
Association of American Universities-Department of Defense Forum
DAVID A.WILSON, President’s Executive Assistant, University of California
Department of Commerce
BOHDAN DENYSYK, Deputy Assistant Secretary, Export Administration, Department of Commerce
Department of Defense
STEPHEN D.BRYEN, Deputy Assistant Secretary, International Economic, Trade and Security Policy, Department of Defense
FRANCIS B.KAPPER, Director, Military Technology Sharing, International Programs and Technology, Office of the Under Secretary of Defense for Research and Engineering, Department of Defense
LEO YOUNG, Director for Research and Technical Information, Office of the Under Secretary of Defense for Research and Engineering, Department of Defense
Department of State
MICHAEL B.MARKS, Special Assistant to the Under Secretary, Office of the Under Secretary for Security Assistance, Science and Technology, Department of State
Intelligence Community
JAN P.HERRING, Chairman, Technology Transfer Intelligence Committee
National Aeronautics and Space Administration
BURTON I.EDELSON, Associate Administrator for Space Science and Applications, NASA
JACK KERREBROCK, Associate Administrator for Office of Aeronautics and Space Technology, NASA
National Science Foundation
DONALD N.LANGENBERG, Deputy Director, National Science Foundation
EDWARD MCGAFFIGAN, Assistant Director for International Affairs, Office of Science and Technology Policy
The Institute of Electrical and Electronics Engineers, Inc.
ROBERT P.BRISKMAN, Assistant Vice President, COMSAT General Corporation
The Panel held three two-day meetings in Washington at which it was briefed by representatives of the departments of Defense, State, and Commerce, and by representatives of the intelligence community, including the Central Intelligence Agency, the Federal Bureau of Investigation, the Defense Intelligence Agency, and the National Security Agency. The Panel also heard presentations by members of the research community and by university representatives. In addition to these briefings, the Rand Corporation prepared an independent analysis of the transfer of sensitive technology from the United States to the Soviet Union.4 To determine the views of scientists and administrators at major research universities, the Panel asked a group of faculty members and administrative officials at Cornell University to prepare a paper incorporating their own views and those of counterparts at other universities (see Working Papers). The Panel also requested and received letters from a group of executives from high-technology industries expressing their views (see Appendix C). The Panel commissioned papers by experts in various aspects of technology transfer and studied the published material on the subject. It examined a few specific scientific areas in some detail.
In order to determine how and where controls might further the national welfare, it is necessary to balance many factors, including the military advantage from controls, their impact on the ability of the research process to serve military, commercial and basic cultural goals, and their effects on the education of students in science and technology. The Panel hopes that this report serves to identify these important issues and to set out recommendations that achieve an appropriate balance.
The Panel is grateful for the assistance provided by the departments of Defense, State, and Commerce, and by the various intelligence agencies. Without their generous help, our task would have been impossible. The liaison representatives of the various departments, agencies, and organizations also contributed to our effort, and we thank them as well. We are also appreciative of the work of the Cornell University committee, which was headed by W.Donald Cooke. We wish to express special thanks to Frank Press, President of the National Academy of Sciences; Courtland Perkins, President of the National Academy of Engineering; and Philip M.Smith, Executive Officer of the National Academy of Sciences for their help and support. I wish to extend my personal thanks to Lawrence McCray, project director, Mitchel Wallerstein, staff consultant, and to Elizabeth Panos, administrative assistant, for their staff support. We are also grateful to Barbara Darr and Allan Hoffman of the COSEPUP staff. Finally, I wish to express my thanks to the individual members of the Panel for their dedicated service in making an early report possible.
Dale R.Corson
Chairman
_______________
Notes:
1. The Panel has concerned itself with scientific communication flowing from a range of research activities embracing basic and applied research and extending over a series of institutions, including universities, industrial laboratories, and government laboratories. A major share of the Panel’s attention has been devoted to university research where no restraints on dissemination of findings—such as restraints to preserve proprietary interests, for example—have existed.
2. The Panel has concentrated its effort primarily on the U.S.-U.S.S.R. relationship, given the level of concern about that problem and the limited time and resources available.
3. The NAS contribution was drawn from funds used for Academy-initiated projects; the funds were provided by the NAS consortium of private foundations. The consortium comprises the Carnegie Corporation of New York, the Charles E.Culpeper Foundation, the William and Flora Hewlett Foundation, the John D. and Catherine T.MacArthur Foundation, the Andrew W.Mellon Foundation, and the Rockefeller Foundation.
4. This paper, among others, is included in the collected working papers used by the Panel. A photocopy is available from the National Academy Press, 2101 Constitution Avenue, N.W., Washington, D.C. 20418.
have been applied recently by Relman7 to lab-created PPPs. The criteria as described by Relman are:
“[Four] criteria to define research for which communication ought to be limited (all of which must be met): (1) research with dual use or military applications, (2) research with a short time to such applications, (3) research when dissemination could give short-term advantage to adversaries, and (4) research when the information was believed not to be already held by adversaries.”
“Inconvenient Truths” in the Pursuit of Scientific Knowledge and Public Health
by David A. Relman
The Journal of Infectious Diseases, Volume 209, Issue 2, 15 January 2014, Pages 170–172, https://doi.org/10.1093/infdis/jit529
Published: 07 October 2013
(See the major article by Barash and Arnon on pages 183–91and Dover et al on pages 192–202,and the editorial commentaries by Popoff on pages 168–9and Hooper and Hirsch on page 167.)
In this issue of The Journal of Infectious Diseases, a group of scientists and physicians from a state public health laboratory present a discovery with important scientific, public health, and security implications, and a difficult dilemma [1, 2]. Their identification of a novel, eighth botulinum neurotoxin (BoNT) from a patient with botulism expands our understanding of Clostridium botulinum and BoNT diversity, C. botulinum evolution, and the pathogenesis of botulism, but it also reveals a significant public health vulnerability. This new toxin, BoNT/H, cannot be neutralized by any of the currently available antibotulinum antisera, which means that we have no effective treatment for this form of botulism. Until anti-BoNT/H antitoxin can be created, shown to be effective, and deployed, both the strain itself and the sequence of this toxin (with which recombinant protein can be easily made) pose serious risks to public health because of the unusually severe, widespread harm that could result from misuse of either [3]. Thus, the dilemma faced by these authors, and by society, revolves around the question, should all of the information from this and similar studies be fully disseminated, motivated by the desire to realize all possible benefits from the discovery, or should dissemination of some or all of the information be restricted, with the goal of diminishing the probability of misuse?
In the early 1980s, Dale Corson, who was president emeritus of Cornell University, led a now-famous study at the US National Academy of Science that culminated in a report entitled Scientific Communication and National Security [4]. The committee explored the growing tension between the principle of openness in science and consequent concerns about national security, which assumed prominence in US public discourse with the development of the atomic bomb and then served as the basis for vigorous debate at the time of their study during the height of the cold war. The report is remembered for having drawn a sharp, “bright” line between scientific information whose communication deserves strict control, that is, national security classification, and information that should be freely disseminated. The committee recommended a long-term national strategy of “security by accomplishment,” to be achieved through a vigorous and open research enterprise. It reminded readers about the “inherent limits on the feasibility and effectiveness of controls,” especially when pursued in the domain of basic scientific research. The persuasive arguments of the Corson committee about a bright line shaped national policy and were cited in President Reagan's National Security Decision Directive 189, which declared in 1985 that “to the maximum extent possible, the products of fundamental research remain unrestricted …[W]here the national security requires control, the mechanism for control of information generated during federally-funded fundamental research … is classification.” [5] This policy has been reaffirmed by subsequent presidential administrations.
What is less well appreciated is that the Corson report also discussed “a small ‘gray area’ of research activities for which limited restrictions short of classification are appropriate” [4]. The Corson committee offered 4 criteria to define research for which communication ought to be limited (all of which must be met): (1) research with dual use or military applications, (2) research with a short time to such applications, (3) research when dissemination could give short-term advantage to adversaries, and (4) research when the information was believed not to be already held by adversaries. They then suggested that classification was not appropriate in all such circumstances, and that there might be other mechanisms of control. As an alternative mechanism, the committee recommended a form of voluntary prepublication control exercised by the investigator. Of interest, given recent political debates, they cited a successful early experiment in voluntary prepublication control for manuscripts dealing with cryptography, involving academia and the National Security Agency.
The Corson “gray area” was largely ignored in subsequent years, in part because there were few concrete and compelling examples of work that might fit in this category and, in part, because the practical aspects of a nonclassification information control mechanism were, and remain, profoundly challenging. Yet, the ongoing revolution in the life sciences now forces us to confront an uncomfortable reality: The same process by which we gain further understanding of biology, invent powerful methods for reengineering genomes and organisms, and derive critical solutions to the problems that ail us and our planet is a path that will predictably generate new and increasingly substantial risks [6]. An important case study in 2012 involved the deliberate engineering of highly pathogenic avian influenza viruses with enhanced properties of transmissibility [7, 8]. The scientific outcome was easily anticipated as it was the stated and intended goal of the investigators, but the risks of the proposed experiments were not widely discussed ahead of time, nor were alternative scientific approaches or risk mitigation strategies. When the National Science Advisory Board for Biosecurity, of which I am a member, initially recommended to the US government, after careful assessment of the risks and benefits, that some of these scientific results not be widely disseminated, the absence of a mechanism, other than classification, for limited distribution of the information confounded policy makers. The need for such a mechanism now deserves renewed serious deliberation and wider discussion, because we are inadequately served by just 2 options, that is, unrestricted dissemination and classification. Some information from life sciences research has an unusually high likelihood of immediately enabling irresponsible or malevolent persons to do grave harm to society, and deserves some control. Yet, classification may not be appropriate, because the burdens of working within the classified environment might hinder needed countermeasure work, or the criteria for national security classification might not be met, such as in the current case where the information is not owned by, produced by or for, or under the control of the US government [9]. A mechanism for short-term, limited distribution is needed while risk mitigation measures are devised (eg, therapies and vaccines), even though the control of distribution will be far from perfect.
The 2 articles in this issue of JID [1, 2] highlight an important alternative mechanism for management of risk in life sciences research, albeit an imperfect one, and take us back to 1982, to Dale Corson and colleagues. The authors of these articles, believing that the sequence information of BoNT/H poses an immediate and unusually serious risk to society, and that the information was unlikely to be already in the hands of those who would seek to do harm, decided to exercise voluntary prepublication control and to withhold this specific information. The more general and less risky aspects of the information were submitted for publication to alert the public to the discovery. This investigator-initiated strategy has merit and deserves careful consideration, but some major caveats should be noted. First, this strategy offers only short-term benefits, as data generated in today's highly interconnected world will inevitably become disseminated. (Corson's “inherent limits on the effectiveness of controls” are even more apparent today.) Given current capabilities in gene synthesis and expression, possession of the sequence is tantamount to possession of the toxin. Therefore, for this strategy to make sense, every effort should be made to exploit this temporary benefit, and to promote immediate, rapid development of an effective countermeasure, that is, anti-BoNT/H antisera. In fact, studies to inform countermeasure development are well under way. Second, this approach poses significant danger to the research enterprise in general if decisions to adopt this approach are made casually, arbitrarily, or frequently. However, I agree with the actions of the authors in this specific case. Although government officials may have participated in a discussion about these papers, to my knowledge relevant stakeholders outside the government were not involved. Going forward, decisions should be based on the best available guidance from experts representing broad, diverse constituencies, including nonscientist representatives of the public, and should be made in a transparent manner.
As more powerful techniques are used to explore the natural world [1, 2] and generate novel biological diversity [7], benefits and risks will both multiply and magnify. And the “gray area” will expand. Voluntary controls may have worked reasonably well for the field of cryptography in the early 1980s because, as the Corson committee remarked, the field was relatively small, its dual use features were obvious, and at the same time, the National Security Agency had high technical competence and an interest in promoting open science. Today's world of the life sciences is much more challenging and consequential.
The life sciences encompass a large number of disciplines and practitioners around the globe, with disparate purposes. Therefore, more expansive, balanced, and dispassionate discussion will be needed, and it must include difficult questions, such as whether there are experiments that should not be undertaken because of disproportionately high risk. In addition, as suggested by Corson et al., we need to make controls more workable, improve the factual basis for decisions on whether and when to exercise such controls, and improve mutual understanding between the government and the scientific community. Finally, for voluntary controls to play a useful role in the management of problematic information in the “gray area,” scientists will first need to recognize their ethical and moral responsibilities to society in the pursuit of knowledge [10]. Scientists have obligations to society that involve more than blind pursuit of information. Like clinicians, scientists have an obligation to do no harm.
Notes
Financial support. This work was supported by the National Institutes of Health (DP1OD000964, R01AI092531, R01GM099534, R01DE023113, U54AI065359), the Doris Duke Charitable Trust, the March of Dimes Foundation, and the Thomas C. and Joan M. Merigan Endowment at Stanford University.
Potential conflicts of interest.
The author is on the board of Seres Health and Novartis Vaccines, and is a consultant for Proctor & Gamble.
The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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For some matHPAIs, the dual use concern is now moot, as details needed for airborne transmission in mammals have already been published.
The recent publication providing the details of the de novo creation of horsepox virus is of great concern, as the methods could be used to resurrect the smallpox virus. Smallpox ravaged the world until it was eliminated in 1980. As Koblentz has pointed out8: “The synthesis of horsepox virus takes the world one step closer to the reemergence of smallpox as a threat to global health security.” The international community must do whatever is possible to prevent the reemergence of smallpox.
The De Novo Synthesis of Horsepox Virus: Implications for Biosecurity and Recommendations for Preventing the Reemergence of Smallpox
by Gregory D. Koblentz
Published Online:1 Dec 2017
https://doi.org/10.1089/hs.2017.0061
Abstract
In March 2017, the American biotech company Tonix announced that a Canadian scientist had synthesized horsepox virus as part of a project to develop a safer vaccine against smallpox. The first de novo synthesis of an orthopoxvirus, a closely related group of viruses that includes horsepox and the variola virus that causes smallpox, crosses an important Rubicon in the field of biosecurity. The synthesis of horsepox virus takes the world one step closer to the reemergence of smallpox as a threat to global health security. That threat has been held at bay for the past 40 years by the extreme difficulty of obtaining variola virus and the availability of effective medical countermeasures. The techniques demonstrated by the synthesis of horsepox have the potential to erase both of these barriers. The primary risk posed by this research is that it will open the door to the routine and widespread synthesis of other orthopoxviruses, such as vaccinia, for use in research, public health, and medicine. The normalization and globalization of orthopoxvirus synthesis for these beneficial applications will create a cadre of laboratories and scientists that will also have the capability and expertise to create infectious variola virus from synthetic DNA. Unless the safeguards against the synthesis of variola virus are strengthened, the capability to reintroduce smallpox into the human population will be globally distributed and either loosely or completely unregulated, providing the foundation for a disgruntled or radicalized scientist, sophisticated terrorist group, unscrupulous company, or rogue state to recreate one of humanity's most feared microbial enemies. The reemergence of smallpox—because of a laboratory accident or an intentional release—would be a global health disaster. International organizations, national governments, the DNA synthesis industry, and the synthetic biology community all have a role to play in devising new approaches to preventing the reemergence of smallpox.
(2) Could a release from the laboratory into the community seed a pandemic?
A calculation9 of the probability of release from a single lab in the Research Enterprise in a single year was found to be 0.20%. For ten labs in the Research Enterprise carrying out research for ten years, the probability of release from one of the labs is about 10 x 10 x 0.20% = 20%, an uncomfortably high number.
Lipsitch10 and Merler11 estimate the probability of a pandemic from a laboratory release ranges from 5% to 50%. Using an intermediate value in that range, 25% or 0.25, the probability of a pandemic in ten years from the Research Enterprise is the probability of release times the probability that a release leads to a pandemic, which is 0.25 x 20% x 0.25 = 5%. The likelihood of a natural pandemic in the next ten years is about 31% 12. Therefore, concern over a pandemic from a Research Enterprise laboratory release should rival our grave concern over a natural pandemic.
