Presented by the Emerging Infectious Diseases & Microbiology Discussion Group of the New York Academy of Sciences
Dual Use Research
Posted February 24, 2012
In December of 2011 the U.S. National Science Advisory Board for Biosecurity (NSABB) took the unprecedented step of requesting that the top-tier journals Science and Nature remove certain methodological details and the identity of the key mutations from the results to be published of two H5N1 avian influenza virus studies. The Board took an interest in these particular studies, one conducted by Ron Fouchier's group at Rotterdam's Erasmus Medical Centre and the other by Yoshihiro Kawaoka's at the University of Wisconsin, because of the possibility that their methods could be used by would-be-bioterrorists to engineer a version of H5N1 capable of human-to-human transmission. Research that could potentially be used for both malicious and beneficial purposes is classified as "dual use" research, and, in the U.S., weighing the threat to national security or public health against the potential benefit of the research is the purview of the NSABB, a group convened by the Office of Biotechnology Activities of the National Institutes of Health. The two papers describe two genetically engineered mutant strains of the avian influenza virus H5N1. The described mutant viruses are easily capable of transmission in a ferret model, thus raising the threat of feasible and dangerous air-borne transmission in humans, some argue. Though human-to-human transmission is not yet reported, there is a high fatality rate for individuals hospitalized after acquiring the naturally occurring H5N1 virus directly from infected birds.
Nature and Science have agreed to consider the NSABB recommendation to redact the papers by omitting certain methodological details and specifics about producing the mutant H5N1 viruses if a mechanism can be put in place for distributing the unredacted versions to those who need the results for public-health intervention or for pursuing the science under safe conditions. On February 2, 2012 the New York Academy of Sciences convened key stakeholders, including representatives from Science, Nature, and the NSABB, along with key scientists in the field, for a lively and timely discussion of Dual Use Research: H5N1 Influenza Virus and Beyond.
Since the NSABB intervened, the conflict of academic freedom in influenza research versus the risk of an accidental or intentional outbreak has been thoroughly debated in the scientific community and among public health, biosecurity, and government representatives. In addition, the controversy has provoked discussion of the likelihood of the results' misuse, of the value of the unfettered exchange of scientific information, and of the probability of the virus's developing the capacity for human-to-human transmission even without the aid of artificial genetic manipulation. In response to the controversy, 39 flu researchers agreed to a voluntary 60-day moratorium on all related research, beginning in January. This period of time will hopefully allow stakeholders to reach a consensus over the current proceedings and to carve out the preliminaries of polices that will resolve similar disagreements in the future. The pause in research also gave 22 influenza and public health experts from around the world, meeting in Geneva on February 16 – 17 at the World Health Organization headquarters, an opportunity to discuss the studies and to make recommendations concerning dissemination of data and materials to researchers around the world.
Editors' note: Since this meeting, a majority of the experts meeting at the World Health Organization has recommended that the two papers should be published in full, though the timeline of publication is delayed while relevant parties determine the details of the process.
Use the tabs above to find a meeting report and to view video from this event.
Panel discussion featuring:
Moderator: W. Ian Lipkin, MD (Columbia University)
Panelists: Arturo Casadevall, MD, PhD (Albert Einstein College of Medicine; Member, NSABB)
Laurie Garrett, PhD (Council on Foreign Relations)
Barbara R. Jasny, PhD (Science)
Véronique Kiermer, PhD (Nature Publishing Group)
Michael T. Osterholm, PhD, MPH (University of Minnesota; Member, NSABB)
Peter Palese, PhD (Mount Sinai School of Medicine)
Vincent Racaniello, PhD (Columbia University)
Alan S. Rudolph, PhD (Defense Threat Reduction Agency)
- 00:011. Meeting introduction by Jennifer Henry
- 04:572. Ian Lipkin introduces the panel
- 13:433. What is the structure of the NSABB?
- 16:104. What triggers referral to the NSABB?
- 18:395. What is the process by which a dual use concern is addressed?
- 22:256. How is dual use research important for public health?
- 26:547. Estimating the true case fatality rate
- 37:478. What experiments should be identified as potentially dangerous?
- 46:209. What is the appropriate role for government in regulating science?
- 55:4010. What are the parameters under which dual use research should proceed?
- 57:2811. Procedures to ensure that dual use research is reviewed before experiments begi
- 00:011. Biotechnology Research in an Age of Terrorism
- 12:352. Sharing data/reagents only with preselected researchers
- 17:053. How many people already have key parts of the influenza manuscripts?
- 21:304. Is a 60-day moratorium on H5N1 research sufficient?
- 25:055. How dangerous is this type of research for public health?
- 33:066. The gap between research scientists and bioterrorism policy analysts
- 36:467. What is the value of redacted papers?
- 45:338. Is the redaction likely to be a one-time exception?
- 48:099. How will the participation of the WHO change the decision-making process?
- 51:1310. Was the NASBB recommendation helpful?
- 53:2811. What might have been done differently?
- 57:0612. Closing remarks by Ellis Rubinstein and Jennifer Henr
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Barbara R. Jasny
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Jasny BR, Zahn LM. Genome-sequencing anniversary. A celebration of the genome, part I. Science 2011;331(6017):546.
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W. Ian Lipkin
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Tokarz R, Kapoor V, Wu W, et al. Longitudinal molecular microbial analysis of influenza-like illness in New York City, May 2009 through May 2010. Virol. J. 2011;8:288.
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Michael T. Osterholm
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Varga ZT, Palese P. The influenza A virus protein PB1-F2: killing two birds with one stone? Virulence 2011;2(6):542-546.
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Racaniello VR. Science should be in the public domain. MBio 2012;3(1).
This Week in Virology (TWiV) is a podcast about viruses, begun in September 2008 by Vincent Racaniello and Dick Despommier. The goal of the podcast to have an informal yet informative conversation about viruses which would be accessible to everyone, no matter what their science background.
Alan S. Rudolph
Rudolph AS, Coughlin JR. Developing advanced toxicology technologies for biomonitoring in national security applications. J. Appl. Toxicol. 2004;24(5):315-316.
Keim PS. Q&A: Reasons for proposed redaction of flu paper. Nature 2012;482(7384):156-157.
Jennifer Henry, PhD
The New York Academy of Sciences
Jennifer Henry received her PhD in plant molecular biology from the University of Melbourne, Australia, with Paul Taylor at the University of Melbourne and Phil Larkin at CSIRO Plant Industry in Canberra, specializing in the genetic engineering of transgenic crops. She became the Editor of Functional Plant Biology at CSIRO Publishing, and then moved to New York for her appointment as Publishing Manager with Nature Publishing Group, where she was responsible for the publication of a range of biomedical journals. Jennifer Henry joined the Academy in 2009 as Director of Life Sciences, and is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology, under the auspices of the Academy's Frontiers of Science program. She also generates alliances with organizations interested in developing programmatic content.
W. Ian Lipkin, MD
W. Ian Lipkin, John Snow Professor of Epidemiology and Professor of Neurology and Pathology at Columbia University, is internationally recognized for the development and implementation of molecular methods for microbial surveillance and discovery. He directs the Center for Infection and Immunity, the World Health Organization Collaborating Centre on Diagnostics, Surveillance and Immunotherapeutics for Emerging Infectious and Zoonotic Diseases, and the Northeast Biodefense Center, and is co-chair of the National Biosurveillance Advisory Subcommittee. A graduate of Sarah Lawrence College, he obtained his MD at Rush Medical College, completed his Medicine Residency at the University of Washington and his Neurology Residency at the UCSF, and completed a Fellowship with Michael Oldstone at The Scripps Research Institute. His contributions include the first use of purely molecular methods to identify an infectious agent; implication of West Nile virus as the cause of the encephalitis outbreak in North America in 1999; invention of MassTag PCR and the first panmicrobial microarray; first use of deep sequencing in pathogen discovery; discovery or molecular characterization of more than 500 viruses including rhinovirus C, Dandenong, and LuJo; and establishment of the largest prospective birth cohort focused on pathogenesis and biomarker discovery. He served in Beijing as an intermediary between the WHO and the Chinese government during the SARS outbreak of 2003, and co-directed SARS research efforts in China with current Minister of Health Chen Zhu.
Arturo Casadevall, MD, PhD
Arturo Casadevall is the Leo and Julia Forchheimer Professor of Microbiology & Immunology at the Albert Einstein College of Medicine of Yeshiva University. He is Chairman of the Department of Microbiology and Immunology and served as Director of the Division of Infectious Diseases at the Montefiore Medical Center at the Albert Einstein College of Medicine from 2000–2006. Casadevall received both his MD and PhD (biochemistry) degrees from New York University. Subsequently, he completed internship and residency in internal medicine at Bellevue Hospital in New York City. Later he completed subspecialty training in Infectious Diseases at the Montefiore Medical Center and at Albert Einstein College of Medicine. Casadevall's major research interests are in fungal pathogenesis and the mechanism of antibody action. In the area of Biodefense, Casadevall has an active research program to understand the mechanisms of antibody-mediated neutralization of Bacillus anthracis toxins. Casadevall was elected to membership in the American Society for Clinical Investigation, the American Academy of Physicians, and the American Academy of Microbiology. He was elected a fellow of the American Academy for the Advancement of Science and has received numerous honors throughout his career. Casadevall is the Editor in Chief of mBio, the first open access general journal of the American Society of Microbiology. He serves in the editorial board of The Journal of Clinical Investigation, The Journal of Experimental Medicine, and The Journal of Infectious Diseases. Previously he served as Editor of Infection and Immunity. He has served on numerous NIH committees including those that drafted the NIAID Strategic Plan and the Blue Ribbon Panel on Biodefense Research. Casadevall served on the NAS committee that reviewed the science behind the FBI investigation of the anthrax attacks in 2001. He is currently a member of the National Science Advisory Board for Biosecurity and co-chaired the NIAID Board of Scientific counselors.
Laurie Garrett, PhD
Laurie Garrett is currently the Senior Fellow for Global Health at the Council on Foreign Relations in New York. Garrett is the only writer ever to have been awarded all three of the Big "Ps" of journalism: The Peabody, The Polk and The Pulitzer. Garrett is also the best-selling author of The Coming Plague: Newly Emerging Diseases in a World Out of Balance and Betrayal of Trust: The Collapse of Global Public Health. Her most recent book is I Heard the Sirens Scream: How Americans Responded to the 9/11 and Anthrax Attacks. During her time as Senior Fellow for Global Health at the Council on Foreign Relations, Garrett has written several reports and articles including: "HIV and National Security: Where are the Links?," A Council Report (Council on Foreign Relations Press, 2005); "The Next Pandemic?" (Foreign Affairs, July/August 2005); "The Lessons of HIV/AIDS" (Foreign Affairs, July/August 2005); and "The Challenge of Global Health" (Foreign Affairs, January/February 2007), "The Future of Foreign Assistance Amid Global Economic and Financial Crisis, A Council on Foreign Relations Action Plan" (2009); "Castrocare in Crisis" (Foreign Affairs, July/August 2010). Garrett is a member of the National Association of Science Writers, and served as the organization's President during the mid-1990s. Garrett also chairs the Scientific Advisory Panel to the United Nations High Level Commission on HIV Prevention in collaboration with UNAIDS. She is an expert on global health with a particular focus on newly emerging and re-emerging diseases, bioterrorism, public health and its effects on foreign policy and national security.
Barbara R. Jasny, PhD
Barbara Jasny serves as the Deputy Editor for Commentary for Science, the weekly journal of the American Association for the Advancement of Science (AAAS). In this position, she coordinates the activities of editors responsible for the Perspectives, Letters, Book Reviews and Policy Forums. She also solicits research papers and evaluates research reports for publication in genetics, medicine, and the social sciences. She has taken the lead in special issues on the genome project, AIDS, molecular medicine, network analysis, and science & society for the past 25 years. Jasny has a BA with honors in Biology from New York University and a PhD in Molecular Biology from Rockefeller University. She has conducted research in virus-host cell interactions, DNA replication, and cellular senescence. She is an elected fellow of the AAAS and has been an advisor to the American Society for Gene Therapy and the Functional Genomics Data Society. She is author of more than 60 research papers, editorials, and overviews, and has been involved in communicating science in books, articles, posters, virtual presentations, CDs, and podcasts.
Véronique Kiermer, PhD
Véronique Kiermer obtained her PhD in molecular biology from the Université Libre de Bruxelles, Belgium. She did postdoctoral work in the laboratory of Eric Verdin at the Gladstone Institute of Virology and Immunology, University of California, San Francisco, studying the transcriptional regulation of HIV. She then worked on gene therapy projects at the biotechnology company Cell Genesys before moving to Nature Publishing Group in 2004. At NPG, she was the founding Chief Editor of Nature Methods and subsequently took on publishing responsibility for the title and other online products. In October 2010, she became Executive Editor for Nature and the Nature journals, overseeing editorial policies, editorial quality assurance and Researcher Services.
Michael T. Osterholm, PhD, MPH
Michael Osterholm is director of the Center for Infectious Disease Research and Policy (CIDRAP), director of the NIH-supported Center of Excellence for Influenza Research and Surveillance within CIDRAP, and a professor in the Division of Environmental Health Sciences, School of Public Health. He is also a member of the Institute of Medicine (IOM) of the National Academy of Sciences and the Council of Foreign Relations. In June 2005 Osterholm was appointed to the newly established National Science Advisory Board on Biosecurity. In addition, from 2001 through early 2005, Osterholm served as a Special Advisor to then-HHS Secretary on issues related to bioterrorism and public health preparedness. He was also appointed to the Secretary's Advisory Council on Public Health Preparedness. In April, 2002, Osterholm was appointed to the interim management team to lead the Centers for Disease Control and Prevention (CDC). Previously, Osterholm served for 24 years (1975–1999) in various roles at the Minnesota Department of Health (MDH), the last 15 as state epidemiologist and chief of the Acute Disease Epidemiology Section. While at the MDH, Osterholm led numerous investigations of outbreaks of international importance, including foodborne diseases, the association of tampons and toxic shock syndrome (TSS), the transmission of hepatitis B in healthcare settings, and human immunodeficiency virus (HIV) infection in healthcare workers. Osterholm has been an international leader on the growing concern regarding our preparedness for an influenza pandemic and the use of biological agents as catastrophic weapons targeting civilian populations. He provides a comprehensive and pointed review of America's current state of preparedness for a bioterrorism attack in his New York Times best-selling book, Living Terrors: What America Needs to Know to Survive the Coming Bioterrorist Catastrophe. He serves on the editorial boards of nine journals, including Infection Control and Hospital Epidemiology and Microbial Drug Resistance: Mechanisms, Epidemiology and Disease.
Peter Palese, PhD
Peter Palese is Professor of Microbiology and Chair of the Department of Microbiology at the Mount Sinai School of Medicine in New York. His research includes work on the replication of RNA-containing viruses with a special emphasis on influenza viruses. Specifically, he established the first genetic maps for influenza A, B and C viruses, identified the function of several viral genes, and defined the mechanism of neuraminidase inhibitors (which are now FDA-approved antivirals). Palese also pioneered the field of reverse genetics for negative strand RNA viruses, which allows the introduction of site-specific mutations into the genomes of these viruses. This technique is crucial for the study of the structure/function relationships of viral genes, for investigation of viral pathogenicity and for development and manufacture of novel vaccines. His recent work in collaboration with Garcia-Sastre has revealed that most negative strand RNA viruses are able to counteract the interferon antiviral response of the infected host. Palese was elected to the National Academy of Sciences in 2000. At present he serves on the editorial board for the Proceedings of the National Academy of Sciences. He has been a Corresponding Member of the Austrian Academy of Sciences since 2002 and a Member of the German Academy of Sciences Leopoldina since 2006. Palese was president of the Harvey Society in 2004–2005 and president of the American Society for Virology in 2005–2006.
Vincent Racaniello, PhD
Vincent Racaniello is Higgins Professor of Microbiology and Immunology at the College of Physicians and Surgeons of Columbia University. He received an AB degree in Biology from Cornell University in 1974. In 1980, for work carried out with Peter Palese, he received the PhD in Biomedical Sciences from Mt. Sinai School of Medicine. After postdoctoral work with David Baltimore at the Massachusetts Institute of Technology, in 1982 he joined the College of Physicians and Surgeons as Assistant Professor of Microbiology. Racaniello is the recipient of an Irma T. Hirschl Career Scientist Award, the Searle Scholars Award, the Eli Lilly Award of the American Society for Microbiology, and an NIH Merit Award. Racaniello has served as an Editor for the Journal of Virology and the Journal of Clinical Investigation, and is currently an Associate Editor at PLoS Pathogens. He previously served as a member of the World Health Organization Steering Committee on Hepatitis/Polio, Chair of the Virology Study Section of the National Institutes of Health, and Co-Chair of the Gordon Conference on Viruses and Cells. He is a co-author of Principles of Virology, Third Edition (ASM Press), an established virology textbook, and blogs and podcasts about viruses at virology.ws. The research in Racaniello's laboratory has focussed on the mechanisms of poliovirus replication and pathogenesis. His research has produced the first infectious clone of an RNA virus, the discovery of the cell receptor for poliovirus, and the establishment of a transgenic mouse model for poliomyelitis. These contributions have revolutionized the study of animal RNA viruses.
Alan S. Rudolph, PhD
Alan S. Rudolph, a member of the Senior Service Executive, is the Director for the Joint Science & Technology Office (JSTO) for the Chemical and Biological Defense Program. Rudolph has led an active career in translating interdisciplinary life sciences into useful applications for biotechnology development. His experience spans basic research to advanced development in academia, government laboratories, and most recently in the non-profit and private sectors. He has published over 100 technical publications in areas including molecular biophysics, lipid self assembly, drug delivery, blood substitutes, medical imaging, tissue engineering, neuroscience and diagnostics. He has served in positions of leadership at the Naval Research Laboratory, Defense Advanced Research Projects Agency and Industry. As Chief Executive Officer of Adlyfe Inc., a diagnostic platform company, and Board Chairman of Cellphire Inc., Rudolph focused on development of novel hemostatic biologics for bleeding injuries. He has also started an international non-profit, connecting the United States and Brazil in biotechnology efforts and science education. He has a doctorate degree in Zoology from University of California at Davis and an MBA from George Washington University.
Anubhav Kaul is a fourth year medical student at Ross University, with a BA in Molecular Biology and Biochemistry from Boston University. His research experience ranges from prostate cancer immunotherapy to clinical studies in cardiology and nephrology, including public health research in chronic disease management and quality control of health care delivery. He plans to pursue a Masters in Public Health upon completion of medical school and subsequently pursue a residency in Internal Medicine.
W. Ian Lipkin, Columbia University
Arturo Casadevall, Albert Einstein College of Medicine; Member, NSABB
Laurie Garrett, Council on Foreign Relations
Barbara R. Jasny, Science
Véronique Kiermer, Nature Publishing Group
Michael T. Osterholm, University of Minnesota; Member, NSABB
Peter Palese, Mount Sinai School of Medicine
Vincent Racaniello, Columbia University
Alan S. Rudolph, Defense Threat Reduction Agency
- No formal mechanisms currently exist by which journals can share potentially harmful research with advisory or regulatory groups.
- A special working group of the National Science Advisory Board for Biosecurity unanimously voted to recommend the exclusion of key methodological details from the published H5N1 studies.
- Experts differ on the case fatality rate of wild type H5N1, but most agree the virus would be devastating if it spread from human to human.
- Panelists debated the merits of ferret models of airborne virus transmission, the value of seroprevalence tests versus hospital diagnoses in determinations of infection rate, and the problems of using natural virus transmission to predict how leaked mutant viruses might behave.
Provoking conversation: The role of the NSABB
The discussion, moderated by Ian Lipkin, a world-renowned pathogen scientist from Columbia University, began with an explanation of the role of the NSABB in this particular controversy and more generally. In particular, panelists discussed how these studies came to the Board's notice. As Arturo Casadevall, a member of the NSABB and a researcher at Albert Einstein College of Medicine, described the organization, since 2005 it has been an advisory board mainly of scientists who report their findings to the federal government. The committee is responsible for biosecurity oversight in "dual use" research, defined by the NSABB as "biological research with legitimate scientific purpose that may be misused to pose a biologic threat to public health or national security." Barbara Jasny, an editor at Science, recalled that the journal's review team held an internal biosecurity evaluation because they were aware of the implications Fouchier's paper presented. However, like any other scientific journal, they do not have any mechanism in place to refer their concerns directly to the NSABB. In fact, it was the staffers at the National Institutes of Health (NIH)—the organization responsible for funding this research—who officially brought the paper to the NSABB's attention.
When asked to explain the process of evaluation, Michael Osterholm, another panel member from the NSABB and a professor at the University of Minnesota, clarified that there is no formal protocol because the NSABB does not have a significant history in dealing with these kinds of cases, in which the research is ready for publication. Generally, the Board prefers to evaluate research at a much earlier stage. Despite the lack of protocol, the NSABB formed a working group to discuss the manuscripts with input from infectious disease experts, the editors of the two journals involved, and the authors of the studies. After their deliberations all 23 members of the NSABB decided to recommend the exclusion of procedural details and of the identities of the specific mutations from the two papers in an effort to prevent the replication of the results (a more contagious virus) by anyone intending harm. Osterholm emphasized that the NSABB does not see itself as a final arbitrator in such issues. Instead, it aims to play an advisory role in the initial stages of discussion, prompting an international dialogue that they hope will give rise to a framework that prioritizes public safety. He firmly stated that the ideal approach should tackle the conflicts earlier on in the process and not when the research has already been done and the manuscript is ready for publication. Osterholm recognized that this process has been a learning experience for NSABB, one that will shape future research evaluation strategies.
The roots of concern: How deadly is H5N1?
The NSABB's and others' concern about publishing these studies' complete methods is not just a generic hesitation about work that makes a virus more contagious. Their objection is particularly fervent—strong enough to motivate recommending redaction—because of the belief that a more contagious H5N1 poses an unusually deadly threat. The debate over case fatality rate for H5N1 stirred contrasting arguments from Michael Osterholm and Peter Palese, from Mt. Sinai School of Medicine. A case fatality rate reflects the percentage of people formally diagnosed with a disease who die of that disease in a given time period. Palese disagreed with the World Health Organization (WHO) data, which list 583 confirmed cases with 344 deaths since 2003, a case fatality rate over 59%. He pointed out that those data only consider hospital cases and do not count any asymptomatic H5N1 individuals. Since individuals are often only brought into hospitals for treatment when their condition becomes more serious, counting only hospital diagnoses can drastically inflate death rates. Based on 10 seroprevalence studies Palese cited in a recent Proceedings of the National Academy of Sciences article, the estimated infection rates ranged from 0.2%–5.6%. Palese argued that seroprevalence studies, which test for the presence of antibodies to virus antigens, better track asymptomatic or minimally symptomatic cases than do hospital numbers. Results from these studies would dramatically reduce the publicized WHO case fatality data if taken into account. Michael Osterholm countered by claiming that the studies Palese cited do not meet the WHO's criteria of H5N1 serology and that they overestimate the number of seropositive subjects. Osterholm suggested that even if the virus is 20 times less virulent than current WHO estimates indicate, the virus would still be more destructive than the 1918 pandemic flu virus if it could spread from human to human. Arturo Casadevall agreed with Osterholm's pandemic scenario but also stressed that we must be careful in using seroprevalence data of a naturally occurring virus to predict the course of an artificially engineered virus. The latter could have far more unpredictable consequences if it leaks out to the environment and mutates spontaneously.
Realizing that there wouldn't be consensus on the validity of the WHO's mortality data and on the specifics of the H5N1 serology assays, Ian Lipkin steered the debate towards a general conversation about "dual use" research and its importance. Barbara Jasny acknowledged the harmful implications of such research, but stipulated that the value of understanding the transferability of H5N1, of analyzing virulence characteristics, and of developing therapeutic strategies in advance of a possible epidemic are benefits that must be weighed along with the risks of "dual use" research.
In addition to assessing the virus's virulence in humans, researchers seeking a measure of the risk posed by the engineered H5N1 must find a reliable predictor of its ability to pass from human to human. The suitability of ferrets—Fouchier's and Kawaoka's chosen subjects—as a model to assess mammalian transmission of the mutant H5N1 virus was also a significant point of discussion. Vincent Racaniello, a virologist from Columbia University, warned the audience that an animal model should be considered hypothetically and not as an exact standard for accurately predicting what will transpire in humans. Peter Palese echoed these beliefs, adding that the ferret model is much too sensitive to model human-to-human transmission and inconclusive results are being used improperly to shut down further scientific investigation that may provide critical insight on the genetic characteristics of influenza. Laurie Garrett, Senior Fellow for Global Health at the Council on Foreign Relations, questioned why these experiments were done on ferret models to begin with if the animals have little value for predicting virulence in humans. By contrast, Arturo Casadevall and Michael Osterholm affirmed that many flu experts from around the world, in their discussions with the NSABB, agreed that the ferret model was a suitable predictor of transmission in humans. Accordingly, these experts advised the NSABB to treat the studies' findings as a serious concern.
Managing method: The proper place of government oversight?
But should the government be the authority on the choice of a particular animal model or a specific method for "dual use" research? What, indeed, is the role of government regulation in such research? Laurie Garrett opined that the task of government is to defend the public from potential danger, and it should promote this type of influenza research if the threat is a natural pandemic. However, according to Garrett, there is a complicating factor in this situation because of the perceived threat of bioterrorism and potential accidents. In such cases, she said, the government has the responsibility to step in and regulate the activities for the sake of public safety. Thus, the definition of threat determines the extent of regulation, which is very difficult to impose on an international level, even more so than on a national level. Garrett conceded that there is little consensus on the role of international governing bodies, and the WHO's controversial international agreement to share influenza strains between countries, for the purpose of promoting research and outbreak preparedness, falls short in compelling developed countries to provide specific benefits (e.g., vaccine donations) to developing countries.
Alan Rudolph of the Defense Threat Reduction Agency provided assurance of progress made by the U.S. government in their efforts to prompt the representatives to global governing bodies to reach agreement on international policies regarding biosecurity. Michael Osterholm suggested that the level of regulation should be proportional to the level of risk, and the NSABB followed this principal during their considerations. Arturo Casadevall added that all research is "dual use" research, meaning that all research has the potential to be harmful in some way, but the NSABB has specified a distinct category called "dual use research of concern" to identify work that warrants careful review and deliberation. The current mutant influenza studies in question, fall under the category of "dual use research of concern" according to the NSABB. Rudolph explained that the NSABB has advised the government on "dual use" research and has helped increase the awareness of risks involved, which will shape policies to come. He also asserted that the agencies and institutions that sponsor the research should play a part in regulating activities.
Putting the H5N1 research in the context of the handling of other (potentially) pandemic viruses, the panelists compared the mutant H5N1 virus to the smallpox virus. Osterholm proclaimed that a smallpox virus leak, which is housed under strict bio-safety level 4 (BSL-4) conditions, would not concern him as much as a leak of influenza would. His fear of smallpox is diminished because there is a proven vaccine and an outbreak can be effectively managed. Casadevall, in support of his colleague, added that smallpox has a longer incubation time, which helps in controlling rapid transmission. Palese strongly disagreed with Osterholm on the seriousness of influenza transmission, stating that H5N1 has been attenuated over the decades, has not been definitively proven to transmit between humans, will not prove to be harmful to humans unless they are exposed to large doses, and is far less dangerous than smallpox.
W. Ian Lipkin, Columbia University
Arturo Casadevall, Albert Einstein College of Medicine; Member, NSABB
Laurie Garrett, Council on Foreign Relations
Barbara R. Jasny, Science
Véronique Kiermer, Nature Publishing Group
Michael T. Osterholm, University of Minnesota; Member, NSABB
Peter Palese, Mount Sinai School of Medicine
Vincent Racaniello, Columbia University
Alan S. Rudolph, Defense Threat Reduction Agency
- Some argued that restricting the flow of scientific information could leave us more vulnerable to a natural or artificial pandemic virus.
- The place of regulation domestically and internationally is uncertain, but clearly more oversight is needed to secure information and material from dual use research.
- Overregulation needs to be avoided, and some scientists fear that redaction will become an institutionalized response to dual use research.
- Restricting information could prevent key studies from being reproduced by other labs—an important part of scientific validation.
Where to from here? Options for dealing with "dual use" research
One alternative to direct government enforcement is the possibility of self-regulation by scientists. Laurie Garrett described the 2004 National Academy of Sciences (NAS) publication Biotechnology Research in the Age of Terrorism, which looks at "dual use" research issues and provides recommendations to regulate the misuse of scientific knowledge. Highlighting the need for greater standardization, Garrett mentioned that the General Accountability Office (GAO), which evaluates high containment biosafety labs (BSL) around the United States, reported increased proliferation of such facilities and questionable adherence to security standards for BSL-3 or BSL-4 labs, those with the highest security ratings. To enable better self-regulation, the NAS report presents seven guidelines to identify microbial experiments of high risk, specifically those which: 1) demonstrate how to render a vaccine ineffective; 2) confer resistance to therapeutically useful antibiotics or antiviral agents; 3) enhance the virulence of a pathogen or render a nonpathogen virulent; 4) increase transmissibility of a pathogen; 5) alter the host range of a pathogen; 6) enable the evasion of diagnostic/detection modalities; 7) enable the weaponization of a biological agent or toxin. Garrett asserted the H5N1 experiments conform to certain guidelines above and pose more potential harm than benefit.
Barbara Jasny indicated that the report recommends a combination of self-governance by scientists and elaboration of existing regulations. She further clarified that the aim of such oversight is to trigger an early review of questionable research by an institutional biosafety committee and to have an international body harmonizing the efforts all over the world. Garrett voiced her concern that much progress needs to be made to empower institutional committees to regulate research activities in a timely and effective manner. Moreover, despite the national setbacks, it is far more difficult to have an international system of regulation since the governing structure is non-existent. Auturo Casadevall cautioned the audience about over regulation in science, especially in clinical research. Excessive regulation, he claimed, hinders progress and discourages researchers. He lamented that Institutional Review Boards' (IRBs') stringent protocols create an unfortunate conflict between overregulation versus academic freedom. He does not want the system to move towards that form of cumbersome regulation.
Restricting the flow of information
In this case, since the research has already been conducted, questions of method are largely moot. The debate now rests on the appropriate response to this and similar research. Weighing the potential danger against what they see as the compelling scientific and public interest in learning all we can about H5N1, the journals proposed sharing the methods with specific influenza researchers. Ian Lipkin questioned the effectiveness of sharing data with pre-selected researchers, given the serendipitous nature of science. Véronique Kiermer, executive editor of Nature, admitted that allowing only select researchers to access the scientific data will limit collaboration, which is vital to the scientific community. She also agreed that it will be challenging to determine a fair screening process to select researchers with whom the work can be shared. Interestingly, according to Jasny, the number of people who already have knowledge of key parts of the manuscript could be as many as 1000. Restriction of information that has the potential for public harm is critical, according to Osterholm, and such restriction should be proportional to the risk involved. Racaniello disagreed and said that the research community often inaccurately predicts both the risks and rewards of research programs. He raised the example of the accidental discovery of E. coli restriction enzymes, which ultimately revolutionized the field of biotechnology. This example and others show, according to Racaniello, how difficult it is to predict the authors of key experiments, and limiting information exchange could reduce the possibility of such fortuitous experiments occurring.
On the issue of the containment of material from these experiments, Osterholm agreed that lab leaks do not happen often, but passionately supported the placement of the mutant H5N1 virus in a BSL-4 setting, in case the virus is found to be transmissible among humans. Palese countered the suggestion, adamantly declaring since in his view the current experiments do not conclusively prove H5N1 transmission in humans, the scientific community cannot live in fear. Shifting the focus from scientists, Laurie Garrett reminded the panel that it is important to include the public as a stakeholder in this debate and the WHO must avoid an agreement solely based on the perspective of scientists. The public has a stake in the containment not just of information about the studies but also of the wild type and mutant viruses themselves. She felt that there is underrepresentation of those outside the research community.
Looking to the future
Based on the NSABB's recommendation, Nature and Science have agreed to consider redacting the papers in question. Panelists were eager to discuss the merits—and the future—of this response. Kiermer believes that the H5N1 studies are still worth publishing, even without the complete methods, because the overall purpose of the papers holds value, and the involved scientists deserve credit for their work. She stated that it is important to have a proper mechanism in place that will provide necessary details to the right people, but those specifications have not been established as yet, and hopefully the moratorium on research and the delayed publication will allow for stakeholders to come to a conclusion about how to protect the public without sacrificing scientific collaboration. Barbara Jasny expressed her hope that if redaction occurred, it would be a unique event, not a sign of practices to come. She emphasized the importance of validating scientific research by the reproducibility of the work's results. Reproducibility, which relies on the scientist-to-scientist exchange of information, is a fundamental principle that should be protected, she explained. Moreover, Jasny appreciated the fact that the authors have understood the implications of their work and have chosen to work with the system, rather than to publish the full content elsewhere. Racaniello, on the other hand, expressed his disapproval of the redaction response: once a precedent has been set, he claimed, it is easily repeatable. Casadevall reassured the audience that no one wants to see redaction, but in this case it could be a temporary measure that limits a potential danger while a consensus can be reached. Garrett expressed that the WHO is in a very difficult position right now in deciding who should have access to virus strains, and the group will have to face some tough decisions ahead. Beyond the issues already discussed by the panel, Garrett brought the audience's attention to the general distrust among developing countries of Western drug companies that have made large profits on vaccines. The vaccines have been developed from isolates discovered in countries who feel they have been exploited for profit because, frequently, neither the vaccines nor the profits return to the poorer nations where the viruses were harvested. The WHO will be dealing with a politically charged climate once stakeholders reconvene in Geneva to further discuss the fate of "dual use" research in general and of mutant H5N1 studies in particular.
The panel discussion ended with a conversation about what could have been done differently to make this situation less politically charged, to render the journals', scientists', governments', and public's response to the research less crisis-driven. Palese and Racaniello concurred that the whole process started out on the wrong foot. Although the authors'—Fouchier's and and Kawaoka's—decision to publish their work through normal channels was admirable, Racaniello criticized Fouchier's characterization of the work. Fouchier's description in his initial interview in Science was "inflammatory," and probably made things worse, according to Racaniello. Silence, however, would not have been the best alternative, Garrett qualified. Kawaoka has added to the uncertainty of the situation by declining to discuss the work until recently, she claimed. Ultimately, much of the crisis could have been allayed by genuine, open, and early discussion among stakeholders from every sector, including the public, Jasny articulated. These conversations, she explained, could have continued from the founding of the NSABB in 2005, and would have, at that time, laid the groundwork for a separate body to evaluate dual use research before it was even funded. Open discussion is a crucial part of achieving understanding and reducing fear of the work and its many implications.