The federal government generally supports the open publication of unclassified, federally funded research results. It does so because wide dissemination may drive innovation, job creation, technology development, and the advance of science. Many federal grants and contracts supporting scientific research urge the publication of research results. Only in cases where security concerns rise to the level of classification does the federal government bar publication of fundamental research. This current federal policy, established in National Security Decision Directive 189, is that fundamental research results should be widely available, and that in the rare case where it is necessary to restrict access, classification is the appropriate mechanism. Advances in technology that have lowered technical barriers in modern biological sciences, making it easier for people, including potential adversaries, to reproduce biological experiments raise questions whether the use of classification as the standard for determining the tradeoff between dissemination and security. Recent events regarding influenza research serve as a case study of the challenges the federal government faces in balancing funding scientific discovery with limiting security concerns. In late 2011, two groups of researchers receiving federal funding separately sought to publish manuscripts in scientific journals describing their successful attempts to increase the transmissibility of a highly pathogenic strain of influenza. This strain of influenza, H5N1, is sometimes referred to as avian or bird flu in the popular press. It causes severe disease in humans, but is not highly contagious between humans. The federal government moved first to restrict publication of the manuscripts. Following additional discussions and deliberations, the federal government recommended publishing modified versions of the manuscripts. Some stakeholders believe the research results should not have been published. They assert that broad dissemination of such research results increases the likelihood that a highly contagious form of the virus will be introduced, either accidently or deliberately, into the human population. Others state that the public health benefits from such research outweigh concerns regarding malicious use. The H5N1 influenza research case study highlights the general tensions among stakeholders and the ramifications of various federal actions and policies. The controversy surrounding the decisions to publish these manuscripts highlights deficiencies in the federal decision-making processes related to dual-use life science research. In addition, the debate about the publication of scientific research with potential security implications cuts across multiple policy issues. These include federal support of research, maintenance of homeland security, and the flow of research information, and may require simultaneous consideration of security, science, health, export, and international policy. Because of the complexity of these issues, analysis according to one set of policy priorities may adversely affect other policy priorities. In addition, the controversy surrounding the decision to publish these experiments has demonstrated flaws in the existing mechanisms to identify and balance the potential public benefits and security trade-offs. Congress has acted in the past to restrict access to pathogens where it deemed the potential risk of their misuse posed a greater threat than the benefits arising from unrestricted access. Congressional policymakers may decide that research results in some areas pose similar risks and may move to impose similar limits through a variety of mechanisms. Conversely, congressional policymakers may determine the risks of information exchange insufficient to warrant additional regulation. This report describes the underlying controversy, the potential benefits and harms of publishing these manuscripts, the actions taken by domestic and international stakeholders, and options to improve the way research is handled to minimize security concerns. The ongoing controversy regarding the appropriateness of funding research on (and publishing the results of) H5N1 influenza transmissibility serves as a case study for the broader challenges of balancing the potential benefits and potential harms from such research. This section outlines the presence of H5N1 influenza in nature; describes and discusses the transmissibility experiments that led to the current policy debate; outlines the potential benefits and harms arising from the conduct and publication of such research; and outlines the various recommendations and actions from various governmental and non-governmental stakeholders. Influenza is a virus that circulates through both human and animal populations. The form of the influenza virus changes frequently. These changes produce various strains with differing properties, including host species, levels of contagiousness, and severity of disease. Strains harmless in one host may be deadly in another. Scientists and public health officials often refer to different influenza virus strains through abbreviation. Influenza viruses have two specific disease-related proteins (H for hemagglutinin and N for neuraminidase), each of which have several varieties denoted by different numbers. For example, the H1N1 influenza virus caused the 2007 "swine flu" human pandemic. A different strain, the H5N1 influenza virus, commonly known as avian or bird flu, began infecting people in China in 1997. This highly pathogenic strain had previously infected only birds. In the initial outbreak, the virus infected 18 people, 6 of whom died. Since then, the virus has spread internationally, infecting humans in at least 15 countries. As of February 2013, the World Health Organization (WHO) has confirmed 615 human cases and 364 deaths from this H5N1 influenza strain. Although highly contagious among birds, the H5N1 influenza virus does not pass easily between people. Nearly all of the known human infections resulted from close contact with infected poultry. However, because viruses constantly change, future versions of H5N1 influenza virus might be more contagious among humans. If the virus did become more contagious among humans and also kept its disease-causing characteristics, a human pandemic with serious disruptions in services and social order might occur. These potential consequences drive federal investments in influenza pandemic preparedness activities, including research on various influenza strains. While scientists know that H5N1 influenza strains naturally change over time, they do not yet understand in detail how these specific changes lead to new viral properties. Gaps in our current scientific understanding limit our ability to determine the likelihood of increased human-to-human transmission. This likelihood could have important public health policy ramifications. For instance, if these changes are likely to occur, then policymakers might increase H5N1 influenza-related countermeasure development efforts. Conversely, if such changes are unlikely or impossible, then policymakers might decrease such efforts or divert federal efforts into more pressing threats. The National Institute for Allergy and Infectious Disease (NIAID) funded multiple researchers to determine the genetic changes that would cause H5N1 strains to become more transmissible among humans. Dr. Yoshihiro Kawaoka, based at the University of Wisconsin-Madison, and Dr. Ron Fouchier, based at the Erasmus Medical Center in Rotterdam, the Netherlands, each led research groups that successfully determined such changes. Both groups used ferret-to-ferret transmission to model human-to-human transmission. Independently, and using different methods, each group found specific genetic changes to the H5N1 influenza virus that make it transmissible through the air between ferrets in separate cages. Dr. Kawaoka's group used standard molecular biological techniques to create a ferret-to-ferret transmissible H5N1 virus. The scientists took the H1N1 virus that caused the 2009 human pandemic and replaced the H1 portion with a genetically modified version of the H5 portion from an H5N1 strain. This hybrid version passed between ferrets housed in separate cages. However, this new virus, unlike the naturally occurring H5N1 virus, did not kill the ferrets. Additionally, his group found that current vaccines and antiviral medications are effective against this new hybrid strain. Dr. Fouchier's group directly infected ferrets with a genetically modified H5N1 virus. After the ferret became sick, virus from the sick ferret was used to directly infect another ferret. After multiple iterations, the H5N1 virus had changed sufficiently to become transmissible between ferrets in separate cages. The scientists determined five specific genetic changes were sufficient to convey airborne transmissibility among ferrets. They found that this new strain of H5N1 virus was less transmissible and caused a less severe disease than naturally occurring seasonal influenza. Additionally, ferrets previously exposed to seasonal flu were immune to infection with the new H5N1 virus. The two groups submitted manuscripts to different scholarly journals. In both cases, the submission was to a publisher not based in the country where the experiments were performed. Dr. Kawaoka submitted his research conducted in the United States to the United Kingdom journal, Nature . Dr. Fouchier submitted his research conducted in the Netherlands to the U.S. journal, Science . The Department of Health and Human Services (HHS) deemed the manuscripts from these two groups as the results of "dual-use" research. In this context, this term describes information or technologies that have the potential to both help and harm society. The HHS defines dual-use biological research as "biological research with legitimate scientific purpose that may be misused to pose a biologic threat to public health and/or national security." Policymakers and stakeholders face difficult calculations when trying to balance the potential benefits of this research against potential harms. Most public health experts agree that an influenza pandemic, of some nature, will occur at some indeterminate time in the future. Research on the influenza virus may provide ways to mitigate the effects of such a pandemic. However, most experts also agree that such research also increases the risk that an influenza pandemic could occur through accidental or deliberate release of a modified virus. The disagreement among experts largely lies in the relative probabilities of these events. No universally accepted method exists to precisely determine these probabilities, and analysts may arrive at different, but equally valid, conclusions. These H5N1 influenza research results provided previously unknown scientific information. In particular, this research identified some of the genes involved in transmitting the disease between mammals. Future experiments may build upon these results to further scientific understanding of how influenza virus causes disease in different animals. Such experiments could create new approaches to treating and preventing the disease.