Spanish Influenza Virus Research Articles

THE SPANISH INFLUENZA VIRUS: TREATS TO THE PORTRAIT AFTER 100 YEARS

The purpose of the study was to compare molecular characteristics of genes and proteins of pandemic influenza strains and find features of the 1918 Spanish influenza virus. Computer analysis has shown that the genes of the Spanish influenza virus in contrast to other pandemic strains contain optimal quantity of long complementary sequences that allow to obtain a supramolecular assembly of 8 virus RNA in according to a model ensuring selective packing of one copy of each virus RNA by the only possible scheme and high transmission to induce infection by single virions. Other pandemic strains contain redundant or insufficient quantity of complementary sequences that allow an assembly of its genome by means of some models including a stochastic one and occurrence of virions with incomplete genome, that is influenza virusts can exist primarily as a swarm of complementation-dependent semi-infectious virions. Analysis of an HA gene of the Spanish influenza virus found out exclusion from its translation code four triplets (CGG, CGA, CGC и CGU) coding arginine. This exclusion is observed in all the HlNl strains isolated during 100 years. Coding arginine in an HA gene of HlNl strains is provided by only triplets AGG and AGA. A NP gene of the Spanish influenza virus in contrast to other pandemics strains is avian-like and its NP protein is characterized by elevated quantity of arginine and decreased quantity of lysine that is considered as viral adaptation to avian body temperature. Prevalence of arginine provides more high positive charge for the Spanish influenza NP protein and its more powerful interaction with RNA and consequently more high thermal stability of the its RNP in comparison with the RNP of other pandemic strains. Potential consequence of existence of the avian-like NP in the Spanish influenza virus could be its high pathogenicity as infection fever creates optimal temperature for virus replication. These new data obtained by computer analysis of genomes in the Spanish influenza virus and other pandemic strains (altogether information about its proteins) can potentially be used to track pre-pandemic strains among circulating influenza A viruses and detect the formation of a possible trajectory of pandemic alert.

The Molecular Mechanisms Underlying the Hijack of Host Proteins by the 1918 Spanish Influenza Virus.

The 1918 Spanish influenza A virus (IAV) caused one of the most serious pandemics in history. The nonstructural protein 1 (NS1) of the 1918 IAV hijacks the interaction between human CrkII and JNK1. Little is, however, known about its molecular mechanism. Here, we performed X-ray crystallography, NMR relaxation dispersion experiment, and fluorescence spectroscopy to determine the structural, kinetic, and thermodynamic mechanisms underlying the hijacking of CrkII by 1918 IAV NS1. We observed that the interaction between a proline-rich motif in NS1 and the N-terminal SH3 domain of CrkII displays strikingly rapid kinetics and exceptionally high affinity with 100-fold faster kon and 3300-fold lower Kd compared to those for the CrkII-JNK1 interaction. These results provide molecular insight into the mechanism by which 1918 IAV NS1 hijacks CrkII and disrupts its interactions with critical cellular signaling proteins.

Pots of Gold at the End of Laboratory Benches and in Freezers.

Whether one is a paleopathologist probing ancient civilizations, a modern-day epidemiologist searching for clues about the natural history of a specific disease process, or even a research entomologist studying the evolution and differences among hundreds of beetle species identified through centuries, the study of previously collected biological specimens repeatedly has proven enlightening. As stated by Baker in her recent comprehensive discussion of biobanks, “High quality data-rich samples are essential for future research.” Often, as the result of investigator initiation or sometimes even by accident, discoveries from unique specimens continue to result in important scientific advances. There is no more appropriate example than the discovery and recovery of the 1918 Spanish influenza virus from human remains preserved in the Alaskan permafrost. Employing such concepts, the U.S. Military for centuries has made (and continues to make) numerous medical/scientific contributions. Not only has the Armed Forces Institute of Pathology itself contributed to scientific knowledge, but the collaboration of this renowned institute with civilian investigators has been a model for joint efforts. Noteworthy is the postmortem evaluation of casualties from the Korean War to uncover enlightening clues toward understanding the then-underappreciated early onset of human atherosclerosis. A common thread throughout such investigations has been the discovery and utilization of technological advances, such as modern molecular biology and imaging methods, to further mine these collected treasures. Laboratory methodology and other scientific inquiry have become more ingenious than were ever imagined by investigators during the original periods of study design and specimen collection decades previously. Because of the frequently unpredictable future value of such gathered specimens, careful oversight and long-term care of such repositories are required. This supplement to Military Medicine contains descriptions of several current instances of such stewardship. The specimen repositories directly or indirectly originated from military-related populations, and are representative of “pots of gold” at the end of laboratory benches from past and present clinical and epidemiologic studies. Individually and collectively these Military Medicine articles emphasize not only the opportunities for innovative biologic and technological approaches to long recognized enigmatic diseases, but the articles also allude to contemporaneous issues inherent in addressing ethical and quality assurance hurdles facing those who make use of these often unexplored treasures. However, the important food for thought discussed in this supplement demands enhanced proactive attention, not only for military-associated investigations, but also by colleagues in the academic and industrial scientific communities who find themselves as custodians/guardians for nonmilitaryassociated repositories of sera, of microorganisms, and of pathological specimens. The included articles describe continuing specific efforts by the Department of Defense (DoD) to create and maintain repositories. Perdue and colleagues’ description of the DoD gigantic serum repository and their discussion of maximizing present and future use of the millions of serum specimens now stored and comprehensively cataloged in this unique collection provide an excellent overview of what is required to create and efficiently maintain potentially usable resources. The description of the United States Air Force Ranch Hand Collection of biological specimens, collected from Vietnam veterans for study of the consequences of herbicide exposure, has important implications for future operations. Of considerable importance is the DoD’s collaboration with the Institute of Medicine (IOM), which has been granted considerable responsibility for this collection. The IOM has prepared to open The Ranch Hand collection to qualified investigators, including those not directly connected to the military as well as to projects of potential importance to current military members and veterans. Similar joint collaboration by the Medical Follow-up Agency of the IOM and the DoD (Air Force) has been initiated for the collection of slightly less than 45,000 sera obtained from Air Force recruits at Warren Air Force Base (AFB), Wyoming, during the Korean conflict. These sera resulted from studies of group A streptococcal infections and prevention of rheumatic fever. Those sentinel studies resulted in the 1954 awarding of a prestigious Lasker Award to the Warren Air Force Base Streptococcal Laboratory, another joint military–civilian effort. Although never foreseen by the civilian–military investigators at the time, study of the Warren serum collection (not described in this supplement) half a century later enhanced understanding of infection with hepatitis C virus (undiscovered at the time of the original studies in 1949–1954) as well as genomic studies of patients with celiac disease (using laboratory techniques not available in the 1940s and 1950s). Opportunities to use evolving technology to prospectively study historical biospecimens are a major thrust of the purpose of this supplement. Department of Pediatrics, University of Minnesota Medical School, MMC 296; 420 Delaware Street Southeast, Minneapolis, MN 55422. The opinions expressed are those of the author and should not be construed to represent those of the Department of Defense. doi: 10.7205/MILMED-D-15-00236

The W-Shaped Mortality-Age Distribution of Novel H1N1 Influenza Virus Helps Reconstruct the Second Wave of Pandemic 1918 Spanish Flu

Interferon is essential in human defense against influenza virus. The non-structural gene segment (NS) of influenza virus has a critical role in counteracting human interferon-mediated antiviral responses. The second wave of 1918 H1N1 Spanish influenza pandemic was characterized by an enhanced mortality and a W-shaped mortality age distribution. In contrast to the U-shaped mortality-age distribution that targeted the very young and elderly during the first wave, young adult population were also affected during the second wave. The NS of the 1918 H1N1 Spanish influenza virus (1918PV) isolated during the second wave contributes to the virulence of 1918PV. This unique NS of 1918PV is able to inhibit human interferon production at both the pre-transcriptional and post-transcriptional level and induce cytokine dysregulation. The NS of 1918PV has entered the swine population in 1918 and re-emerged in the 2009 novel H1N1 influenza A pandemic virus (2009PV). Both seasonal and pandemic novel H1N1 influenza A viruses produced a W-shaped mortality age distribution. Information from the 2009 novel H1N1 Influenza A pandemic may help to reconstruct the mysterious surge in mortality during the second wave in the 1918 H1N1 Spanish influenza A pandemic. The W-shaped mortality-age distribution of 2009PV indicates the importance of a universal influenza vaccination policy for public protection. The high incidence of cytokine dysregulation and Streptococcus pneumoniae co-infection in hospitalized patients reflects the importance of pneumococcal vaccination and the development of immunomodulating agents that can control influenza-induced cytokine dysregulation.

Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages

Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.

Deadly H7N9 Influenza Virus: A Pandemic in the Making or a Warning Lesson?

Deadly H7N9 Influenza Virus: A Pandemic in the Making or a Warning Lesson?

Targeted PGE2 inhibition enhances anti-viral immunity through induction of Type I interferon in macrophages (P6180)

Abstract The 1918 Spanish Influenza virus pandemic had a major impact on the rise in popularity of non-steroidal anti-inflammatory drugs (NSAIDs). Although these drugs are used extensively for the management of Influenza symptoms, their role in anti-viral immunity is poorly understood. NSAIDs act mainly by inhibiting cyclooxygenase enzymes involved in the synthesis of all prostaglandins, including PGE2. We now show that during Influenza infection, upregulated PGE2 inhibited macrophage type I interferon production and apoptosis via EP2 and EP4 receptors, thereby increasing virus replication. This inhibitory role of PGE2 was not limited to innate immunity since both antigen presentation and T cell mediated immunity were also suppressed. Inhibition of microsomal prostaglandin E-synthase 1 (mPGES-1), and thereby PGE2, in human Mϕ was protective against Flu infection. These data show that the mPGES-1/PGE2 pathway is specifically targeted by Influenza virus to evade host anti-viral immunity and propose that specific inhibition of PGE2 may serve as a new treatment for viral infection.

Seasonal Trivalent Inactivated Influenza Vaccine Protects against 1918 Spanish Influenza Virus Infection in Ferrets

The influenza virus H1N1 pandemic of 1918 was one of the worst medical catastrophes in human history. Recent studies have demonstrated that the hemagglutinin (HA) protein of the 1918 virus and 2009 H1N1 pandemic virus [A(H1N1)pdm09], the latter now a component of the seasonal trivalent inactivated influenza vaccine (TIV), share cross-reactive antigenic determinants. In this study, we demonstrate that immunization with the 2010-2011 seasonal TIV induces neutralizing antibodies that cross-react with the reconstructed 1918 pandemic virus in ferrets. TIV-immunized ferrets subsequently challenged with the 1918 virus displayed significant reductions in fever, weight loss, and virus shedding compared to these parameters in nonimmune control ferrets. Seasonal TIV was also effective in protecting against the lung infection and severe lung pathology associated with 1918 virus infection. Our data demonstrate that prior immunization with contemporary TIV provides cross-protection against the 1918 virus in ferrets. These findings suggest that exposure to A(H1N1)pdm09 through immunization may provide protection against the reconstructed 1918 virus which, as a select agent, is considered to pose both biosafety and biosecurity threats.

Elicitation of Anti-1918 Influenza Virus Immunity Early in Life Prevents Morbidity and Lower Levels of Lung Infection by 2009 Pandemic H1N1 Influenza Virus in Aged Mice

The Spanish influenza virus pandemic of 1918 was responsible for 40 million to 50 million deaths and is antigenically similar to the swine lineage 2009 pandemic influenza virus. Emergence of the 2009 pandemic from swine into humans has raised the possibility that low levels of cross-protective immunity to past shared epitopes could confer protection. In this study, influenza viruslike particles (VLPs) were engineered to express the hemagglutinin (HA) and genes from the 1918 influenza virus to evaluate the duration of cross-protection to the H1N1 pandemic strain by vaccinating young mice (8 to 12 weeks) and then allowing the animals to age to 20 months. This immunity was long lasting, with homologous receptor-blocking antibodies detected throughout the lifespan of vaccinated mice. Furthermore, the 1918 VLPs fully protected aged mice from 2009 pandemic H1N1 virus challenge 16 months after vaccination. Histopathological assessment showed that aged vaccinated mice had significant protection from alveolar infection but less protection of the bronchial tissue than adult vaccinated mice. Additionally, passive transfer of immune serum from aged vaccinated mice resulted in protection from death but not morbidity. This is the first report describing the lifelong duration of cross-reactive immune responses elicited by a 1918 VLP vaccine in a murine model. Importantly, these lifelong immune responses did not result in decreased total viral replication but did prevent infection of the lower respiratory tract. These findings show that immunity acquired early in life can restrict the anatomical location of influenza viral replication, rather than preventing infection, in the aged.

Pandemic 2009 H1N1 vaccine protects against 1918 Spanish influenza virus

The 1918 influenza A virus caused the most devastating pandemic, killing approximately 50 million people worldwide. Immunization with 1918-like and classical swine H1N1 virus vaccines results in cross-protective antibodies against the 2009 H1N1 pandemic influenza, indicating antigenic similarities among these viruses. In this study, we demonstrate that vaccination with the 2009 pandemic H1N1 vaccine elicits 1918 virus cross-protective antibodies in mice and humans, and that vaccination or passive transfer of human-positive sera reduced morbidity and conferred full protection from lethal challenge with the 1918 virus in mice. The spread of the 2009 H1N1 influenza virus in the population worldwide, in addition to the large number of individuals already vaccinated, suggests that a large proportion of the population now have cross-protective antibodies against the 1918 virus, greatly alleviating concerns and fears regarding the accidental exposure/release of the 1918 virus from the laboratory and the use of the virus as a bioterrorist agent.

High frequency of cross-reacting antibodies against 2009 pandemic influenza A(H1N1) virus among the elderly in Finland

Since May 2009, the pandemic influenza A(H1N1) virus has been spreading throughout the world. Epidemiological data indicate that the elderly are underrepresented among the ill individuals. Approximately 1,000 serum specimens collected in Finland in 2004 and 2005 from individuals born between 1909 and 2005, were analysed by haemagglutination-inhibition test for the presence of antibodies against the 2009 pandemic influenza A(H1N1) and recently circulating seasonal influenza A viruses. Ninety-six per cent of individuals born between 1909 and 1919 had antibodies against the 2009 pandemic influenza virus, while in age groups born between 1920 and 1944, the prevalence varied from 77% to 14%. Most individuals born after 1944 lacked antibodies to the pandemic virus. In sequence comparisons the haemagglutinin (HA) gene of the 2009 pandemic influenza A(H1N1) virus was closely related to that of the Spanish influenza and 1976 swine influenza viruses. Based on the three-dimensional structure of the HA molecule, the antigenic epitopes of the pandemic virus HA are more closely related to those of the Spanish influenza HA than to those of recent seasonal influenza A(H1N1) viruses. Among the elderly, cross-reactive antibodies against the 2009 pandemic influenza virus, which likely originate from infections caused by the Spanish influenza virus and its immediate descendants, may provide protective immunity against the present pandemic virus.

RNA Polymerase Trio from 1918 Influenza Strain Might Explain Its Lethality

Scientists continue to investigate factors that could account for the high lethality of the Spanish influenza virus, which killed at least 20 million people during the 1918 pandemic. Recent findings point to a set of RNA polymerase genes plus a nucleoprotein that apparently enabled the 1918 virus to move from nasal passages and grow in the lungs, causing severe edema and hemorrhage among the infected, according to virologist Yoshihiro Kawaoka at the University of Wisconsin (UW), Madison, and his collaborators. Their findings could make the flu RNA polymerase complex a marker for pandemic strains as well as a target for new drugs.

Influenza vaccination of healthcare workers, oseltamivir resistance and prepandemic vaccination

Since the Second European Influenza Conference in 2005, the field of influenza research has advanced immensely. The main topics discussed were the possible mandatory vaccination of healthcare workers against seasonal influenza, the oseltamivir resistance, the pandemic and prepandemic vaccination strategies and the mathematical modeling of a pandemic. A key discussion was on the efficacy of seasonal vaccination of the elderly. Young scientists presented promising work on influenza transmission in the guinea pig model, the pathogenicity of the re-engineered 1918 Spanish Flu influenza virus and the global migration routes of influenza viruses.

The Yuck Factor When Disgust Meets Discovery

Imagine you lived in a drought-stricken area and were told that from now on your tap water would come from “recycled sewage.” Might the word “yuck” describe your gut response? If your answer is yes, then you’ve got lots of company. Most people instinctively reject fearsome or repugnant things, especially when those things are unfamiliar. If shared by masses of people, that collective repugnance can fuel a social force with the power to shape environmental and public policy. The so-called yuck factor, a term coined by University of Pennsylvania bioethicist Arthur Caplan to describe the influence of instinctive responses against new technology, has a wide scope. In California, it’s derailed projects for converting wastewater into drinking water in several municipalities. It’s been cited in public opposition to foods from cloned animals and genetically modified (GM) crops. It’s even been named as a barrier to programs for trading carbon dioxide emission credits on the open market, says Asa Lofgren, an economist at Goteberg University, Sweden, who points to widespread aversion to the notion that companies could buy rights to pollute. Generally speaking, “yuck factor” has become a catchall phrase to describe technophobic sentiments that vary by what triggers them. The disgust elicited by drinking reclaimed wastewater, for instance, differs from the moral outrage induced by human cloning. Meanwhile, science routinely generates technologies that—though they might initially be seen as repugnant—are also borne of real need. For instance, wastewater reclamation, the process by which sewage water is treated to augment drinking, industrial, and agricultural water supplies, responds to the growing problem of drought. In this case, the yuck factor—exacerbated perhaps by the use of terms such as “recycled sewage” and “toilet-to-tap”—stands in the way of a solution to dwindling water supplies that experts generally view as cost-effective and safe. Galvanized by the yuck factor, opponents in Redwood City, California, delayed a wastewater reclamation project for nearly two years. And about six hours north, in Fountain Valley, a group dubbed the Revolting Grandmas led opposition to the Orange County Groundwater Replenishment System, which is the largest wastewater reclamation plant in the world. Responding to opponents’ demands, engineers now pump highly treated wastewater leaving the plant into an underground basin, where it filters through layers of sand and gravel before being piped to the homes and businesses that use it. Ironically, the water coming out of the basin isn’t as clean as the treated water going into it, according to an article in the 8 August 2008 New York Times Magazine—during its trip through the natural filters it picks up trace elements and contaminants that must later be removed by the water utility. The underground filtration step is taken, says director of recharge operations Adam Hutchinson, strictly to allay psychological concerns. But the yuck factor could also be said to serve a useful purpose. Excrement does pose health risks, and the public is therefore wise to ask questions about the safety of drinking reclaimed wastewater. Likewise, genetic technologies have the capacity to fundamentally alter life as we know it, in some cases with uncertain benefits. By giving pause to technological progress, the yuck factor opens new opportunities for dialogue between scientists and the public. In some cases, that dialogue might show that a technology’s benefits outweigh the repugnance that goes with it. In others, it pushes scientists to make a better case for why a given technology should be pursued at all. Given the influence wielded by instinctive responses to new technology, Caplan asserts that policy makers need to better understand these responses and take them seriously. “Savvy marketers and good advertising people know how to appeal to emotion, gut rationality, and visceral fears,” he says. “That’s what they’re selling—the manipulation of ‘yuck’—and more often than not, this is what determines who wins or loses in science policy debates. If you really want to overcome that, you have to become sophisticated about how experts manipulate emotion. And if you’re going to assess what’s admissible in terms of public policy, your argument has got to be better than to simply say ‘I don’t like it.’”

Origin of the 1918 Spanish influenza virus: A comparative genomic analysis

To test the avian-origin hypothesis of the 1918 Spanish influenza virus we surveyed influenza sequences from a broad taxonomic distribution and collected 65 full-length genomes representing avian, human and “classic” swine H1N1 lineages in addition to numerous other swine (H1N2, H3N1, and H3N2), human (H2N2, H3N2, and H5N1), and avian (H1N1, H4N6, H5N1, H6N1, H6N6, H6N8, H7N3, H8N4, H9N2, and H13N2) subtypes. Amino acids from all eight segments were concatenated, aligned, and used for phylogenetic analyses. In addition, the genes of the polymerase complex (PB1, PB2, and PA) were analyzed individually. All of our results showed the Brevig-Mission/1918 strain in a position basal to the rest of the clade containing human H1N1s and were consistent with a reassortment hypothesis for the origin of the 1918 virus. Our genome phylogeny further indicates a sister relationship with the “classic” swine H1N1 lineage. The individual PB1, PB2, and PA phylogenies were consistent with reassortment/recombination hypotheses for these genes. These results demonstrate the importance of using a complete-genome approach for addressing the avian-origin hypothesis and predicting the emergence of new pandemic influenza strains.

Estimates of the reproduction numbers of Spanish influenza using morbidity data

There have been several studies of the transmissibility of the 1918 (Spanish) influenza virus, which has attributed to >20 million deaths. Many of the analyses to date have involved fitting predictions from a transmission model to the observed epidemic curves from different settings. Using morbidity data from cities in Europe and America and from confined settings during the 1918 influenza pandemic, we contrast the use of several different methods based on the growth rate and final size of the epidemic, which do not rely on transmission models, to estimate the effective and basic reproduction numbers. The effective reproduction number (the average number of secondary infectious cases produced by a typical infectious case in a given population) for the 1918 influenza virus was in the range 1.2-3.0 and 2.1-7.5 for community-based and confined settings, respectively. Assuming further that 30 and 50% of individuals were immune to Spanish influenza after the wave in April 1918 and the first subsequent wave, respectively, these findings imply that, in a totally susceptible population, an infectious case could have led to 2.4-4.3 and 2.6-10.6 cases in community-based and confined settings, respectively. These findings for community-based populations confirm the relatively low transmissibility of the 1918 (Spanish) influenza virus, which has been found by other studies using alternative data sources and methods.

When risk outweighs benefit

In October 2005, a team of US scientists, headed by Jeffery Taubenberger from the US Armed Forces Institute of Pathology (Rockville, MD, USA), published the full sequence of the highly virulent strain of influenza virus that caused the Spanish influenza pandemic in the winter of 1918–1919 and killed up to 50 million people worldwide (Taubenberger et al , 2005). Further work based on the sequence led to the synthesis of an influenza strain containing all eight gene segments from the 1918 pandemic virus, which showed a high virulence and mortality rate when tested in mice (Tumpey et al , 2005). Both the sequencing and the reconstruction of the Spanish influenza virus are paradigmatic proof that recent developments in genetics, genomics and other areas of the biomedical sciences might create new possibilities for biological warfare. The resurrected 1918 virus has been described as “perhaps the most effective bioweapons agent now known” (von Bubnoff, 2005), and, given the availability of its full genome sequence on the Internet, its reconstruction by rogue scientists is now a real possibility. > …we need internationally harmonized and legally binding rules for conducting dual‐use research, in order to prevent the misuse of biological knowledge Not surprisingly, the publication of the Spanish influenza research triggered a controversial debate within, but not exclusive to, the scientific community, as arms‐control experts questioned whether it was wise to publish a detailed account of its genome and recipe for resurrection. This debate, although necessary, has some essential shortcomings as it focuses solely on the question of whether to publish such work, and lacks a systematic approach to a general risk–benefit analysis in biomedical research. In addition, the case of the Spanish influenza publications and their relatively superficial assessment by a biosecurity advisory board in the USA exemplifies the fact that we need internationally harmonized and …

The Genesis of a Pandemic Influenza Virus

Pandemic influenza viruses pose a significant threat to public health worldwide. In a recent Nature paper, Taubenberger et al. (2005) now report remarkable similarities between the polymerase genes of the influenza virus that caused the 1918 Spanish influenza pandemic and those of avian influenza viruses. Meanwhile, Tumpey et al. (2005) reporting in Science show that the reconstructed 1918 Spanish influenza virus kills mice faster than any other influenza virus so far tested.

Better Never Than Late

Editor-in-Chief L ast week, this space contained an editorial by Phillip Sharp, dealing with the difficult problems raised by the publication of information about certain “dual-use” technologies. The term arises because papers dealing with modified human pathogens that are also “select agents” might yield great public health benefits but also could be used by terrorists against that same public. A U.S. National Academies committee chaired by Gerald Fink recommended in a 2003 report that a National Science Advisory Board for Biosecurity (NSABB) be established. As Sharp's editorial reported, that body was consulted with regard to Science 's publication of the paper by Tumpey et al. on the reconstruction of the 1918 Spanish influenza virus. It voted unanimously in favor of publication. That may sound like a happy ending, but it wasn't entirely happy nor is it the whole story. The paper's history contains some lessons about how this kind of dual-use problem should be managed. We recognized that the work might raise questions about the propriety of publication, and we considered this during the process of scientific peer review. We followed an established procedure in which we solicit views from experts who have knowledge about security issues. The authors located at the U.S. Centers for Disease Control and Prevention (CDC) were urged to consult with CDC Director Julie Gerberding and with Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Disease. Amy Patterson, director of the Office of Biotechnology Activities (the office responsible for NSABB matters) at the National Institutes of Health, was also informed. All three felt that the public health benefits of the study far outweighed any biosecurity risks. ![Figure][1] CREDIT: SCIENCE Having received these assurances by 16 September and thus confident about moving forward, we were prepared to send pages to the printer early in the week of 26 September. On that day, the editorial staff went off to Science 's annual retreat in West Virginia. Alas, on the evening of 27 September, a call was relayed from the Office of the Secretary of the U.S. Department of Health and Human Services (HHS), indicating belated concerns about the paper. There followed a series of conference calls involving various HHS officials, including Patterson and Assistant HHS Secretary Stewart Simonson, who reported that HHS Secretary Michael Leavitt was insisting on review by the NSABB. I told them that in 24 hours the issue would be at the printer, and reminded them that the NSABB's own charter makes it clear that it does not screen individual papers. Simonson ordered that the NSABB committee be polled—just as the issue was being printed—and a day later, we learned of its approval. A virologist on the NSABB board suggested adding an editorial addressing some of the biosecurity issues. We gave them this page: Phillip Sharp was persuaded to write a piece on short notice, and produced splendidly. He and I did some final edits on Sunday night so that it could be squeezed into the issue at the last possible moment. What can be learned from all this? To begin with, Science did the right thing in consulting with the proper authorities, both our own and those at HHS. The 11th-hour intervention from the secretary's office, it has been explained to us, was to give the NSABB a real experience with a “live” issue. That may have been a useful purpose, but it did cause some hardship to editors and authors alike. There are other issues in such cases that should concern the scientific community. First, there is a real question of authority here. Government officials can advise, and should be listened to thoughtfully. But they can't order the nonpublication of a paper just because they consider the findings “sensitive.” No such category short of classification exists, as the Reagan-era Executive Order National Security Decision Directive 189, still in force, makes clear. If a paper should not be published because of biosecurity risks, then it should be classified. Second, the NSABB should regard this first exercise as a helpful one-off and turn to its mandate of developing principles rather than making decisions on individual papers. So would I, given our own convictions, the timing, and what we had learned from our consultations with Gerberding, Fauci, and others, have published the paper even if the NSABB had voted otherwise? Absolutely—unless they had it classified. [1]: pending:yes

Sialobiology of Influenza: Molecular Mechanism of Host Range Variation of Influenza Viruses

The gene pool of influenza A viruses in aquatic birds provides all of the genetic diversity required for human and lower animals. Host range selection of the receptor binding specificity of the influenza virus hemagglutinin occurs during maintenance of the virus in different host cells that express different receptor sialo-sugar chains. In this paper, functional roles of the hemagglutinin and neuraminidase spikes of influenza viruses are described in the relation to 1) host range of influenza viruses, 2) receptor binding specificity of human and other animal influenza viruses, 3) recognition of sialyl sugar chains by Spanish influenza virus hemagglutinin, 4) highly pathogenic and potentially pandemic H5N1, H9N2, and H7N7 avian influenza viruses and molecular mechanism of host range variation of influenza viruses, 5) role of the neuraminidase spike for the host range of influenza viruses, and 6) Development of anti-influenza drugs.