Grippe. Sweating Sickness. Flu. The ever changing names for influenza show just how long and well recognized the disease has been throughout history— and how tough and deadly it has been. Perhaps most famously, it swept the globe as the deadly “Spanish flu” of 1918. Yet recently the viral illness has returned to the headlines—in the form of “swine flu” and “bird flu”—and has generated concern within the scientific community and the public at large.

What accounts for the renewed interest in, and the fear of, influenza in the past decade? This retrospective of influenza articles published in Scientific American from 1889 to 2012 demonstrates that influenza has always been an important public health topic. These articles report on the last five major influenza pandemics, which occurred in 1889, 1918, 1957, 1968 and 2009. The collection also follows animal influenza viruses that have pandemic potential, including human infections with swine influenza in 1976 and lethal avian influenza infections, which have caused serious concern since 1997. The historical and contemporary articles offer a fascinating view into the gradual understanding of the complex biology of the virus and the ongoing effort to treat and prevent infection by it. Despite tremendous advances, such as the advent of vaccines and antiviral agents, influenza continues to thwart our best efforts at control, leaving us still frustratingly at the mercy of this mercurial virus. And in some ways, we are just as vulnerable to a devastating pandemic of influenza today as we were in 1889.

The 1889 pandemic emerged in the early microbiology era, and influenza was, for the first time, characterized as an infectious disease, then a new con- cept. The 1918 pandemic caused the most severe influenza outbreak ever re- corded, leaving up to 50 million dead across the globe. Many studies, reflected in the 1918 articles reprinted here, refuted a proposed bacterial cause in favor of a “filterable agent,” or virus, with bacteria causing secondary infections. The 1918 pandemic also led to well-recognized outbreaks of influenza in swine, which eventually resulted in the isolation of the first influenza virus from a pig in 1930. Shortly thereafter, researchers isolated influenza viruses from infected patients, and the era of influenza virology was born. The next several decades led to significant advances in our understanding of influenza biology and the development of protective vaccines by the late 1940s.

In 1957 and 1968 two new strains of influenza emerged in people to cause global pandemics, which could be mitigated for the first time by vaccination, along with antibiotics for secondary bacterial pneumonias. In the 1990s a new class of anti-influenza viral drugs, the neuraminidase inhibitors, which block a key protein necessary for viral reproduction, were developed and licensed.

Our knowledge of influenza viral ecology has also rapidly expanded during the past 124 years. Identification of influenza in pigs, horses, poultry and wild aquatic birds has turned a bright spotlight on the incredible diversity of influenza viruses in animals and the importance of animal influenza as the source of pandemic strains in the human population.

New molecular genetic advances in the 1990s revolutionized the study of influenza. They enabled scientists to produce infectious influenza viruses entirely from cloned genetic material and to sequence and reconstruct the virus that caused the 1918 pandemic. These advances were contemporaneous with the emergence of a lethal strain of bird influenza, H5N1, which has devastated poultry populations in Southeast Asia. More ominously, H5N1 strains have been able to directly infect a small number of people, leading to ongoing concern that it could cause a major pandemic. Unexpectedly, with so much focus on the risk posed by bird flu strains in Asia, a new pandemic did emerge in 2009. Yet instead of being avian-based, it derived from two swine influenza virus strains and first appeared in North America, reminding us of this virus’s agility—and unpredictability.

We now know the genetic composition of the last four pandemic viruses and that the 1957, 1968 and 2009 viruses are all descended, at least in part, from the 1918 pandemic virus—having been “updated” by swapping out viral genes with various influenza viruses adapted to other host animals. Researchers are now hard at work determining what genetic combinations and mutations are needed to produce new strains of animal influenza that could infect humans and spread among people efficiently enough to cause a pandemic. This work has the promise to unlock the molecular mysteries of how pandemics emerge. But it also creates the concern that this knowledge could be used for bioterrorism or lead to outbreaks because of accidental release.

Balancing these competing needs is a challenge our society must now face. Molecular advances also provide the potential of new drugs and vaccines that might provide more protection against all forms of influenza virus. Such “universal” compounds are now within reach, provided we continue to support responsible research. It is fascinating to look back at these influenza time capsules from the past 124 years. I hope a future retrospective of our current efforts to forestall this devastating disease will be full of similar successes.

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