As late fall turns to winter, perennial concern arises over influenza. Some people are frightened about the flu for good reasons; others have unwarranted fears based on limited knowledge of flu epidemics such as the one that broke out in 1918. The reasonable fears we have stem from the particular vulnerabilities of some groups, such as the elderly, and it is these vulnerable groups that account for the roughly twenty thousand people who die in the United States each year from influenza. That is about half the number of people who die from AIDS, but unlike people at risk for AIDS, those at risk for flu are more evenly distributed across society, so most Americans have had an experience with an elderly relative or acquaintance who has either succumbed to or had a close call with influenza. The danger is similar for most countries in temperate climates.

The unwarranted fears are based on the expectation of an influenza plague as lethal as the 1918 pandemic, during which there were over thirty times as many influenza deaths in the United States as occur in a normal year. About one out of every hundred people on earth died from influenza within twelve months. For the past quarter century, influenza experts have been anxiously searching for new strains that resemble the viruses responsible for the 1918 catastrophe. In particular they have been looking at the form of the two protein molecules that stick out of the surface of the influenza virus. One protein is hemagglutinin, which allows the virus to bind to our cells for entry. The other is neuraminidase, which keeps the flu virus molecules from sticking to each other. These proteins are so closely watched not because the particular form they took in the 1918 viruses made those viruses harmful. Rather it is because the two proteins are the easiest for the immune system to "see." The virus is wrapped in a cell membrane to disguise it from the immune system, and hemagglutinin and neuraminidase stick out from this camouflage the way hands stick out of a shirt. The immune system generates antibodies to the proteins, and scientists can detect the presence of the antibodies. If influenza experts detect a combination of these proteins that is similar to the combination of the 1918 pandemic viruses, which is referred to as HlNl (for hemagglutinin type 1 and neuraminidase type 1), alarm spreads.

That happened in 1976, causing a cascade of events that flowed out of control. When a large proportion of the population has not been exposed to a particular flu virus, the potential for a global outbreak of influenza is especially great. Flu experts were anxious in 1976 because they were nearing a period when immunity to the HlNl combination would virtually have disappeared from the population. People who were infected as babies in 1918 and survived were about sixty years old in 1976. So everyone who was less than sixty years old had no immunity to the 1918 virus. The anxiety was magnified by political forces, which pushed through a "swine flu" vaccination program, which caused a paralytic disease called Guillain-Barr6 syndrome in about five hundred people, about twenty-five of whom died. The benefits of the program are hard to gauge. Probably no more than a few lives were saved from a flu outbreak that apparently burned out on its own.

Concern over a pandemic of an HlNl virus was justified, but anxiety about a revisitation of a virus with the harmfulness of the 1918 influenza viruses was not. The flu experts of 1976 needed to add the insight of evolutionary medicine to their biochemical perspectives. They reacted too strongly and too quickly to the discovery of HlNl on the viruses isolated in 1976. It would be like seeing a person with a Hitler-style mustache giving a political speech in 1976, concluding that the person was a threat to world peace, and then initiating attempts to incarcerate him. The similarity in the outward appearance of the 1976 viruses to those of 1918 did not indicate that they would have a similar level of harmfulness. The HlNl marker had been present on dangerous viruses, but there was no reason to think that it made the viruses dangerous—with its high mutation rate, the influenza virus can generate tremendous variation within a matter of weeks while still retaining the same HlNl marker.

An evolutionary approach to the influenza threat considers conditions that allow transmission from sick individuals. One could hardly imagine conditions as conducive to high virulence as those along the Western Front in World War I. If a person is packed into close quarters with other people, for example, in a trench or in army barracks, and then becomes sick, the others close by would have a good chance of being infected. People who fell sick at the front were typically transported to triage hospitals behind the lines; there the flu viruses in the sick person would have another set of potential victims just a cough away. Within a few hours a sick person would be whisked from the triage hospital to an overcrowded permanent hospital. Some of these hospitals were built to house about two hundred patients but were funneling through two thousand a day during the latter part of 1918; soldiers in these hospitals were packed into rooms and overflowed into hallways. Most were quickly transported to other hospitals—for example, by being stacked in train cars. In such a system an immobilized person could infect hundreds of additional people before his infectious period ended.

But did the first sign of the super-nasty influenza strains arise at the Western Front? In an attempt to understand the origins of the 1918 pandemic, one of the twentieth century's leading experts on infectious disease, Macfarlane Burnet, tried to reconstruct events in a short article. They traced the pandemic influenza to army recruits stationed in the United States during the spring and summer of 1918. But the lethality of these infections did not seem to be out of the ordinary. The first cases with the notoriously high lethality were recorded in U.S. troops at the Western Front in the fall of 1918. Both the theory and the evidence therefore implicate the Western Front as the source of the epidemic. This is not the kind of idea that can be tested with controlled experiment. But as long as people do not re-create the opportunities for transmission from immobilized people that were created during 1918, the idea can be evaluated over time by many weaker tests rather than a single strong one, much as the hypothesis of human origins from ancestral apes has been evaluated by many weak tests. If the idea is correct, we will see some things in the future and fail to see other things. We will see flu viruses that have the H1N1 combination but do not have exceptionally high virulence. We will fail to see a recurrence of a pandemic influenza with the kind of lethality that characterized the 1918 pandemic.

In 1990, I first put this prediction in print, emphasizing that we were at that time passing through the period when flu experts were expecting a revisitation of H1N1 viruses. With people born in 1918 being over eighty at the time of this writing, we have passed almost completely into the period of maximum vulnerability to a revisitation of HlNl viruses. And so far the predictions of evolutionary medicine have proved correct—we have not experienced another epidemic

influenza with anything like the virulence of the 1918 infections.

But this evolutionary perspective is still foreign to most influenza researchers. They now regularly incorporate evolutionary reconstructions of the various influenza viruses to determine which viruses are related to which other viruses. But they still confuse the sources of

variation—the mutation and recombination of genes—with the process of evolution by natural selection. And they still confuse similarity of hemagglutinin and neuraminidase molecules among different virus strains with similarities in the virulence of these strains. This kind of confusion opens the door to future mistakes mirroring the mistakes that occurred in 1976 and led to the overuse of the swine flu vaccine. By failing to investigate the selective processes that favor increased or decreased virulence of virus strains, experts still run the risk of spending too much time and too many resources in attempts to block a 1918-type pandemic, and too little time on how to deal with the more imminent threats.