Viral Sex

Genetic drift and shift (reassortment)

The few genes the influenza virus has are distributed among eight discrete strands of RNA within each virus. It must be a nightmare for the virus to package each new outgoing progenitor with the correct RNA octet. Why not just keep all its genes on a single strand? Because with separate strands, influenza viruses can have sex.²¹⁶

Variability is the engine of evolution. Survival of the fittest only works if there are some more fit than others and some less so. That is how natural selection works—how, over time, species can adjust to unpredictable changes in their environment. If all progeny are identical, if all progeny are simply clones of the parent, then the species has less flexibility to adapt. This is thought to be why the birds and the bees evolved to combine genetic endowments with one another in order to reproduce. This genetic mixing greatly increases variation among the offspring.

Suppose two completely different types of influenza viruses take over the same cell. They each make millions of copies of their eight individual RNA strands. Then what happens? As each new progeny virus buds from the cell, it can mix and match genes from both “parents.” This segmented nature of the genome allows different flu viruses to easily “mate” with each other, swapping segments of RNA to form totally new hybrid viruses.²¹⁷ This is one way pandemics can be made.

Only one strain of influenza tends to dominate at any one time within the human population.²¹⁸ Since 1968 that strain has been H3N2. Each year, the virus’s protruding spikes drift subtly in appearance, but the virus is still H3N2, so antibodies we made against the virus in previous years still recognize it as somewhat familiar and confer us some protection. As such, year after year for decades now, H3N2 has been kept in check by our immune systems thanks to our prior run-ins with the virus.

If the virus didn’t change its appearance at all from year to year, our immunity could be absolute, and like chicken pox we’d never get the flu again. Because the appearance of the virus does drift a bit annually, every year some of us do come down with the flu. For most of us, though, the illness only lasts a few days before our prior partial immunity can vanquish the familiar foe and we can get on with our lives.

Pandemics happen when a dramatically different virus arrives on the scene, an influenza virus to which we have no prior immunity. This can happen when the virus undergoes an entire “shift,” acquiring a new H spike. This is where gene swapping can come in.

The 1918 pandemic virus was H1N1. It came back in subsequent years, but by then it was old hat. Those who had survived the virus during the pandemic retained much immunity. The annual flu strain remained H1N1, infecting relatively few people every year for decades until 1957, when an H2N2 virus suddenly appeared as the “Asian flu” pandemic of 1957. Because the world’s population had essentially only acquired immunity to H1 spikes, the virus raced around the globe, infecting a significant portion of the world’s population. For example, half of U.S. schoolchildren fell ill.²¹⁹ Thankfully, it was not very virulent and only killed about a million people worldwide.²²⁰ H2N2 held seasonal sway for 11 years. In 1968, the H3N2 “Hong Kong Flu” virus triggered what is generally considered the last pandemic and has been with us every year ever since. It attacked even fewer people than the H2N2 flu—only about 40% of U.S. adolescents got sick—and killed fewer still. Experts suspect that partial immunity to at least the N2 spike afforded a baseline level of protection.²²¹ Since 95% of the surface spikes are hemagglutinin and only 5% are neuraminidase,²²² though, and the hemagglutinin directly determines infectivity, it is the appearance of a new H spike that triggers a pandemic.²²³

If only one type of human virus dominates at one time, with which viruses can the dominant virus swap genes? Birds are the reservoir from which all human and nonhuman animal influenza genes originate. Pandemic viruses can arise when human influenza dips into the bird flu gene pool and pulls out some avian H or N combination that the present human generation has never seen before. The human virus has lots to choose from, since birds harbor 16 different hemagglutinin spikes and 9 different spikes of neuraminidase.²²⁴

Researchers speculate that sometime shortly before February 1957, somewhere along the road between Kutsing and Kweiyang in southern China, an H2N2 bird flu virus may have infected either a pig or a person already suffering from the regular H1N1 seasonal human flu, and an unholy viral matrimony took place.²²⁵ From one of those co-infected cells came a human-bird crossbreed virus containing five of the original human viral gene segments and three new segments from the bird virus, including the new H and the new N spikes.²²⁶ Then, in 1968, the virus swapped its H2 for an H3 from another bird flu strain. With each new avian addition, the virus became sufficiently alien to the human immune system to quickly blanket the globe.

So there were three influenza pandemics in the 20th century—in 1918, 1957, and 1968—but, as the director of the National Institute for Allergy and Infectious Diseases has said, “There are pandemics and then there are pandemics.”²²⁷ The half-and-half bird/human hybrid viruses of 1957 and 1968 evidently contained enough previously recognizable human structure that the human population’s prior partial exposure dampened the pandemic’s potential to do harm. But the pandemic strain of 1918 was wholly avian-like.²²⁸ Instead of diluting its alien avian nature, the 1918 bird flu virus, as Taubenberger—the man who helped resurrect it—notes, “likely jumped straight to humans and began killing them.”²²⁹ The same could be happening with H5N1. The human immune system has never been known to be exposed to an H5 virus before. As the WHO points out, “Population vulnerability to an H5N1-like pandemic virus would be universal.”²³⁰

H5N1 has developed a level of human lethality not thought possible for influenza. Half of those known to have come down with this flu so far have died.²³¹ H5N1 is good at killing, but not at spreading. To trigger a pandemic, the virus has to learn how to spread efficiently from person to person. Now that the genome of the 1918 virus has been completely sequenced, we understand that it may have taken only a few dozen mutations to turn a bird flu virus into humanity’s greatest killer.²³² Already we see in H5N1 some of those changes taking form.²³⁴ The further H5N1 spreads and the more people it infects, the greater the likelihood that it might lock in mutations that could allow for efficient human-to-human transmission. “And that’s what keeps us up at night,” said the chair of the Infectious Diseases Society of America’s task force on pandemic influenza.234 “It’s like a frequent flyer program,” explains another flu expert. “Take enough trips and you can go anywhere.”²³⁵

Recent research funded by the National Institutes of Health (NIH) suggests that influenza viruses mutate even faster than previously thought.²³⁶ Some scientists theorize the existence of a “mutator mutation” that makes replication even sloppier, predisposing the virus for the species jump.²³⁷ As if its sloppiness and segmentation don’t create enough novelty for our immune system, influenza viruses have devised a third way to mutate. The process of swapping genes between two viruses has been named “reassortment,” like reshuffling two decks of cards—one human deck, one bird deck, with eight cards each. A process now known as “recombination” allows influenza viruses to swap mere pieces of individual RNA strands with each other. It’s as if the virus not only reshuffles both decks together, but also cuts each card in half and then randomly tapes the halves back together.²³⁸ Masters of metamorphosis indeed.

All influenza viruses are capable of high rates of mutation, but never has the scientific world seen a virus like H5N1. Very few human pathogens even approach 50% mortality. The director of the Center for Biosecurity of the University of Pittsburgh recently noted this at a congressional briefing: “Death rates approaching this order of magnitude are unprecedented for any epidemic disease.” University of Minnesota’s Osterholm describes the spectre of a deadly superflu as “the beast lurking in the midnight of every epidemiologist’s soul”—the “Ace of Spades in the influenza deck.”²³⁹

Robert Webster, chair of the Virology Division of St. Jude Children’s Research Hospital in Tennessee, is arguably the world’s top bird flu expert. He is often referred to as the “pope” of influenza researchers.²⁴⁰ In characteristically unpapal language, Webster puts it bluntly. H5N1, he said, is “the one that scares us shitless.”²⁴¹