The Great Influenza: The Epic Story of the Deadliest Plague in History - John M. Barry (2004)
Part II. THE SWARM
NO ONE WILL EVER KNOW with absolute certainty whether the 1918–19 influenza pandemic actually did originate in Haskell County, Kansas. There are other theories of origin. (For a fuller discussion of them see Afterword.) But Frank Macfarlane Burnet, a Nobel laureate who lived through the pandemic and spent most of his scientific career studying influenza, later concluded that the evidence was “strongly suggestive” that the 1918 influenza pandemic began in the United States, and that its spread was “intimately related to war conditions and especially the arrival of American troops in France.” Numerous other scientists agree with him. And the evidence does strongly suggest that Camp Funston experienced the first major outbreak of influenza in America; if so, the movement of men from an influenza-infested Haskell to Funston also strongly suggests Haskell as the site of origin.
Regardless of where it began, to understand what happened next one must first understand viruses and the concept of the mutant swarm.
Viruses are themselves an enigma that exist on the edges of life. They are not simply small bacteria. Bacteria consist of only one cell, but they are fully alive. Each has a metabolism, requires food, produces waste, and reproduces by division.
Viruses do not eat or burn oxygen for energy. They do not engage in any process that could be considered metabolic. They do not produce waste. They do not have sex. They make no side products, by accident or design. They do not even reproduce independently. They are less than a fully living organism but more than an inert collection of chemicals.
Several theories of their origin exist, and these theories are not mutually exclusive. Evidence exists to support all of them, and different viruses may have developed in different ways.
A minority view suggests that viruses originated independently as the most primitive molecules capable of replicating themselves. If this is so, more advanced life forms could have evolved from them.
More virologists think the opposite: that viruses began as more complex living cells and evolved—or, more accurately, devolved—into simpler organisms. This theory does seem to fit some organisms, such as the “rickettsia” family of pathogens. Rickettsia used to be considered viruses but are now thought of as halfway between bacteria and viruses; researchers believe they once possessed but lost activities necessary for independent life. The leprosy bacillus also seems to have moved from complexity—doing many things—toward simplicity—doing fewer. A third theory argues that viruses were once part of a cell, an organelle, but broke away and began to evolve independently.
Whatever the origin, a virus has only one function: to replicate itself. But unlike other life forms (if a virus is considered a life form), a virus does not even do that itself. It invades cells that have energy and then, like some alien puppet master, it subverts them, takes them over, forces them to make thousands, and in some cases hundreds of thousands, of new viruses. The power to do this lies in their genes.
In most life forms, genes are stretched out along the length of a filament-like molecule of DNA, deoxyribonucleic acid. But many viruses—including influenza, HIV, and the coronavirus that causes SARS (Severe Acute Respiratory Syndrome)—encode their genes in RNA, ribonucleic acid, an even simpler but less stable molecule.
Genes resemble software; just as a sequence of bits in a computer code tells the computer what to do—whether to run a word processing program, a computer game, or an Internet search, genes tell the cell what to do.
Computer code is a binary language: it has only two letters. The genetic code uses a language of four letters, each representing the chemicals adenine, guanine, cytosine, and thymine (in some cases uracil substitutes for thymine).
DNA and RNA are strings of these chemicals. In effect they are very long sequences of letters. Sometimes these letters do not form words or sentences that make any known sense: in fact, 97 percent of human DNA does not contain genes and is referred to as “nonsense” or “junk” DNA.
But when the letters spell out words and sentences that do make sense, then that sequence is by definition a gene.
When a gene in a cell is activated, it orders the cell to make particular proteins. Proteins can be used like bricks as building blocks of tissue. (The proteins that one eats generally do end up building tissue.) But proteins also play crucial roles in most chemical reactions within the body, as well as in carrying messages to start and stop different processes. Adrenaline, for example, is a hormone but also a protein; it accelerates the heart to create the fight-or-flight response.
When a virus successfully invades a cell, it inserts its own genes into the cell’s genome, and the viral genes seize control from the cell’s own genes. The cell’s internal machinery then begins producing what the viral genes demand instead of what the cell needs for itself.
So the cell turns out hundreds of thousands of viral proteins, which bind together with copies of the viral genome to form new viruses. Then the new viruses escape. In this process the host cell almost always dies, usually when the new viral particles burst through the cell surface to invade other cells.
But if viruses perform only one task, they are not simple. Nor are they primitive. Highly evolved, elegant in their focus, more efficient at what they do than any fully living being, they have become nearly perfect infectious organisms. And the influenza virus is among the most perfect of these perfect organisms.
Louis Sullivan, the first great modern architect, declared that form follows function.
To understand viruses, or for that matter to understand biology, one must think as Sullivan did, in a language not of words, which simply name things, but in a language of three dimensions, a language of shape and form.
For in biology, especially at the cellular and molecular levels, nearly all activity depends ultimately upon form, upon physical structure—upon what is called “stereochemistry.”
The language is written in an alphabet of pyramids, cones, spikes, mushrooms, blocks, hydras, umbrellas, spheres, ribbons twisted into every imaginable Escher-like fold, and in fact every shape imaginable. Each form is defined in exquisite and absolutely precise detail, and each carries a message.
Basically everything in the body—whether it belongs there or not—either carries a form on its surface, a marking, a piece that identifies it as a unique entity, or its entire form and being comprises that message. (In this last case, it is pure information, pure message, and it embodies perfectly Marshall McLuhan’s observation that “the medium is the message.”)
Reading the message, like reading braille, is an intimate act, an act of contact and sensitivity. Everything in the body communicates in this way, sending and receiving messages by contact.
This communication occurs in much the same way that a round peg fits into a round hole. When they fit together, when they match each other in size, the peg “binds” to the hole. Although the various shapes in the body are usually more complex than a round peg, the concept is the same.
Within the body, cells, proteins, viruses, and everything else constantly bump against one another and make physical contact. When one protuberance fits the other not at all, each moves on. Nothing happens.
But when one complements the other, the act becomes increasingly intimate; if they fit together well enough, they “bind.” Sometimes they fit as loosely as the round peg in the round hole, in which case they may separate; sometimes they fit more snugly, like a skeleton key in a simple lock on a closet door; sometimes they fit with exquisite precision, like a variegated key in a far more secure lock.
Then events unfold. Things change. The body reacts. The results of this binding can be as dramatic, or destructive, as any act of sex or love or hate or violence.
There are three different types of influenza viruses: A, B, and C. Type C rarely causes disease in humans. Type B does cause disease, but not epidemics. Only influenza A viruses cause epidemics or pandemics, an epidemic being a local or national outbreak, a pandemic a worldwide one.
Influenza viruses did not originate in humans. Their natural home is in birds, and many more variants of influenza viruses exist in birds than in humans. But the disease is considerably different in birds and humans.
In birds, the virus infects the gastrointestinal tract. Bird droppings contain large amounts of virus, and infectious virus can contaminate cold lakes and other water supplies.
Massive exposure to an avian virus can infect man directly, but an avian virus cannot go from person to person. It cannot, that is, unless it first changes, unless it first adapts to humans.
This happens rarely, but it does happen. The virus may also go through an intermediary mammal, especially swine, and jump from swine to man. Whenever a new variant of the influenza virus does adapt to humans, it will threaten to spread rapidly across the world. It will threaten a pandemic.
Pandemics often come in waves, and the cumulative “morbidity” rate—the number of people who get sick in all the waves combined—often exceeds 50 percent. One virologist considers influenza so infectious that he calls it “a special instance” among infectious diseases, “transmitted so effectively that it exhausts the supply of susceptible hosts.”
Influenza and other viruses—not bacteria—combine to cause approximately 90 percent of all respiratory infections, including sore throats.*
Coronaviruses (the cause of the common cold as well as SARS), parainfluenza viruses, and many other viruses all cause symptoms akin to influenza, and all are often confused with it. As a result, sometimes people designate mild respiratory infections as “flu” and dismiss them.
But influenza is not simply a bad cold. It is a quite specific disease, with a distinct set of symptoms and epidemiological behavior. In humans the virus directly attacks only the respiratory system, and it becomes increasingly dangerous as it penetrates deeper into the lungs. Indirectly it affects many parts of the body, and even a mild infection can cause pain in muscles and joints, intense headache, and prostration. It may also lead to far more grave complications.
The overwhelming majority of influenza victims usually recover fully within ten days. Partly because of this, and partly because the disease is confused with the common cold, influenza is rarely viewed with concern.
Yet even when outbreaks are not deadly as a whole, influenza strikes so many people that even the mildest viruses almost always kill. Currently in the United States, even without an epidemic or pandemic, the Centers for Disease Control estimates that influenza kills on average 36,000 people a year.
It is, however, not only an endemic disease, a disease that is always around. It also arrives in epidemic and pandemic form. And pandemics can be more lethal—sometimes much, much more lethal—than endemic disease.
Throughout known history there have been periodic pandemics of influenza, usually several a century. They erupt when a new influenza virus emerges. And the nature of the influenza virus makes it inevitable that new viruses emerge.
The virus itself is nothing more than a membrane—a sort of envelope—that contains the genome, the eight genes that define what the virus is. It is usually spherical (it can take other shapes), about 1/10,000 of a millimeter in diameter, and it looks something like a dandelion with a forest of two differently shaped protuberances—one roughly like a spike, the other roughly like a tree—jutting out from its surface.
These protuberances provide the virus with its actual mechanism of attack. That attack, and the defensive war the body wages, is typical of how shape and form determine outcomes.
The protuberances akin to spikes are hemagglutinin. When the virus collides with the cell, the hemagglutinin brushes against molecules of sialic acid that jut out from the surface of cells in the respiratory tract.
Hemagglutinin and sialic acid have shapes that fit snugly together, and the hemagglutinin binds to the sialic acid “receptor” like a hand going into a glove. As the virus sits against the cell membrane, more spikes of hemagglutinin bind to more sialic acid receptors; they work like grappling hooks thrown by pirates onto a vessel, lashing it fast. Once this binding holds the virus and cell fast, the virus has achieved its first task: “adsorption,” adherence to the body of the target cell.
This step marks the beginning of the end for the cell, and the beginning of a successful invasion by the virus.
Soon a pit forms in the cell membrane beneath the virus, and the virus slips through the pit to enter entirely within the cell in a kind of bubble called a “vesicle.” (If for some reason the influenza virus cannot penetrate the cell membrane, it can detach itself and then bind to another cell that it can penetrate. Few other viruses can do this.)
By entering the cell, as opposed to fusing with the cell on the cell membrane—which many other viruses do—the influenza virus hides from the immune system. The body’s defenses cannot find it and kill it.
Inside this vesicle, this bubble, shape and form shift and create new possibilities as the hemagglutinin faces a more acidic environment. This acidity makes it cleave in two and refold itself into an entirely different shape. The refolding process somewhat resembles taking a sock off a foot, turning it inside out, and sticking a fist in it. The cell is now doomed.
The newly exposed part of the hemagglutinin interacts with the vesicle, and the membrane of the virus begins to dissolve. Virologists call this the “uncoating” of the virus and “fusion” with the cell. Soon the genes of the virus spill into the cell, then penetrate to the cell nucleus, insert themselves into the cell’s genome, displace some of the cell’s own genes, and begin issuing orders. The cell begins to produce viral proteins instead of its own. Within a few hours these proteins are packaged with new copies of the viral genes.
Meanwhile, the spikes of neuraminidase, the other protuberance that jutted out from the surface of the virus, are performing another function. Electron micrographs show neuraminidase to have a boxlike head extending from a thin stalk, and attached to the head are what look like four identical six-bladed propellers. The neuraminidase breaks up the sialic acid remaining on the cell surface. This destroys the acid’s ability to bind to influenza viruses.
This is crucial. Otherwise, when new viruses burst from the cell they could be caught as if on fly paper; they might bind to and be trapped by sialic acid receptors on the dead cell’s disintegrating membrane. The neuraminidase guarantees that new viruses can escape to invade other cells. Again, few other viruses do anything similar.
From the time an influenza virus first attaches to a cell to the time the cell bursts generally takes about ten hours, although it can take less time or, more rarely, longer. Then a swarm of between 100,000 and 1 million new influenza viruses escapes the exploded cell.
The word “swarm” fits in more ways than one.
Whenever an organism reproduces, its genes try to make exact copies of themselves. But sometimes mistakes—mutations—occur in this process.
This is true whether the genes belong to people, plants, or viruses. The more advanced the organism, however, the more mechanisms exist to prevent mutations. A person mutates at a much slower rate than bacteria, bacteria mutates at a much slower rate than a virus—and a DNA virus mutates at a much slower rate than an RNA virus.
DNA has a kind of built-in proofreading mechanism to cut down on copying mistakes. RNA has no proofreading mechanism whatsoever, no way to protect against mutation. So viruses that use RNA to carry their genetic information mutate much faster—from 10,000 to 1 million times faster—than any DNA virus.
Different RNA viruses mutate at different rates as well. A few mutate so rapidly that virologists consider them not so much a population of copies of the same virus as what they call a “quasi species” or a “mutant swarm.”
These mutant swarms contain trillions and trillions of closely related but different viruses. Even the viruses produced from a single cell will include many different versions of themselves, and the swarm as a whole will routinely contain almost every possible permutation of its genetic code.
Most of these mutations interfere with the functioning of the virus and will either destroy the virus outright or destroy its ability to infect. But other mutations, sometimes in a single base, a single letter, in its genetic code will allow the virus to adapt rapidly to a new situation. It is this adaptability that explains why these quasi species, these mutant swarms, can move rapidly back and forth between different environments and also develop extraordinarily rapid drug resistance. As one investigator has observed, the rapid mutation “confers a certain randomness to the disease processes that accompany RNA [viral] infections.”
Influenza is an RNA virus. So is HIV and the coronavirus. And of all RNA viruses, influenza and HIV are among those that mutate the fastest. The influenza virus mutates so fast that 99 percent of the 100,000 to 1 million new viruses that burst out of a cell in the reproduction process are too defective to infect another cell and reproduce again. But that still leaves between 1,000 and 10,000 viruses that can infect another cell.
Both influenza and HIV fit the concept of a quasi species, of a mutant swarm. In both, a drug-resistant mutation can emerge within days. And the influenza virus reproduces rapidly—far faster than HIV. Therefore it adapts rapidly as well, often too rapidly for the immune system to respond.