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.
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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.
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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 c
ell 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.
CHAPTER EIGHT
AN INFECTION is an act of violence; it is an invasion, a rape, and the body reacts violently. John Hunter, the great physiologist of the eighteenth century, defined life as the ability to resist putrefaction, resist infection. Even if one disagrees with that definition, resisting putrefaction certainly does define the ability to live.
The body's defender is its immune system, an extraordinarily complex, intricate, and interwoven combination of various kinds of white blood cells, antibodies, enzymes, toxins, and other proteins. The key to the immune system is its ability to distinguish what belongs in the body, 'self,' from what does not belong, 'nonself.' This ability depends, again, upon reading the language of shape and form.
The components of the immune system (white blood cells, enzymes, antibodies, and other elements) circulate throughout the body, penetrating everywhere. When they collide with other cells or proteins or organisms, they interact with and read physical markings and structures just as the influenza virus does when it searches for, finds, and latches on to a cell.
Anything carrying a 'self' marking, the immune system leaves alone. (It does, that is, when the system works properly. 'Autoimmune diseases' such as lupus or multiple sclerosis develop when the immune system attacks its own body.) But if the immune system feels a 'nonself' marking (either foreign invaders or the body's own cells that have become diseased) it responds. In fact, it attacks.
The physical markings that the immune system feels and reads and then binds to are called 'antigens.' The word refers to, very simply, anything that stimulates the immune system to respond.
Some elements of the immune system, such as so-called natural killer cells, will attack anything that bears any nonself-marking, any foreign antigen. This is referred to as 'innate' or 'nonspecific' immunity, and it serves as a first line of defense that counterattacks within hours of infection.
But the bulk of the immune system is far more targeted, far more focused, far more specific. Antibodies, for example, carry thousands of receptors on their surface to recognize and bind to a target antigen. Each one of those thousands of receptors is identical. So antibodies bearing these receptors will recognize and bind only to, for example, a virus bearing that antigen. They will not bind to any other invading organism.
One link between the nonspecific and specific immune response is a particular and rare kind of white blood cell called a dendritic cell. Dendritic cells attack bacteria and viruses indiscriminately, engulf them, then 'process' their antigens and 'present' those antigens - in effect they chop up an invading microorganism into pieces and display the antigens like a trophy flag.
The dendritic cells then travel to the spleen or the lymph nodes, where large numbers of other white blood cells concentrate. There these other white blood cells learn to recognize the antigen as a foreign invader and begin the p
rocess of producing huge numbers of antibodies and killer white cells that will attack the target antigen and anything attached to the antigen.
The recognition of a foreign antigen also sets off a parallel chain of events as the body releases enzymes. Some of these affect the entire body, for example, raising its temperature and causing fever. Others directly attack and kill the target. Still others serve as chemical messengers, summoning white blood cells to areas of invasion or dilating capillaries so killer cells can exit the bloodstream at the point of attack. Swelling, redness, and fever are all side effects of the release of these chemicals.
All this together is called the 'immune response,' and once the immune system is mobilized it is formidable indeed. But all this takes time. The delay can allow infections to gain a foothold in the body, even to advance in raging cadres that can kill.
In the days before antibiotics, an infection launched a race to the death between the pathogen and the immune system. Sometimes a victim would become desperately ill; then, suddenly and almost miraculously, the fever would break and the victim would recover. This 'resolution by crisis' occurred when the immune system barely won the race, when it counterattacked massively and successfully.
But once the body survives an infection, it gains an advantage. For the immune system epitomizes the saying that that which does not kill you makes you stronger.
After it defeats an infection, specialized white cells (called 'memory T cells') and antibodies that bind to the antigen remain in the body. If any invader carrying the same antigen attacks again, the immune system responds far more quickly than the first time. When the immune system can respond so quickly that a new infection will not even cause symptoms, people become immune to the disease.
Vaccinations expose people to an antigen and mobilize the immune system to respond to that disease. In modern medicine some vaccines contain only the antigen, some contain whole killed pathogens, and some contain living but weakened ones. They all alert the immune system and allow the body to mount an immediate response if anything bearing that antigen invades the body.
The Great Influenza Page 12