An Elegant Defense

by Matt Richtel

  The breadth of the answer would elude scientists for years. The question was the right one.

  Dr. Ehrlich had a theory. It was both brilliant and wrong. He thought that maybe the human defense system was built around a lock-and-key mechanism. When a disease came along, special cells of the body would come into contact with and attach to the virus or bacteria. Dr. Ehrlich gave a name to the attachment. He called it Antikörper. In English: antibody.

  The idea was that antibodies would attach to parts of the disease called antigens. The antibody was the key and the antigen was the lock. Then the antibodies would help destroy the cell. There were a few problems with Dr. Ehrlich’s theory, advanced though it was. For one, he thought the immune cells carried with them sets of keys called “side chains” that could take the right shape and fit into a lock. This was not right but was still a remarkable guess given his lack of technology, and his idea gave rise to one of the single most important words in the language of the immune system. Antibody.

  For all the wonder of this discovery, and I’ll tell you much more, there is a telling problem with the name antibody. It suggests antibodies go against the body—anti-body.

  Don’t take my word for it. Even some historians in the field have written that the language is complex, even counterintuitive. “The word contains a logical flaw,” reads an authoritative recount of the history of the word. Even more broadly, one pioneering immunologist laughed knowingly when describing the complex vernacular of the immune system and said, “You’ve got a glossary problem.”

  This is consistent with a theme you’ll hear over and over again in the development of the science of the immune system. This group of scientists, immunologists, would win no awards for marketing. They wouldn’t be allowed anywhere near Madison Avenue with words like antibody and antigen, macrophage, phagocytosis, glial cell, and on and on.

  Dr. Ehrlich also discovered a universe of different cell types, ones with different edges and shapes and seemingly different functions—and broadened the peculiar language of immunology with cell names like basophils and neutrophils.

  Were they part of our defense or something else?

  Over time, questions and observations piled up. No wonder. The immune system is one of the world’s most complex organic systems, equaled perhaps only by the human brain, with its origins long preceding the evolution of our species.

  The distant echoes of its beginnings can be found 3.5 billion years ago, roughly when bacteria, the first cellular organisms, appeared. Using sophisticated chemical and molecular tools, scientists have discovered that some bacteria appear to have sophisticated immune systems, which include the ability to identify specific alien threats and encode memories of them so that, upon invasion, these can be neutralized.

  Then about 500 million years ago, a split occurred, resulting in what would evolve into two major immune system lineages. One lineage belongs to non-jawed vertebrates, such as the lamprey and the hagfish. They developed a defense network that is both fundamentally different from ours and nearly as sophisticated. By comparison to ours, theirs is like an ancient language with different lettering, an alternate scripting of the genetic code that confers many of the same defense advantages.

  Twenty million years later, around 480 million years ago, the other lineage finds its roots. We know this because creatures that lived that long ago, like the shark, rely on this second lineage. And so do human beings. In the most fundamental sense, we share an immune system with sharks and other jawed vertebrates.

  The fact that our version of the immune system has been around that long speaks to its power. Evolution doesn’t let things slide that long unless they work.

  It is an ever-vigilant, omnipresent peacekeeping force in the Festival of Life.

  6

  The Festival

  Picture a festival—a wide-open, take-all-comers bash. This is life inside your body.

  Cells swarm inside you, many keeping to their own areas, regions, organs. They are doing the business of survival and it can be an efficient, well-programmed, though busy, affair. Blood pumps; chemicals flow and fluctuate; conditions change with movement, temperature, thought, emotion, age, and illness; and our invisible machine carries out the orders packaged by sturdy genetic code.

  Among these billions of cells, the janitors and manual laborers quietly swarm life’s festival, swallowing up detritus and helping rebuild and fix scaffolding after the occasional tissue damage or disruption. They are part of the immune system. So are sentinels and spies that mingle among our cells, picking up signals, rubbing molecule to molecule, collecting data as they brush by, a passive but zealous presence. Is new tissue growing that is cancerous? Is an organ damaged? Are cells spitting out chemicals suggestive of stress to some part of the body, lack of sleep, duress?

  And the immune system looks for unwelcome invaders.

  Has the body been visited by a pathogen, virus, bacterium, or parasite—perhaps an inhaled ne’er-do-well, or one that entered through a cut in the skin or through invisible excrement insufficiently washed in a bathroom, or picked up on the subway and wiped from the back of a hand into the nose? These pathogens, unlike the healthy cells in our own bodies, don’t like to stay in a particular area. They are built to cross borders, push into virgin tissue, spread, eat, and replicate.

  Once inside, the pathogen mingles with our cells, reproduces, makes a colony. It takes over an edge of the party and spreads. At this point, one or more of a number of first-line immune system cells suspect danger. These have names like neutrophil, natural killer cell, and dendritic cell. They are constituents of a fire brigade. What follows is swelling, pain, fever. This is inflammation. In the festival of your life, a bar fight has broken out—not yet a full-blown war because it is relatively contained, and your immune system aims to keep it that way.

  Many different possible scenarios can follow.

  By way of example, inflammation intensifies as immune cells show up in force and devour the infection. Some immune cells blow themselves up in the process. Others nip off parts of the infection and carry them away to be assessed in a defense hub called a lymph node. There, the bits of infection are shared with swarms of passing defenders called T cells and B cells. These are the immune system’s most advanced fighters; they are, in fact, two of the most effective biological structures in the world. What makes T cells and B cells so remarkable is that they are extremely specific. Each one of the billions of them in your body is tailored through a quirk of genetics to recognize a very specific infection. Once a T cell or B cell finds its evil mate, its infection doppelgänger, it can set in motion a powerful defense, following hard on the innate reaction, bringing defenders trained specifically to bounce out this particular antigen. Explosions! Implosions! Toxic gas attacks! Good guys eating bad guys!

  Sounds like good news, right? Not so fast.

  Keeping the peace in the Festival of Life is fraught with its own danger. Inflammation is not fun for the person experiencing disease, and it can put us at risk. The immune response can be accompanied by fatigue, fever, chills, and aches and pains. In millions of people, excessive immune response is its own chronic disease. This is why the immune system, all things being equal, is designed foremost to keep the peace. Excessive force ends badly. The skirmish hurts, the festival is interrupted, the party gripped by anxiety. Life’s balance has been upset.

  It’s a nearly impossible line the immune system must walk, trying not to overreact in the face of pathogens that are also honed by evolution to survive. They are the cunning, violent, and sometimes stupidly brutal festival crashers.

  These begin attacking before birth, are nasty, and are everywhere.

  7

  Festival Crashers

  As a newborn, in the birthing ward, you are given an injection. The needle punctures your skin, the very first line of your defense network. The threat didn’t even come through the line at the party’s velvet rope—not through your mouth or nose. It was sliced in through the roof.
The steel invades the tissue. It will likely be clean of bacteria. Regardless, it will cause a localized response, a virtual panic among your cells.

  Months later, you might get scratched by the family cat. The cat may carry a microbe. So might the mosquito that landed on your crib and punctured your skin. Mobilization again, within an instant, the most sophisticated defense network in the known world explodes into action.

  Or if you are born in a developing country, your mother may give you a sip of water. It will have a parasite in it, a worm. The parasite will descend into your gut. It will settle there and feed.

  These are the simplest scenarios. It’s possible to imagine endless other circumstances, especially when it comes to a pantheon of bad actors that would make of us their food, their sustenance.

  Allow me to introduce you to the villains and the challenges they present. They are highly varied, numbering in the thousands, at least. They take myriad shapes and have their own array of tactics and weapons. When I try to imagine their range, I picture the scene from the original Star Wars where Han Solo winds up in a fight with a bounty hunter at a bar known as the Mos Eisley Cantina. Nefarious and odd-looking characters fill the party: wind-instrument-blowing band members that look like their bulbous brains are on the outside; a gorilla-resembling alien with cone-like horns; a bounty hunter with a prickly green head; and so forth. They are serial killers and suicide bombers—Ebola viruses, staphylococci, bird flu, pneumonia viruses or bacteria, syphilis spirochetes, smallpox viruses, polioviruses, and on and on.

  As a group, they are known as pathogens, agents that cause disease. It is tempting to think of viruses and bacteria as pathogens, and some of them are, but hardly all. Billions of bacteria cells live inside our bodies without causing harm. In fact, the estimates I’ve seen indicate that as few as 1 percent are likely to make you sick. And there’s a very good chance that you have cancer inside you at this moment, but it is essentially harmless. Like any good story, it can be tough to tell good from evil and indifferent.

  The dangerous ones, though, would, unchecked, take no prisoners.

  First, bacteria. These are likely one of the earliest life-forms, dating to 3.5 billion years ago. What made them early survivors is that they can grow by themselves as long as they have a food source. They are in this way a self-contained unit. They are small. You can fit several thousand bacteria inside a human cell. For such little things, they can be not just deadly but so lethal that they can change the trajectory of human history, shape culture, rewrite the times. The Black Plague, in the fourteenth century, killed 30 percent or more of Europe’s population. Black or bubonic plague is caused by one of the deadliest pathogens known to man, Yersinia pestis, a flea-borne bacterium named for the man who discovered it in 1894, Alexandre Yersin. Just goes to show, you should be careful what you discover. Here are a few other bacteria you don’t want feeding off you: E. coli, salmonella, tetanus bacillus, staphylococci, and syphilis spirochetes.

  Next up: viruses.

  Bacteria, small as they are, though, dwarf viruses. You can fit several thousand viruses in a bacterium.

  Some of the nastier viruses are flu, Ebola, rabies, smallpox. A challenge for viruses is that they tend to be able to reproduce and grow only after they have first invaded a cell and taken over the machinery that it uses to replicate itself.

  There is a theory about the origin of viruses that helps explain their nature. Perhaps bacteria came first, and then more complex cells. Then, bit by bit, some bacteria shed parts of their genetic material through random mutation and evolution, and some of those less complex organisms found a way to infect and live off cells, including mammal cells. Those viruses survived. A second theory suggests that viruses peeled off and evolved from our cells, excreta from the human self that found a way to live off and inside of us.

  Arguably, the most famous virus of our time is the human immunodeficiency virus, or HIV. It belongs to a special category called retroviruses. These organisms have the ability to invade a cell and then integrate themselves into our DNA. They mix with us. Imagine how vexing that is for the immune system, trying to discern alien from self. Meanwhile, there’s another twist: About 8 percent of our genetic material was formed from retroviruses. That means we’ve mingled with these viruses and they’ve become part of us, to the point that they can be not only helpful but essential. An example is the placenta, which may have evolved from a retrovirus in such a way that it helped enable the transmission and sharing of material between mother and child.

  Finally: parasites.

  Parasites can be much more sophisticated than even bacteria, especially the bigger of these noxious organisms.

  They are known as eukaryotic, or “protest,” parasites, which is the fancy term for organisms that aren’t quite evolved enough to be plants or animals. Some are worms. “Tiny slivers in the tree of life,” as Eric Delwart, a molecular virologist at the University of California at San Francisco, described them to me.

  They sometimes are deadly, like malarial sporozoan parasites, sleeping sickness trypanosomes, and that giant risk in unsanitary conditions, giardia. And parasites are sometimes so deadly that, like the Black Plague, they have shaped human history through their genocidal capacities. Such is the case with malaria, a parasite that divides quickly in the blood, essentially overtaking a circulatory system.

  Bacterium, virus, parasite.

  These festival crashers share some important commonalities.

  The dumbest ones are so eager to reproduce and to use our bodies to feed on or replicate that they wind up killing us—in effect, killing the host. Ideally, from their perspective, they’d infect us and then they’d have us share them with another person and keep jumping from human to human. But if they fail to do that, they just reproduce themselves, without an off switch, until we’re toast and they are too. “They’re stupid in that they can get carried away and kill all of us,” one immunologist told me.

  Another commonality is their mobility. They move around and through barriers in our bodies more easily than other cells. In fact, many cells are quite content to stay in their region or organ, their area of the Festival of Life. Pathogens break through the barriers. Bacteria, for instance, can have little tails, called flagella, little motors that give them bursts of acceleration. A salmonella bacterium, for instance, swallowed with food, might use this propulsive tail to burst through the lining of the gut and into the body. It is built to invade.

  The next challenge, and it’s a big one, is that these organisms are highly variable.

  Bacteria and viruses replicate very quickly—bacteria can multiply every twenty or thirty minutes, some viruses faster. Each act of reproduction creates an opportunity for a change, a mutation, a moving around of genetic sequences that can turn a virus or bacteria that our body has figured out how to fight into a virus or bacteria that our body does not know how to defend itself against.

  The human reproductive cycle gives rise to a new generation roughly every twenty years. We can’t possibly survive an arms race with organisms that change at so much more rapid a pace.

  Another way to think about it is that bacteria can divide so quickly that if left unchecked, they could take over our entire body in four days. But our own cells divide relatively slowly, such that they create about sixteen new ones from each cell on a given day. Math is working against us.

  So how could it be that a single human body could be prepared to deal with so many threats, including ones that might not even exist yet? Think of it: Our immune systems need to cope with rapid-fire mutations from reproducing pathogens—or a protein-based life-form from outer space.

  This conundrum is amplified by more simple math. We have a limited number of genes. In the 1970s, that number was thought to be around 100,000 genes in the human genome. Since then, we have learned the number is actually much smaller, perhaps 19,000 to 20,000.

  How can we possibly defend ourselves?

  “God had two options,” Jason’s cancer doctor
told me. “He could turn us into ten-foot-tall pimples, or he could give us the power to fight 10 to the 12th power different pathogens.” That’s a trillion potential bad actors.

  Why pimples? Pimples are filled with white blood cells, which are rich with immune system cells (I’ll elaborate in a bit). In short, you could be a gigantic immune system and nothing else, or you could have some kind of secret power that allowed you to have all the other attributes of a human being—brain, heart, organs, limbs—and still somehow magically be able to fight infinite pathogens.

  “This is what makes the immune system so profound,” Jason’s doctor said.

  Much of what I’ll explicate in this book is that magic, the way we can survive without being just one big pimple.

  Meanwhile, though, there are several other fundamental challenges to our immune system—along with the variety and mutability of bad actors.

  One such hurdle has to do with the heart. It’s a liability. The trouble with such a powerful central circulatory system is that it pumps blood around our entire body, and fast. Blood moves from head to toe in seconds. So if a pathogen gets into the bloodstream, Whoosh! This can quickly become a condition called sepsis—infection in the blood—which can be deadly. A major role of the immune system is to keep infection out of our circulatory system.

  Another basic structural complication for the immune system comes from the reality of defending a living creature that must have the ability to grow and heal. The body has to regenerate tissue, all of the time, and replace damaged or outdated cells. Take, for instance, the simple example from the birthing ward: When the vaccination pierces the baby’s skin, the body must be able to replace that divot of skin. This is the case too when a splinter stabs or the cat bites. Otherwise, we’d just degrade, erode, bit by bit, like a hill of sand in the rain.

  In order to heal, our cells must divide, proliferate. This might sound obvious and simple. But it’s precarious for the immune system. That’s because it must simultaneously allow new tissue to be developed while also watching with enormous care for bad cells, mutations that are rotten, incomplete, or faulty. That’s called cancer.