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.
Only in recent years have we learned that the immune system helps with cell division, promoting healing and rebuilding tissue. But in the process of helping rebuild the body, the immune system can have a hard time discerning bad or mutated cells, ones that look much like us, which are mostly self, but part alien. If it can’t tell the difference or gets tricked in some other way by the cancer so that it ignores the usual signals that halt the division of malignant cells, what follows is uncontrolled and reckless growth that is disruptive to normal tissue architecture and function. The immune system can wind up protecting the malignancy.
The line that the immune system must walk is a tightrope over an abyss, with death to the left and the right.
Survival depends on knowing what is self and what is alien. The immune system must cope with three major challenges: the variability of bad actors, the central circulatory system that sends rivers of blood throughout our body in seconds, and the need to heal.
And the immune system must do all that without so overheating that it kills us in the process. It walks the most delicate path. It succeeds with the help of peacekeepers so effective that their work could be mistaken for magic.
The last seventy years in immunology have been a pursuit to understand how the trick works, how our defense apparatus does what it does, at the core. This astounding journey took an arc that moved from a crude conceptual understanding of the immune system and worked down to the molecular level. As a result, medicine can now get in on the magic and begin to meddle with your health inside the machine of your elegant defense.
To explain how this all this applies to your health—and that of Jason, Linda, Merredith, and Bob—I will spend the next hundred or so pages telling you the story of scientific discovery. It goes like this, in brief: scientists got an idea about these things called T cells and B cells, started applying big conceptual knowledge through life-saving vaccines and transplants, and then these imaginative and innovative immunologists delved into the tiny fragments of the immune system, the cogs, and built a blueprint of the machine. They understood, as I’ll describe, what inflammation is about, and the molecules that make up our communications network. With each advance of science came another practical step, like building medicines by replicating our defense cells, and then would come another extraordinary scientific leap, like the discovery only a few years ago of a second immune system.
You can think of the immunologists as explorers or Argonauts, pick your metaphor. The deeper and further they got beyond the shore and surface, past the conceptual and theoretical and into the detail, the healthier we got, the longer we lived. Their discoveries saved hundreds of millions of lives, and they are impacting your life and health right now.
So join me on a tour of crucial discoveries and their meaning, starting in a shed in England.