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Kindle Notes & Highlights
by
Matt Richtel
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October 17 - October 25, 2019
The complex defense network of cells attacks each cold virus—two to three a year—surveys the countless malignancies that threaten to become cancer, holds in check viruses like herpes that colonize huge swaths of the population, and confronts hundreds of millions of cases each year of food poisoning. Only recently have we begun to understand the pervasive role of our immune system in the brain, where damaged or outdated synapses get pruned by the organ’s own immune cells, allowing ongoing neurological health.
The immune system is often described with the language of war, one that pits our internal forces against evil disease by using powerful cells capable of surveillance and spying, surgical strikes and nuclear attacks.
And yet, for all these threats, the war metaphor is misleading, incomplete—even arguably dead wrong. Your immune system isn’t a war machine. It’s a peacekeeping force that more than anything else seeks to create harmony. The job of the immune system is to circulate through this wild party, keeping an eye out for troublemakers and then—this is key—tossing out bad guys while doing as little damage to other cells as possible. This is not just because we don’t want to hurt our own tissue. It is also because we need many of the alien organisms that live on and in us, including the billions of
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Like an out-of-control police state, an unchecked immune system can grow so zealous that it turns as dangerous as any foreign disease. This is called autoimmunity. It is on the rise. Fully 20 percent of the American population, or 50 million Americans, develops an autoimmune disorder.
house. Smoking tests the immune system like few human habits; the tiny nicks and cuts to the soft lung tissue don’t just create persistent injury but force cells to divide to replace the hurt tissue. Cell division heightens the possibility for malignancy, cancer. This is just simple math, and it can be deadly.
Robert T. Hoff became an immune system marvel on Halloween night of 1977. He was dressed as a mummy.
The setting was the University of Padova in northern Italy, at the end of the sixteenth century. There was at that time a young researcher named Fabricius ab Aquapendente who liked to cut things up. He dissected eyes, ears, animal fetuses, and occasionally humans. But history remembers him for a chicken.
In the biography, she defined inflammation as “a curative reaction of the organism, and morbid symptoms are no other than the signs of the struggle between the mesodermic cells and the microbes.”
Nine years later, in 1891, a contemporary of Metchnikoff’s named Paul Ehrlich—a godfather of immunology who was based in Berlin—began a search for a “magic bullet.”
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 distant echoes of its beginnings can be found 3.5 billion years ago, roughly when bacteria, the first cellular organisms, appeared.
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.
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.
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.
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.
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.
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.
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.
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.
Black or bubonic plague
Next up: viruses. Bacteria, small as they are, though, dwarf viruses. You can fit several thousand viruses in a bacterium.
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.
Finally: parasites. Parasites can be much more sophisticated than even bacteria, especially the bigger of these noxious organisms.
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.
Another commonality is their mobility. They move around and through barriers in our bodies more easily than other cells.
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
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.
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.
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.
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.
Jacqueline died on Christmas Day. Three years later, in New Jersey, researchers isolated streptomycin, the first antibiotic that could kill tuberculosis. Selman Abraham Waksman, the head of the lab at Rutgers University where the discovery was made, won the Nobel Prize for its discovery in 1952.
In 1900, for instance, the leading causes of death per 100,000 patients were pneumonia and flu, followed by tuberculosis and gastrointestinal infection. Heart disease and cancer were well down the list.
The doctor who saw him at Walter Reed was an eventual immune system luminary named Colonel Ogden Bruton.
infection. Antibodies, to repeat, are keys that help detect and connect to parts of disease. Cells with antibodies circulate your Festival of Life, looking for their malicious matches.
What the boy and the test told the researchers was that when antibodies weren’t present, something terrible could happen.
A nasty divide erupted among immunologists about the core source of the body’s defenses. One camp thought the antibody was the center of the action. This was a substance, a process, a chemical reaction of some kind that helped attack alien threats. It was called antibody-mediated immunity. But others thought the T cell was the center of all the action. Their philosophy was called cell-mediated immunity. It meant that these T cells ruled the day.
B cells can also recognize pathogens more directly using a special kind of receptor called an antibody. Antibodies are protein molecules with extraordinary abilities, and they are central to the immune system.
Like an antenna, antibodies pick up signals. But each antibody is finely tuned. It picks up only one type of signal. In fact, so particular is each antibody that most of the billions of white cells coursing through us generally have unique antibodies on their surfaces. So unlike most antennae—say, radio towers—the antibody receptor doesn’t pick up just any signal. It picks up one. It is evolved to connect to a single kind of organism.
What the antibody attaches to is its own little nub or receptor on a cell. The thing it attaches to is called an antigen. An antigen is the mate to an antibody. The antibody and the antigen bind to each other, like a lock and a key.
It’s not that our elegant defenses won’t mount an attack against these diseases absent a vaccine, but the attack might well be insufficient given the time it takes for the immune system to identify the bug and start manufacturing enough soldiers to fight back. In the meantime, you might well die.
Smallpox was spread through the air, by sneezes, coughs, or close interaction with a victim. It killed 30 percent of those who contracted it. Its lethality has to do with the way it and related viruses pull a stunt on the immune system. The infections can block the transmission of a distress signal that calls killer immune cells into action.
The setting was Gloucestershire, England, in 1796. It is hallowed ground well-trodden in the history books. Dr. Jenner noticed that the cow’s milkmaids had pustules but didn’t seem to get the deadly disease. From a cowpox lesion of a milkmaid, he poisoned an eight-year-old boy. The boy lived. Somehow this cowpox strain was the right varietal to spark an immune system defense. Happy birthday, world’s first vaccine!
One history, written by a Yale doctor and historian named John Paul, is quoted as saying that Brodie’s vaccine was tested on 3,000 children, but “something went wrong, and Brodie’s vaccine was never used again.” A history published in the New York Times is more explicit: Children were left paralyzed.
In 1952, as Time magazine reported, the worst outbreak yet infected 58,000 Americans, killing 3,000 and paralyzing 21,000.
Broadly, antibiotics work by taking advantage of differences between human cells and bacterial cells; for instance, bacterial cells have walls that human cells do not. Antibiotics can prevent bacteria from building such walls.
Whereas vaccines prompt our own response, antibiotics import a response from the outside, and that is an absolutely critical distinction for our everyday health. The reason is that when you add an outside force, you disrupt the natural order. Even if the goal is preservation of life, and even if it works, that doesn’t mean the process is without important risks. In the case of antibiotics, these terrific killers don’t just kill off bad bacteria; they target good stuff too, including bacteria crucial to your health and well-being.
How can your T cells and B cells react to a pathogen they’ve never seen, never knew existed, and were never inoculated against, and that you, or your doctors, in all their wisdom, could never have foreseen? This is the infinity problem. For years, this was the greatest mystery in immunology.
Tonegawa wound up at the University of California at San Diego, at a lab in La Jolla, “the beautiful Southern California town near the Mexican border.” There, in multicultural paradise, he received his PhD, studying in the lab of Masaki Hayashi and then moved to the lab of Renato Dulbecco. Dr. Dulbecco was born in
But when he compared the segments to identical regions in mature B cells, the result was entirely different. This was new, distinct from any other cell or organism that had been studied. The underlying genetic material had changed. “It was a big revelation,” said Ruslan Medzhitov, a Yale scholar. “What he found, and is currently known, is that the antibody-encoding genes are unlike all other normal genes.”
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