An Elegant Defense: The Extraordinary New Science of the Immune System: A Tale in Four Lives

by Matt Richtel

the very mechanisms that defend our individual health appear to play a role in such essential functions as how we pick mates—helping us to avoid incestuous pairings that might damage our collective security and survival.

The immune system’s policing job gets complicated by the porous nature of our bodies’ borders. Just about every organism that wants to get inside us can do so.

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.

Fully 20 percent of the American population, or 50 million Americans, develops an autoimmune disorder. By some estimates, 75 percent are women, with conditions like rheumatoid arthritis, lupus, Crohn’s disease, and irritable bowel syndrome (IBS)—each terrible, frustrating, debilitating, hard to diagnose.

Diabetes, the leading killer in the country, is caused by the immune system’s going to war against the pancreas.

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.

In the medical realm, Robert Hoff is a veritable state treasure. His body parried HIV, and death, as perhaps no one had done before him, so his precious immune system offered insights and promise for the rest of us too.

Broadly, it is hard to overstate the toll taken by autoimmunity. Of the five top-selling drugs on the market, three treat autoimmunity, including the world’s bestselling medication, Humira, used to suppress the immune system for treatment in a variety of illnesses. It boasts nearly $20 billion in annual sales.

What we can see clearly now is that arthritis sufferers, people with celiac disease or lupus, even people who suffer seemingly mysterious bouts of fatigue, fever, and pain, all share an often-invisible threat: an elegant defense that is out of balance, an immune system that has overcompensated, been triggered to act without proper constraint.

the way autoimmunity plays out, not just the physical agony but the often unending frustration involved in trying to diagnose these complex medical conditions.

Merredith had been diagnosed with at least three autoimmune disorders, including lupus and rheumatoid arthritis. Merredith’s immune system had turned on her own body as if it were itself an alien threat. She was almost never without a challenge, often running a low-grade fever twenty days or more every month, a few days of that as high as 100. It was just enough to create regular fatigue, not enough to knock her out completely.

Dissecting a fowl one day, Fabricius noticed an odd region beneath the chicken’s tail. He found a saclike organ, which he called the bursa, a word that shares its derivation with the modern word purse. Henceforth, the bursa of Fabricius.

On July 23, 1622, an Italian scientist named Gaspare Aselli dissected a “living well-fed dog,” recounts one history of this seminal surgery. In its stomach, he observed “milky veins.” This observation wasn’t consistent with an understanding of a circulatory system carrying red blood.

Aselli’s dissection set off a period of exploration that the history calls lymphomania, a fascination with a little understood bodily fluid called lymph, along with the dissection and vivisection of hundreds of animals.

Phagocytosis is the process by which the devouring happens. (And congratulations, reader! You’ve been introduced to the language of immunology, at times one of the most maddening and even counterintuitive lexicons ever contrived.)

At the moment of invasion, the body has an initial reaction that involves the swarming of eater cells, and the experience is not always pleasant. This is what we call inflammation. Know this about Metchnikoff: The man was way ahead of his time.

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.

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.

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.

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.

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.

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.

In the most fundamental sense, we share an immune system with sharks and other jawed vertebrates.

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.

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.

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.

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.

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.

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,

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.

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.

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.

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.

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.

the placenta, which may have evolved from a retrovirus in such a way that it helped enable the transmission and sharing of...

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.

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.

“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).

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.

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.

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.

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.

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 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.

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.

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.

The Swiss treated the disease by injecting air into the chest to cause a lung to collapse. The hope was that this would crush the bacteria and then give the lung a period of rest so that it could reset. Later, while the family was in Shanghai, Jacqueline’s father would take her for rides in the countryside so she could breathe fresh air. Meanwhile, as her father tried in vain to help her, he also fought in his modest way to battle fascism, secretly helping to smuggle Frenchmen from the French concession onto boats leaving China for Britain.

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. A century earlier, the first publication of The New England Journal of Medicine in the early 1800s lists a study of causes of death that includes 942 patients, nearly a third of whom died from consumption. Almost 50 deaths were stillborns, slightly fewer succumbed to typhus, only 5 had cancer, and a single patient, who, well, medicine could do little about, was struck by lightning.