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

by Matt Richtel

For instance, 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.

Together, autoimmunity is the third most common disease category in the United States (after cardiovascular disorders and cancer). 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.

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.

Bacteria and viruses replicate very quickly—bacteria can multiply every twenty or thirty minutes, some viruses faster.

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.

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.

The B cells came from bone marrow and generated antibodies. The T cells matured in the thymus and could either fight or direct action. They are generals and soldiers.

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Even before science knew all these things, one absolutely essential and common trait of the T cell and B cell stood out: they can learn. These cells are highly adaptive, which is why they are referred to as the “adaptive immune system.” This capability to adapt explains a practical development that is one of the most important life-saving discoveries in our species’s history. Enter the vaccine.

The antibody-encoding genes are unlike all other normal genes.

Or if you prefer a different metaphor, the body has randomly made hundreds of millions of different keys, or antibodies. Each fits a lock that is located on a pathogen. Many of these antibodies are combined such that they are alien genetic material—at least to us—and their locks will never surface in the human body. Some may not exist in the entire universe. Our bodies have come stocked with keys to the rarest and even unimaginable locks, forms of evil the world has not yet seen, but someday might. In anticipation of threat from the unfathomable, our defenses evolved as infinity machines.

Even after a successful transplant, though, the recipient can need a lifelong regimen of immunosuppression.

“The T-lymphocytes, even though they were reactive against that very virus, were not able to kill virus-infected cells from another strain of mice.”

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An individual’s elegant defense didn’t care simply about the infection; it cared about the infection when it attacked its own personal habitat.

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The T cells first determine if you specifically have come under attack. The concept is called the major histocompatibility complex, or MHC—another immunological term that goes down like cold lemonade on a freezing day. The net consequence of MHC is that it allows T cells roaming the Festival of Life to avoid killing what Doherty calls the “normal guys” that happen to be nearby. “The assassination is precise, local, and very specifically targeted!

Studies have shown the MHC gene gives off a scent. The scent is used as a factor in how people choose their mates. If one person’s MHC is too similar to another’s, the MHC will act as a repellent. The scent of MHC that is sufficiently different will act as a magnet.

MHC could be part of the reason that incest has evolved to be so abhorrent.

“From 1976 to 1979, I was scared shitless to publish it,” Dr. Dinarello said. “How can a molecule produced by a human monocyte that causes fever in rabbits also cause a lymphocyte reaction in mice? It was heresy for immunologists.”

“When interferon is secreted, you feel sick. It causes aches and pains; you feel terrible,” Zoon explained. Your behavior is being modified—not by the virus directly, but by the response.

“If you fail to make anti-inflammatory cytokines, you die of mild inflammation.” That’s how powerful this system is. Mild inflammation, wholly unchecked, can kill. Dinarello likes the analogy that the immune system has turned the body into a police state. “You need inflammation to protect against invaders. You need policemen. But if police get too rambunctious, they cause damage and kill innocent people.”

Political and cultural defense systems run amok, hypersensitive, reacting without checks such that they can no longer tell what will spare and preserve them—what keeps them in homeostasis—and what will be their undoing at their own hands.

In a retrovirus, the RNA turns viral; it has contracted a virus. The viral RNA is equipped with a special enzyme that causes a process called reverse transcriptase, which turns the RNA into DNA. In other words, the virus causes the process to go in the opposite, or reverse, direction from the typical genetic process by which DNA instructs RNA. Here RNA has become DNA, and that DNA integrates into the nucleus of the cell and into an organism’s own DNA. Thus this virus has essentially co-opted the organism to make copies of itself—copies that are hard to detect. It squirts out of the cell as viral RNA, infects another cell, and the cycle goes on.

“Over the past century declining family size, improvements in household amenities, and higher standards of personal cleanliness have reduced the opportunity for cross infection in young families,” the paper reads. “This may have resulted in more widespread clinical expression of atopic disease, emerging in wealthier people, as seems to have occurred in hay fever.”

At a core level, we have created a mismatch between our immune system—one of the longest surviving and most refined balancing acts in the world—and our environment.

The concordance between findings from studies in humans and in mice was remarkable: in both studies protection was accompanied by lower levels of eosinophils, higher levels of neutrophils, generally suppressed cytokine responses, and no increase in levels of T regulatory cells or interleukin-10. Thus, the finding that these features were largely dependent on innate immune pathways in mice suggests that innate immune signaling may also be the primary target of protection in the Amish children, in whom downstream adaptive immune responses may also be modulated.

microbiota have developed with the deliberate ability to interact with and stimulate our immune system.

In that respect, Treg cells are not so unusual. What makes them worthy of note here is that there is a decent chance they wouldn’t exist without the presence of the microbiome in the gut. What Mazmanian discovered, using experiments in mice, is that Treg cells don’t get developed when certain gut bacteria are missing. In other words, when the microbiome of the mouse is incomplete, so is the immune system.

That relationship has always been in flux, but the pressures on the relationship have intensified because of human technology, like antimicrobial soaps, antibiotics, and nonorganic foodstuffs. These advances, wonderful in certain respects, hallmarks of human innovation, are so powerful that they have sharply thrown off the tenuous balance between bacteria and us.

There also was a severe reaction involving the natural killer cells too. Remember that these are among the first-line defenders in the immune system—the heavy artillery. During exams, there was a sharp fall in the number of natural killer cells that circulated outside the bone marrow.

It’s tempting to anthropomorphize the cancer and think of it as cunning, or strategic, but, really, cancer is a product of the same evolutionary processes that lead to our own survival, or that of any other species or organisms.

“I’ll tell you one thing. It’s freeing as hell. I spend a lot more time thinking about stuff I love thinking about, writing and playing tennis and even playing music, rather than where my next date is coming from. And having kids and a wife you love—well, it’s impossible to describe how great it is until you’re in it.”

“What happens today is that many people are living with imaginary bears at every step of their lives—something in the news or around the bend is going to get them.” What followed was what he called a “norepinephrine high.”

Leaving semantics and returning to substance, he said that norepinephrine and epinephrine can start to feel, perversely, exciting. “You get addicted to it. You need it. Suddenly it’s going on all the time. The brain is driving it. Now you get all the disruptions of excess. You get dis-regulation of the immune system.”

It is also impossible to overstate, as it speaks to my health and, I suspect, the health of many. I emerged as someone with a sense of confidence to trust myself, which in turn allowed me to listen to the parts of life that excited and motivated me, the kinds of environments and friends that made me comfortable, and the things that I needed to shed as inauthentic. I’d found self.

The more consistent I became with myself, the more I jettisoned what was alien, the healthier I got. I also tell this story because it allowed Jason and me to become real friends, on a much more honest footing than we’d shared as kids.

One interesting bit of medical industry trivia arises here as well. When you see a drug with mab on the end, you now know it stands for monoclonal antibody.

The immune system is making trade-offs to keep the peace, to maintain homeostasis, to let the individual live as long as is practical. It’s just math.

Xenophobia, blind nationalism and racism, is an autoimmune disorder. A culture, tone-deaf in its own defense, attacks so aggressively that it puts itself at serious risk. Biology’s lessons, honed like water-polished stone, teach us that cooperation with our species’ diversity is undeniably key to harmony and survival.

It also helps to cry, she says. She means we need to release stress. Otherwise the stress leads to inflammation, poor mood, fatigue, and heightened inflammation, and that can have lots of correlates. It can affect mood.

This teaches us clearly that our survival, as individuals and a species, is best served by cooperation. This may sound obvious, but civilization, even of late, has been dominated by the push and pull of our competing instincts to cooperate and alienate, to see what people share in common or prey on what divides them.

These effects are so devastating that it is difficult at some points to know the difference in the effects between pathogen and inflammation.

There’s a significant lesson here for society. In our quest to build a perfect and efficient world, we have overcorrected.

These examples are not arguments against progress. This is not Luddite talk. But it is an argument for awareness. Sometimes we cannot control our world and hold it too tightly without squeezing some of the life from it.

The more active you stay, body and brain, the more you signal your internal systems that you continue to play a vital role in your own survival and the survival of the species. This leads to a virtuous cycle in which key internal mechanisms continue to regenerate, allowing you to play a vital role and, when you do that, pushing the cycle on. By contrast, if you grow stagnant, physically and mentally, the system is signaled that you are calling it quits and it need not “waste” resources on your survival.

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