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

by Matt Richtel

In an immature B cell, the strands of V, D, and J material are in separate groupings, and they are separated by a relatively massive distance. But as the cell matures, a single, random copy of V remains, along with a single each of D and J, and all the other intervening material drops out. As I began to grasp this, it helped me to picture a line of genetic material stretching many miles. Suddenly, three random pieces step forward, and the rest drops away. The combination of these genetic slices, grouped and condensed into a single cell, creates, by the power of math, trillions of different and virtually unique genetic codes.

Simply put, if all of our defense systems were the same, a single deadly disease could come along and wipe out the lot of us.

This tension between sameness and individuality leads to certain trade-offs. One of them is that we cannot easily exchange our parts—say, my leg for yours or my immune system for yours. In fact, a defense system that works wonders protecting one person can be quite deadly in the life of another. The broader history of transplantation helped yield key clues to the extraordinary specificity of our defense networks.

Many of these battlefield and deathbed stories would lead me to realize a hard reality about science and scientists, especially immunologists. Often, great discoveries have been made on the cusp of death through experimentation on a patient.

The essential idea, if it’s not already obvious, is to lessen the reactivity of the body’s defenders so they do not attack the transplanted organ as foreign. This broadens the possible transplant matches.

Work by a French immunologist, and others, isolated in human beings the first antigen that reacted against other human beings. These are called isoantigens—antigens within the same species.

This development made it possible for doctors to test ahead of time which transplant matches might be the best fits by eliminating candidates whose tissues were likely to clash. The fancy immunological term to describe isoantigens is human leukocyte antigen (HLA).

“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.” In other words, the immune system was able to discern a cell that was self and had been infected from a cell that was not self. The immune system killed only the infected ones that were self. An individual’s elegant defense didn’t care simply about the infection; it cared about the infection when it attacked its own personal habitat. Italicized because it’s a key scientific insight.

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.

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.

This tells us that, while the immune systems are different, certain defense functions seem essential for survival. One such function is redundancy. There are multiple molecules and cells in both systems, including some proteins that seem to do virtually the same thing—whether it be attacking, inducing attack, or slowing it.

“Inflammation is—very generally speaking—the body’s immune system’s response to stimulus.”

I’ve already introduced you to one of the key cells. It is called a macrophage. It is the cell type observed a hundred years ago by Élie Metchnikoff, the Russian scientist who, as I described earlier, stabbed a starfish larva with a splinter and, looking through the microscope, saw wandering cells swarm to the site of the insult.

devouring other cells in the region of the splinter. The technical term for one cell eating another is phagocytosis. That word derives from the Greek word phageîn, which means to eat. So the macrophages are big (macro) eaters. These cells are like the love child of a janitor and a cop who eats first and asks questions later. They attack cells in the region that might be damaged or infected by consuming them and then chemically blitzing the devoured particles.

The dendritic cells roam the Festival of Life, brushing up against guests at the packed affair, and presenting their identities to the T cells. If an antigen were perceived as foreign, it would stimulate a heavy response, what is known as a mixed leukocyte reaction, or MLR, a major inflammation of T cells and B cells and other immune cells.

In fact, T cells and B cells, together known as lymphocytes, make up only as much as 40 percent of the white blood cells. The monocytes comprise 5 percent, give or take. The biggest chunk is made up of cells known as neutrophils. They are both spies and assassins.

The neutrophils might dip into tissue or an organ for a bit, look for pathogens and, finding none, then return to the bloodstream, to continue monitoring and smelling. They can pick up scents, or chemical releases, of pathogens.

In much smaller concentration in the body are two other defenders, the eosinophil (less than 5 percent of the white blood cell population) and the basophil (less than 2 percent). Combined, they are known as granulocytes. This name reflects their function. These cells contain tiny enzymatic granules that digest and destroy pathogens.

The strangest thing happened. There was an immune reaction. The spleen’s immune cells attacked. That alone wasn’t necessarily at odds with previous learning; after all, perhaps the immune cells had antibodies that recognized something foreign. But, quite oddly, the attack didn’t involve any B cells or T cells. The response was less specific than the targeted nature of B cell and T cell attacks. These “new” cells swarmed instantly in a kind of raw, generic manner that seemed more consistent with a knee-jerk attack than the specified, deliberate nature postulated by clonal selection theory.

A partial answer came from the mid-1970s revelation about fever—a discovery set off by the temperature spikes exhibited by the Caribbean woman who showed up at Yale and that became the obsession of Dr. Charles Dinarello.

And it came from a monocyte, one of those immune cells like the macrophage (which devours refuse and pathogen), but one that now appeared to have much broader function. Dr. Dinarello called it a leukocytic pyrogen—a fire starter born of the white blood cells, the leukocytes.

“He realized, ‘Oh my god, it’s not coming from the neutrophil. It’s coming from the monocyte,’” recalled Dr. Fauci, who worked with Dr. Dinarello on the eleventh floor. When Dr. Fauci related the

Broadly, the leukocytic pyrogen was a kind of mediator, communicator. Interleukin-1, the first interleukin, was born. Dr. Dinarello might fairly be called its midwife. Armed with this knowledge alone, you’re on your way to earning a bachelor’s degree in immunology. The story doesn’t quite end there. Maybe the most important part was yet to come, and it would make Dr. Dinarello quite a controversial figure.

A scientist who headed up efforts at the World Health Organization to develop world policy to limit use of antibiotics told me that philosophically, there’s a lesson that goes counter to a century of marketing: We’re not safer when we try to eliminate every risk from our environment.

This act goes to the heart of another key aspect of the increase in allergy and autoimmunity. It also concerns our overall health and the balance of the immune system. Meet your friendly neighborhood bacteria: the microbiota.

The paper from Boulder notes that human beings have virtually the same set of genetic material—you and I are 99.9 percent similar in our underlying genetic building blocks. But the microbiome—the underlying genetic material of the bacteria in our gut or hand—can differ by 80 to 90 percent. (Worth

This lining, it was thought, kept our microbiota from getting into the rest of the body and thus away from the immune system. This theory is called immunological ignorance. The immune cells, in effect, were thought to be ignorant of these bacteria among us. This thinking was incomplete, if not outright incorrect. Mazmanian and others have since found that the gel that lines the gut is colonized by the microbiota, and their presence puts them very much in close proximity to cells that can trigger an immune response. On the other side of that gel-like wall is a line of cells, called epithelial cells, that is heavy with immune triggers.

Dr. Barres postulated to me that evolution has allowed such a process to go forward because older human beings are less valuable to the species. “There’s nothing in evolution that would select for good brain health when you’re aging. You’re already through reproduction.”

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. “Crying is beneficial,” she says. It’s an acknowledgement of who and where you are, an embrace of self at a given time and, as such, it helps the immune system by sparing it from having to deal with the repressed anxiety. Crying “is not fun. It’s painful. But you feel better in many cases thereafter, as opposed to eating the chocolate doughnut.”

It seeks peace with its surrounding environment. This is a far different idea from the one I began with when I started to learn about the immune system and assumed—as I suspect many people do—that its chief jobs are to defend and attack. Defend, yes; attack, not necessarily. In fact, the immune system is constantly seeking to maintain harmony, not just by limiting its attacks to all but the most necessary ones, but also by cooperating with the organisms that surround and invade it. At its core, it tries to discern self from other, but having done so, it doesn’t just destroy what is alien.

In fact, among the biggest misconceptions that I took into this book was that it is better to have a superpowered immune system. The advertisements are everywhere urging “Boost your immunity!” Wrong.

Dr. Fauci, one of the leading scientific lights in the world, said that when he hears ads promising to boost your immune system, “it almost makes me chuckle. First of all, it is assuming your immune system needs boosting, which it very likely doesn’t. If you do successfully boost your immune system, you might boost it to do something bad. Even with the very dramatic positive results we’re getting from immune therapy with cancers, we’re looking at clinical trials with very, very toxic side effects. It doesn’t just suppress the cancer but puts in a bunch of things that put system out of whack.”

And there is arguably no more powerful medicine on earth than antibiotics. They are vital for our survival. Full stop. But their widespread use also threatens now to cause the evolution of bugs that will make past plagues look like the common cold.

The takeaway here is to understand the risks and the motivations of companies selling the drugs that address diseases. “The pharmaceutical industry has made a business out of targeting them with specific drugs and antibodies. I can’t stand it any longer,” said Dr. Dinarello, who helped us understand fever and interleukins. “Psoriasis, arthritis, bowel disease. The industry is targeting different ways of treating them—all targeting cytokines.” But the risk is infection, even cancer. Why? Because, as you now know, you’re tinkering with a very sensitive system.

For those who seek a different path, like Merredith, there are things we can manage, things that science shows us are powerful. The best examples are those over which we have complete control: sleep, exercise, meditation, and nutrition.

Or you can take your cue from Dr. Ephraim Engleman, who was an immunology giant who by most standards lived forever. At one hundred and four, he got his driver’s license renewed. He still commuted to the office to study autoimmune disease. He died just shy of his hundred and fifth birthday. He was in his lab, at the University of California at San Francisco, where he pioneered research into causes and cures of rheumatoid arthritis. The

An obituary published by the university listed his self-professed secrets for longevity: Avoid air travel, have lots of sex, keep breathing, and most appropriately, enjoy your work, whatever it is, or don’t do it. So there’s

I tie these points together with my own observation drawn from the sum of my research. 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, physica...

The reason is that the immune system hasn’t evolved to defend us as individuals. It has evolved to defend our genetic material and the species as a whole. It does an extraordinary job of keeping us alive until we reproduce and then rear our offspring. After that, it does an even better job of moving us out of the way.

“Evolution has decreed we cannot live forever,” Dr. Miller said. “Nature, evolution, has decreed you’ve got to make way for the next generation.” Ruslan Medzhitov, the Yale scholar whose pioneering work illuminated the innate immune system, echoed this thought and added a point that no medicinal fix we contrive will lead us to live forever. “There is no ultimate solution. There is no free lunch. If you cure cancer, you will have more cases of neurodegenerative disease. If you cure neurodegenerative disease, a major plague will come for people who are a hundred years old. There is no ultimate solution, nor should there be.”

The Meaning of Jason holds two competing principles in exquisite balance: We must continue to strive, dream, and exercise all the passions that have gotten us this far, while also doing a much better job of accepting death. Death is not just inevitable, not just programmed into us and facilitated in ways by our immune system. It is essential for our survival. It is not an easy leap to at once be driven by terror of death and yet embrace it with humility and grace. Our continued health lies in creating this balance, as elegant as the balance struck by the immune system itself.

I dared not dream of having such offspring and somehow did. The prospective horror of leaving behind a son and daughter, a family, or losing one, has become palpable. Like so many, I count my blessings every day. Each day, I count with a little more gratitude. We have a finite time in this Festival of Life. It is beautiful. It hurts.

Dr. Mike McCune,