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

by Matt Richtel

The researchers let the cancers blossom. Then they injected the mice with a molecule—an antibody—that was aimed at disrupting any connection that the cancer cells might be trying to make to the CTLA-4. The idea was to see if they could keep the cancer from turning on the brakes of the immune system by disrupting the communication between the cancer and the immune system. “We were just trying things out,” Krummel said. A few days later, Allison came in to check out the progress. “I went, ‘Holy shit! It cured all the mice.’”

“They get a signal. They kill themselves. If it didn’t work, people would get diabetes, multiple sclerosis, lupus,” he said. “By far this negative selection is the central tolerance, to get rid of T cells; 90 percent of every T cell that’s developed gets killed.” He’d figured out what CTLA-4 did. “CTLA-4 is there to protect you from being killed by your immune system.”

But as is true of many construction projects, permits must be obtained. The body must accept that what is being built is approved of as “self.” Anything seen as alien to the point of being pathogenic will be destroyed, and the site will not be rebuilt. There is a dangerous corollary. Once permission is given, once the new cells being nourished are deemed “self,” the construction can go on with zeal. The trouble is, the new cells aren’t always self. Sometimes they are cancer.

In the 1990s, Werner started to put the pieces together. What she and others discovered begins to explain why things like smoking or coal mining or sunbathing are so carcinogenic. Each activity injures the tissue and damages the DNA. When the tissue is damaged, the immune system kicks in and cleanses the site and helps stimulate new tissue growth. The trouble is that when the DNA is damaged, the new cells that grow can be malignant cells, some that are made up of self but that are different enough to behave like a cancer. These cells aren’t playing by the normal rules of the body and staying within their boundaries. Add all this together and you can wind up with cancerous cells that are protected and even nurtured by the immune system.

When someone smokes a cigarette, tiny little wounds are created inside the fragile pink tissue of the lung. Into the lungs pour several thousand chemicals, including a number of them that not only damage the DNA but that interfere with repair of DNA. Meanwhile, the police and fire brigade of the immune system shows up, and the process of wound healing begins. New cells are created. Over and over and over, cigarette after cigarette, year after year. (Smoking is a chronic activity, as opposed to, say, inhaling fewer chemicals less directly at the occasional campfire.) In the case of smoking, the malignant cells are fed and protected by the same system that cleaned out the wound in the first place and made sure that no pathogens were there to inflict harm.

Similarly, sun exposure, absent sunscreen, presents another opportunity for a wound and an inflammatory response, which, combined with mutations directly induced by UV irradiation, enhance the risk of the development of skin cancer, including the particularly dangerous melanoma. Other toxins that come into the body, whether food toxins or chemical ones, can also create wounds, places of insult, even minor, that require repair, inflammation, rebuilding. Each minor assault is a chance for cell division and an immune system response that, while intended to cleanse, might also lead to cancer. Smokers are almost certain to get cancer at some point, due to the very certitude of math. If you’re a smoker, you might have cancer right now. In fact, you probably have cancer right now. Most likely, though, it lacks the precise types of genetic changes that will let it proliferate by, in particular, co-opting the immune system. Just because cancer exists doesn’t mean it will take hold.

CTLA-4 turns out not to be the only such brake. One of the others is known as PD-1. The PD stands for programmed death, which I’ve briefly described already. It is a molecule on a T cell that causes the immune system to self-destruct—in effect, to commit suicide.

Dr. Honjo and his team went deeper into the origins and function of programmed death and found that when they disrupted or knocked out the PD-1 gene in mice, a huge portion of the rodents developed autoimmune disorders approximating lupus.

one of the key reasons that Jason’s cancer was out of control was that his immune system was standing down. It had received a signal to stop from the cancer. The drugmakers wanted to interrupt that signal in a systematic way, block it, by shielding the T cell receptor from receiving the signal to stand down.

BEAM, coupled with the emotional challenge of transplantation itself, is so intense that the procedures don’t go forward until a patient is assessed on three levels: Is he responding to the chemo, and is he both physically and emotionally able to survive the experience?

To understand what Bob is teaching us, Dr. Migueles contrasted him with what we now know about how most people react to HIV. Like Bob, they also recognize and confront the virus. They might even recognize and mount a response to the same pieces of virus. The key difference between the immune responses in patients like Bob and the mainstream way of attacking HIV appears to involve the quality and strength of the response. Bob’s CD8 T cells proliferate, or reproduce themselves, to high levels when they reencounter HIV. As they do so, they increase their killing machinery and load their guns to become even better killers. These serial killers efficiently destroy any infected cells in their midst in a focused fashion. The CD8 T cells from most other individuals with HIV mount a much weaker response and have lower killing ability. HLA-B57 and a few other “protective” HLAs probably predispose a person’s immune system to have this impressive response to the virus in a way that we still do not understand, but one does not need HLA-B57 to develop this major immune system offensive.

This is particularly profound because Bob’s own diverse state—as a homosexual—left him, for most of his life, shunned, an outcast, like so many pitiful souls cursed by an ignorant society for being themselves. Now we can see, though, that Bob’s diversity isn’t just obviously one part of the human mosaic; it is one essential for our survival. The more diversity we have—physically, spiritually, intellectually—the better our balance. Just as in the immune system and microbiome. More diversity, more tools.

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.

The glia come in three flavors: astrocytes, oligodendrocytes, and microglia.

In the case of mice with glaucoma, Dr. Barres and his coauthors found an extraordinary relationship between these immune functions and the disease. When mice develop glaucoma, it triggers the microglia to begin eating synapses, including healthy synapses. It’s like the brain’s immune system is turning on itself.

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.”

I went to the company’s website, and that’s where I found additional disclosures. The FAQ on Otezla states: The exact way in which Otezla works in people with psoriasis or psoriatic arthritis is not completely understood. Based on laboratory studies, what is known is that Otezla blocks the activity of an enzyme inside the body called phosphodiesterase 4 (PDE4). PDE4 is found inside the inflammatory cells in the body and is thought to affect the process of inflammation. By blocking PDE4, Otezla is thought to indirectly affect the production of inflammatory molecules, helping to reduce inflammation inside the body. To Dr. Dinarello, the issue of the side effects of these medicines underscores a simple message: “It reveals how sensitive the immune system is to suppression.” Buyer beware. Be aware. Take care. You tinker with the immune system at your own risk.

One particular study, published in 2018, shows the importance of exercise to the immune system and longevity. The study looked at the immune systems of people aged fifty-five to seventy-nine, comparing more sedentary people with regular cyclists. The people who exercised showed several crucial differences in their elegant defenses: The cyclists produced more new T cells from the thymus, and they had fewer cytokines that cause the thymus to decay. The upshot of the research is that exercise slows the natural aging process of the immune system.

“Cancer happens in everyone,” Dr. Jacques Miller, who a lifetime ago discovered the role of the thymus, told me as we discussed the meaning of the immune system and life. The brain will fail, the organs will shut down, the lungs will flood. Some of these will owe to breakdown of our defenses, some to an overwhelming pathogen, but some, like cancer, will arise from a complicity of the immune system itself. 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.”