by Matt Richtel
Only in recent years have we learned that the immune system helps with cell division, promoting healing and rebuilding tissue. But in the process of helping rebuild the body, the immune system can have a hard time discerning bad or mutated cells, ones that look much like us, which are mostly self, but part alien. 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 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.
And the immune system must do all that without so overheating that it kills us in the process. It walks the most delicate path. It succeeds with the help of peacekeepers so effective that their work could be mistaken for magic.
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.
To explain how this all this applies to your health—and that of Jason, Linda, Merredith, and Bob—I will spend the next hundred or so pages telling you the story of scientific discovery. It goes like this, in brief: scientists got an idea about these things called T cells and B cells, started applying big conceptual knowledge through life-saving vaccines and transplants, and then these imaginative and innovative immunologists delved into the tiny fragments of the immune system, the cogs, and built a blueprint of the machine. They understood, as I’ll describe, what inflammation is about, and the molecules that make up our communications network. 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.
You can think of the immunologists as explorers or Argonauts, pick your metaphor. The deeper and further they got beyond the shore and surface, past the conceptual and theoretical and into the detail, the healthier we got, the longer we lived. Their discoveries saved hundreds of millions of lives, and they are impacting your life and health right now.
So join me on a tour of crucial discoveries and their meaning, starting in a shed in England.
8
The Mystery Organ
In 1941, the world was at war and so were the insides of Jacqueline Miller. A slender and beautiful seventeen-year-old brunette, she coughed until her throat turned raw. She carried with her a spittoon to gather the bloody sputum she rejected from her tattered lungs. For four years, she’d battled tuberculosis, and things were growing dire.
She was helped little by her family’s relative wealth and the opulent setting in which she lived. Her father, the manager of a Franco-Chinese bank, had secured a placement in Shanghai, helping the family escape from Europe after Nazi Germany’s invasion of France. They took a hurried car ride to Italy and lucked onto the last passenger boat out of Trieste. In China, the family lived in a modern cylindrical five-story house with twenty-four servants—“like kings,” recalled Jacques Miller, Jacqueline’s little brother, who had himself been born in France. He was ten years old, and would go on to make profound discoveries about the immune system.
In the months before Christmas of 1941, Jacqueline’s cough got worse. Jacques watched and listened and tried to make sense of it all. “I overheard the doctor speaking to my mother and telling her we know nothing about how infectious diseases are gotten rid of by the body,” Jacques told me. Now in his late eighties, his powerful brain has hardly been slowed by time.
Back then, he recalled, a question nagged at him as he watched his sister. “My sister and I lived in the same room, in the same house with Jacqueline. We never got sick. Why was that?”
Tuberculosis is caused by a bacteria characterized by the waxy surface of its cells. It typically invades the lungs and is infectious, but Jacqueline’s little brother and sister didn’t contract it. Were their bodies not introduced to it, had they fought it off, or were their genetics different such that they weren’t susceptible to it in the first place? Why was it that an alien life-form was taking over this little girl’s body, growing inside her, as her defenses lay as ravaged and ineffectual as the Polish and French armies?
All good questions that would be answered with time, but the most pressing one was whether anything could be done for Jacqueline.
What they had already tried is almost laughably, painfully primitive. Prior to the war and their move to China, the family spent time in Switzerland, a hub of tuberculosis treatment. 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.
When Jacqueline took a drastic turn for the worse that December, “she lost a lot of weight. She looked like a skeleton, like a cadaver,” Jacques said, looking back. “I felt horrible.”
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.
“If only my sister had hung on two more years, she would’ve been cured,” Jacques said.
Indeed, Jacqueline’s death came at an inflection point for medicine and immunology. Science was beginning to put disease on the run. It is remarkable now to look back at what once killed us and see the precipice of discovery.
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.
Approximately 60 million people died in World War II: 15 million on the battlefield, while civilian casualties made up the lion’s share of the deaths, according to the National WWII Museum. That was about 3 percent of the 1940 global population.
We died and we were killing each other, and science and society wrestled with these problems, but immunology, to this point, was not a big part of the conversation. It was a backwater. The immunologists had lots of hypotheses about how our bodies defended themselves, but our internal systems were largely invisible, given the relatively primitive nature of our technology. The field was poised for an explosion of learning.
Jacques Miller graduated from medical school in 1956, and he was accepted as a research fellow at the Chester Beatty Research Institute in South Kensington, in London. It was an institution, and an era, in which many researchers focused on cancer, in part because more people were dying from it, as they outlived the infections that had killed people for millennia.
There was another reason to study cancer
. The atomic bombings of Hiroshima and Nagasaki led to soaring incidences of leukemia. The radiation from the bomb caused cells to change at a ghastly rate, and it damaged DNA so that the new cells were mutated ones. The more the cells changed, the more they turned into enduring cancers, the kinds that prove so elusive to the immune system. In these bombing victims scientists had a pool for experimentation, and they dove in to understand this pitiable new demographic. The focus on cancer wasn’t limited to Japan. The atomic explosion catalyzed such research worldwide.
Dr. Miller’s discovery of the T cell’s origin owes indirectly to the scientific consequences from this research done into radiation and leukemia in mice.
Mice, mice, mice. This bears repeating because the blossoming of this pivotal period of immunology took place in animal research subjects, largely mice. Immunologists, virologists, and others did their work with these plentiful rodents. In the case of leukemia, researchers irradiated lots of mice to give them cancer. They studied which ones contracted cancer and under what circumstances. The idea was to practice on mice to see if there was anything that might be done to help those wretched souls in Nagasaki and Hiroshima who had been so terribly irradiated.
The research at the time also led to what appeared to be an unrelated curiosity: A small subset of the mice were observed to spontaneously contract leukemia—whether or not they were irradiated. Scientists noted that this spontaneous occurrence of cancer originated in a small, leaflike organ called the thymus.
The name derives from the word thymos, meaning “warty excrescence,” which in even plainer language is basically a swelling or a node, an outgrowth. The thymus has two sides, vaguely shaped like leaves or butterfly wings, and is located above the breastbone.
The thymus was long thought to be worthless. Utterly, completely without value to human life, a waste of space, a mysterious vestige of evolution, or God failing to fully clean up after creation.
What happened next is quintessential immunology, a combination of accident, brilliantly conceived experimentation, and controversy.
The satellite office to which Dr. Jacques Miller had been assigned outside London in the late 1950s might hardly be called a laboratory. He worked in a shed, no bigger than a one-car garage. The mice he used were kept in cages in a horse stable.
Dr. Miller’s first experiment entailed trying to replicate a previous experiment that had found a new strain of leukemia. It came from extracting leukemic tissue from a mouse with cancer, grinding the tissue down, turning it into a liquid, and injecting it into one of the mice that seemed otherwise to have a low propensity of getting leukemia. The cancer, like a virus, spread to the new mouse.
There was a twist. This worked only if the leukemic filtrate was injected into a newborn mouse, not an adult. Why did just newborn mice get sick? Dr. Miller had an idea of how to answer the question.
“I did something nobody else did,” Dr. Miller recalled.
Dr. Miller became expert in removing a mouse thymus, performing thymectomies. He wasn’t the first, but he took it to extreme lengths, trying all kinds of permutations. In a significant one, he took a mouse and gave it a leukemic filtrate at birth. After a short period of time, he took out the mouse’s mature thymus and replaced it with the thymus of a baby mouse. The mouse would promptly get leukemia. In fact, the adult mice contracted cancer at whatever point they got the immature thymus. “If I replaced it at one month after adult thymectomy, two months, three months, six months. One after the other,” Dr. Miller said.
This was at least an oddity and interesting, but was it extraordinary? Did this mean the thymus played a bigger role in health than anyone had ever shown?
Dr. Miller stumbled by accident on a revelation. Remember that he had removed the thymus glands from day-old mice to put them into adult mice. Now he had a group of mice with their thymuses removed. They were the supposed throwaways, rodents sacrificed to science. But Miller noticed they weren’t just dying; first they were getting terribly, unusually sick. They were losing weight, shrinking—dying wretched, disease-racked deaths. That seemed odd. “When that happens, you want to open them up and see what the hell is going on,” Miller said. He discovered lesions spread across their livers. It looked like hepatitis. They had been overtaken by infection.
So now he had two powerful data points. Mice with an immature thymus could get leukemia. Mice with no thymus whatsoever appeared to be defenseless against disease.
Dr. Miller hypothesized the heretical—that the thymus was of tremendous significance. He then took one more key step to prove it. It’s a brilliant idea that he nonetheless dismisses as obvious. He took two mice. He removed the thymus from one at birth. Then he took skin from the other mouse and grafted it onto the one without a thymus.
Dr. Miller did this because it had long been known that skin grafts usually failed, because a healthy immune system rejected the foreign tissue. It was not “self.” So he presumed that a mouse without an immune system couldn’t recognize foreign skin grafted onto its body. Without an immune system, it wouldn’t attack the grafted skin.
Dr. Miller hoped that by putting foreign skin grafts onto the baby mice without a thymus, he could prove the link between the immune system and the thymus, an organ that had previously been considered worthless. Here is what he wrote later about his experiment:
“The results were incredibly spectacular. The mice failed to reject such skin,” he said. “The grafts grew luxuriant tufts of hair, and, to convince myself, I even transplanted some mice with four grafts, each from a different strain with a different color.” He added, “None of the grafts were rejected, and the recipients looked like they had patchwork quilts on their backs.”
He ran the mice through a battery of blood tests, sort of like the ones you might undergo if you go to a doctor and get a complete blood count, but much more primitive. Baby mice, deprived of the thymus, had many fewer of the white blood cells with only one nucleus. These already had the name lymphocytes.
This must mean, Dr. Miller thought, that these cells had come from the thymus. “Thymus-derived cells,” he called them.
Thymus. T. T cells.
Now, more than fifty years later, Dr. Miller still exhibited a great excitement when he shared the story. I could hear his sense of wonder, followed by an undercurrent of pride and frustration as he explained what happened next. The scientific community didn’t believe him. At a meeting of the British Society for Immunology in 1961, he showed slides of his patchwork-quilt mice. His findings were dismissed on a variety of grounds: He’d used a bad strain of mice; disease from the horse stables had infected the mice somehow and perverted the results; whatever he’d learned in mice would have nothing to do with humans.
Dr. Miller published a short paper in the prestigious journal The Lancet—with the “bold postulate that the thymus was the site responsible for the development of immunologically competent small lymphocytes.” It was his Madame Curie moment. This little leaflike organ, considered a waste of space, long since bypassed through evolution, was central to the immune system.
That revelation was huge but partial—because Dr. Miller didn’t know exactly what the thymus was doing. That would come later. But now you know a first puzzle piece in the modern era of immunology, along with a crucial piece of trivia about the origin of the T cell and the fact that it is central to survival.
Dr. Miller thought he’d figured out the main player in the immune system. “I thought it was the only cell,” he said of the T cell, “and it could do anything.”
He couldn’t have been more wrong on that count, but not many people were paying attention. While the insular world of immunology included geniuses celebrated among their peers and feted with Nobel prizes, immunologists were not widely acclaimed; for the most part, immunology was not a draw for most serious scientists, not where the action was. For med students, it was a subject to overlook—“one or two pages in a med school textbook,” said Dr. Anthony Fauci, director of the National Institute of A
llergy and Infectious Diseases at the National Institutes of Health. “It wasn’t ready for incorporation into the main body of science.”
The immunologists were just getting started.
9
The B-Word
Turn back the clock a decade to 1951, when an eight-year-old boy with an unusual and disturbing medical history showed up at Walter Reed General Hospital in Bethesda. In the prior eighteen months, the boy had suffered at least eighteen bouts of pneumonia and other life-threatening infections. While the boy could fight off some infection—he was still alive, after all—his body seemed largely unable to mount an immune defense.
The doctor who saw him at Walter Reed was an eventual immune system luminary named Colonel Ogden Bruton. Dr. Bruton ran a test to look for antibodies. At the time, there was a broad conceptual understanding that antibodies were involved in the recognition and targeting of 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. These mechanics, and others, were not yet understood at the time the sick boy came into Walter Reed. But the concept of antibodies had been established. Bruton ran a then-cutting-edge test to look for antibodies. Compared to other parts of the blood, antibodies have a relatively weak electrical charge. So the test involved putting blood into an electrical field and separating out a subset of fluid known as gamma globulins, which contain the antibodies.
The eight-year-old boy didn’t have any gamma globulins. He wasn’t making antibodies. This was the first known case of primary immunodeficiency. “Its discovery,” notes a biography of Bruton published by the U.S. National Library of Medicine, was “likened in importance to the discovery of yellow fever . . . as an epoch-making contribution to medicine.” What the boy and the test told the researchers was that when antibodies weren’t present, something terrible could happen.
