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

by Matt Richtel

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.

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.

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.

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 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.

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.

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.

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.

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.

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 Allergy and Infectious Diseases at the National Institutes of Health. “It wasn’t ready for incorporation into the main body of science.”

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.

A nasty divide erupted among immunologists about the core source of the body’s defenses. One camp thought the antibody was the center of the action. This was a substance, a process, a chemical reaction of some kind that helped attack alien threats. It was called antibody-mediated immunity. But others thought the T cell was the center of all the action. Their philosophy was called cell-mediated immunity. It meant that these T cells ruled the day. The centuries-old mystery chicken from Fabricius helped resolve the debate.

In 1960, whites in the United States lived about 70.5 years on average. Nonwhites, which was the other broad category measured by the government, lived on average to 63.5. There were lots of contributing factors, including environment and its interaction with the immune system. Scientific revelations about this would come later. Also worth noting at that time, women lived longer (75 years) than men (66.5 years), a disparity consistent in whites and nonwhites.

culture, environment, discrimination, all of it contribute to individual and societal identities, how we define our communities, see self, and nonself, ideas that are core to how the immune system polices our bodies but also how we define and police our societies.

Cooper started to study the autopsy reports. Again, he found this conundrum: There were plenty of white blood cells—lymphocytes—but very few antibodies. The thymus seemed to be working, but for the most part, the overall immune system was not working. That’s when it hit him. “There were two lineages of lymphocytes,” he said. In other words, the T cell wasn’t the only game in town. The immune system wasn’t connected only to the thymus. There must be more.

A next clue came from researchers in Denver who were experimenting with (what else?) mice. They discovered that even when a mouse lost its thymus, it could still mount some defense. And the defense appeared to originate from the bone marrow in the mouse.

He attempted to describe his seminal experiment linking T cells and B cells. He tried me. I will not try you. It is indeed extremely complicated, involving the creation of a hybridized mouse of two different strains—mixing and matching bone marrow and thymus, and looking for the source of immune system cells.

Miller’s complex experiment helped show that one set of immune system cells came from the thymus and another from the bone marrow. There were differences between these types of cells that defined the relationship between them. The T cells began in the bone marrow and then moved to the thymus, where they matured. They seemed to be very authoritative cells. The T cells could fight disease or infection directly.

Then there are the B cells. They originate in the bone marrow. These cells were what Dr. Miller called “antibody-forming precursor cells”—they were ready to be armed in some way to fight disease. But it appeared that B cells required some instruction, some additional information to act. That information seemed to come from the T cells, which were instructing other cells in how to attack.

Broadly, white blood cells are different in key ways from the red blood cells that most of us associate with “blood.” Red blood cells, for one thing, appear red, not white. So there’s that. The two kinds of cells also have fundamentally different contours. Red blood cells look like beautiful circles carved with graceful indentations. White blood cells resemble baseballs covered in spikes. Many of these spikes are receptors. They send and receive signals. These cells are information hubs, and they can be vicious killers.

T cells and B cells are the most specialized part of the system. They are particularly crucial when you face a complex or unusual bacteria or virus. This is because these B cells and T cells are incredibly targeted. They are the cells able to manufacture precise killers tailored to specific diseases.

Let’s say it’s flu season. You’re on an airplane or a bus, and someone coughs. You’re in your cubicle at work. You’re a full five feet away from the infected person. Not far enough, says the Centers for Disease Control and Prevention (CDC), which puts the flu’s range of travel by sneeze or cough at six feet. Or you can get flu on your skin through a touch on a handrail that a carrier has touched not long before. A kiss, a hug, a handshake. You wipe your nose, and now the virus has a warm and comfy place to reproduce.

When you are first infected, your body generates a kind of generic response. It is during this period that your elegant defense is waiting for your T cells and B cells to generate a powerful response. The delay can take five to seven days.

Many times, then, the best case is that you’re sick for a few days while this immune response kicks in. Again, this doesn’t mean you’re without defenses until that point, but it means you’re without precision defenses, like a T cell or a B cell.

On the surface of T cells, some of the spikes are able to identify the signature, or fingerprint, of pathogens, the bad guys. However, for the most part the T cells don’t recognize the pathogen directly.

B cells can also recognize pathogens more directly using a special kind of receptor called an antibody. Antibodies are protein molecules with extraordinary abilities, and they are central to the immune system.

Like an antenna, antibodies pick up signals. But each antibody is finely tuned. It picks up only one type of signal. In fact, so particular is each antibody that most of the billions of white cells coursing through us generally have unique antibodies on their surfaces. So unlike most antennae—say, radio towers—the antibody receptor doesn’t pick up just any signal. It picks up one. It is evolved to connect to a single kind of organism.

The antibodies on the surface of these cells discover the organism that is their match, or mate, by running into it. Literally crashing into or rubbing onto it.

What the antibody attaches to is its own little nub or receptor on a cell. The thing it attaches to is called an antigen. An antigen is the mate to an antibody. The antibody and the antigen bind to each other, like a lock and a key.

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.”

Vaccines are a boot camp for the immune system. The inoculations prime and teach the immune system, effectively training the T cells and B cells and giving them a cheat sheet.

It’s not that our elegant defenses won’t mount an attack against these diseases absent a vaccine, but the attack might well be insufficient given the time it takes for the immune system to identify the bug and start manufacturing enough soldiers to fight back.

Smallpox was spread through the air, by sneezes, coughs, or close interaction with a victim. It killed 30 percent of those who contracted it. Its lethality has to do with the way it and related viruses pull a stunt on the immune system. The infections can block the transmission of a distress signal that calls killer immune cells into action.

Variolation usually didn’t work, though. In most cases, the immune system didn’t get sufficiently educated to, or stimulated against, smallpox.

From a cowpox lesion of a milkmaid, he poisoned an eight-year-old boy. The boy lived. Somehow this cowpox strain was the right varietal to spark an immune system defense. Happy birthday, world’s first vaccine!

Africans had been doing this for a while though.

Researchers discovered that successful vaccines were strong enough to provoke a powerful response by the immune system, but weak enough—attenuated is the scientific term—to keep it from being as nasty as the infection itself.

The first polio epidemic was recorded in 1894, 132 cases in Vermont. Of the infected, 1 to 2 percent were paralyzed.

The poliovirus gets quickly into the bloodstream, after entering through the mouth and growing in the throat and gastrointestinal tract. It winds up in the nervous system, where it attaches to nerve cells and invades them. It then takes over the nerve cell’s manufacturing process to reproduce itself—thousands of copies in an hour. Then it kills the cell and moves on to infect others.

The two competing scientists had similar ideas. They infected monkeys with polio and tried to make a human vaccine with the nerve tissue. In Brodie’s case, he then mixed the liquefied monkey tissue with formaldehyde, called formalin, hoping to “deactivate” the virus. It would present enough, the theory went, to provoke an immune response, but would not be powerful enough to actually infect. Not so much.

Dr. Kolmer had the same results, though he took a slightly different approach. He took the monkey nerve tissue, mixed it with chemicals, and refrigerated the mixture to attenuate it. Dr. Paul’s history calls it a “veritable witch’s brew.” More infected children.

In 1952, as Time magazine reported, the worst outbreak yet infected 58,000 Americans, killing 3,000 and paralyzing 21,000.

Alas, this happy ending comes with an asterisk. The first big batch of vaccine wasn’t properly made. Cutter Laboratories in California, one of the main producers of the vaccine, inoculated more than 200,000 children in 1955, and within days there were reports of paralysis. Within a month, the program was discontinued, and investigations revealed that the Cutter vaccine had caused 40,000 cases of polio, leaving 200 children with varying degrees of paralysis and killing 10.

Broadly, antibiotics work by taking advantage of differences between human cells and bacterial cells; for instance, bacterial cells have walls that human cells do not. Antibiotics can prevent bacteria from building such walls.

Whereas vaccines prompt our own response, antibiotics import a response from the outside, and that is an absolutely critical distinction for our everyday health. The reason is that when you add an outside force, you disrupt the natural order. Even if the goal is preservation of life, and even if it works, that doesn’t mean the process is without important risks.

If you’ve ever taken antibiotics and gotten diarrhea, you’re in good company. The antibiotics are killing off bacteria in your gut that help you digest. They are doing real damage inside your gut, even as they get rid of the pathogens that could turn off the lights in your Festival of Life.

How can your T cells and B cells react to a pathogen they’ve never seen, never knew existed, and were never inoculated against, and that you, or your doctors, in all their wisdom, could never have foreseen? This is the infinity problem.

A clear, noteworthy phenomenon was taking shape: Immunology and its greatest discoveries were an international affair, discoveries made through cooperation among the world’s best brains, national boundaries be damned.

He was cutting segments of genetic material from within B cells. He began by comparing the segments from immature B cells, meaning, immune system cells that were still developing. When he compared identical segments in these cells, they yielded, predictably, identical fragments of genetic material. That was consistent with all previous knowledge. But when he compared the segments to identical regions in mature B cells, the result was entirely different. This was new, distinct from any other cell or organism that had been studied. The underlying genetic material had changed.

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

As Tonegawa explored further, he discovered a pattern that described the differences between immature B cells and mature ones. Each of them shared key genetic material with one major variance: In the immature B cell, that crucial genetic material was mixed in with, and separated by, a whole array of other genetic material. As the B cell matured into a fully functioning immune system cell, much of the genetic material dropped out. And not just that: In each maturing B cell, different material dropped out.