An Elegant Defense

by Matt Richtel

  But there was more that made the boy’s case vexing. He didn’t have antibodies, but he still had white blood cells and was still able to fight off some viruses. The boy’s thymus was intact too.

  This conundrum vexed scientists. What were the defense’s main components?

  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 1952, the year after the boy showed up at Walter Reed, a young scientist at Ohio State University was watching his professor dissect and autopsy a goose. The scientist later wrote that he watched his professor remove the bursa and asked, “What is that? What is its function?”

  “Good question. You find out,” the professor replied. The scientist noted that with this suggestion, “the search began.”

  He deduced that the bursa of Fabricius—that seemingly vestigial organ in the back of the bird—grew very quickly in the chick’s first three weeks of life. Two years later, in 1954, a fellow researcher discovered that chickens with the bursa removed could not generate a response to vaccine because they made a very low volume of antibodies.

  No bursa, few antibodies.

  That sure doesn’t sound like a vestigial organ either. It suggested that, in birds at least, antibodies might come from the bursa. But humans have no bursa.

  The curiosity would be resolved in part by Dr. Max Cooper, a physician shaped, like Dr. Miller, by painful historical reality. His biography isn’t a sideshow. It’s part of the immune system story.

  Dr. Cooper grew up in the 1940s and early 1950s in rural Mississippi. He lived in a tiny town in which he worked at every kind of odd job—as a janitor at the school, behind the counter at the drug store, in the oil field, delivering newspapers. His parents were unusual in that they had high levels of education and so, to young Max Cooper, the most revered man in town was the doctor—“the pinnacle of society,” he recalled. Max knew what he wanted to do.

  He graduated from medical school at Tulane, where, during his final year, he saw a patient with digestive problems. The man was a conductor on the Panama Limited, a train that traveled between Chicago and New Orleans. He was distinguished.

  And he was on the “colored” side of Charity Hospital in New Orleans, because in those days the hospital was segregated. Dr. Cooper examined the patient and then made a presentation to the senior doctor, called the attending physician.

  “Mr. Brown’s chief complaint is that—” he began before the attending physician interrupted.

  “Who told you to call this nigger Mr. Brown?” the physician said. “Would your father have taught you to call this nigger Mr. Brown? We don’t do that here at Tulane.”

  “Yes, sir,” Dr. Cooper responded, and then spent a lifetime regretting he had not responded differently.

  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.

  Dr. Cooper began to think about the differences among people, and their defenses. And as you’ll see, 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.

  By now it was the mid-1960s and Jacques Miller had published his seminal work about the thymus. At the University of Minnesota, Dr. Cooper, fascinated by the emerging debate about the immune system, became interested in a rare disorder you’d wish on no one. It is called Wiskott-Aldrich syndrome. The patients suffer severe immune deficiency.

  “They could get a fever blister, and if their body couldn’t control it, it became a widespread infection that killed them,” Dr. Cooper said. They typically died within three years.

  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.

  One clue had come from the chicken. Without a bursa, the chicken had many fewer antibodies. To hone in on the answer, Dr. Cooper and his colleagues experimented on chickens and discovered that indeed, one set of immune cells appeared to come from a chicken’s bursa and another from the thymus. So now the two parts of a chicken’s body that had seemed to have had no purpose were now seen as key to producing a lineage of immune cells.

  But humans aren’t chickens (thank you, author!). We have no bursa. So where might our antibodies come from?

  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.

  One of the researchers theorized that the cells from the thymus and the cells from the bone marrow were working together. Perhaps, the researcher thought, cells from the thymus could somehow produce the antibody but only with help from the cells originating in the bone marrow.

  The researcher added: “These are not problems which the present analysis can resolve.”

  Jacques Miller was back on the case. He helped put the final pieces together.

  “It’s very complicated to describe,” Dr. Miller told me by phone from Australia. “It will be hard for you to understand.”

  “Try me.”

  “It’s a very, very classic experiment.”

  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.

  What Dr. Miller found out “changed the course of immunology!” he wrote to me in an email, and he wasn’t bragging. It was true. (And it is also true that there were many other crucial contributions to the subject made by other scientists at the time.)

  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.

  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.

  At least that was the theory at the time. There was a lot of validity to it, as well as even more missing information.

  Dr. Miller strove to generate clever names for these t
wo lineages of immune fighters. He couldn’t come up with anything particularly clever or useful. Several years later, though, they got their names from a connection that seems obvious to us now. The B cells come from the bursa or bone marrow, and the T cells from the thymus, and “since then, hardly an article has appeared in any immunological journal without mentioning the words T cells or B cells,” Dr. Miller would later write.

  This was wonderful and also theoretical. A T cell, a B cell. Nifty names. How did they function? If they worked together, how did they communicate?

  10

  T Cells and B Cells

  Now you know how the T cell and B cell got their names. Still, the breadth of their purpose would take decades to understand, with nuance added virtually every year. For a long time, conceptually, the T cell and B cell were considered the core of the immune system and, to some, its only part.

  It turns out they are both essential yet also heavily reliant on another group of potent killer cells, as well as an array of communications and surveillance systems.

  But what are the T cells and B cells, and what’s this got to do with you?

  Remember the milky-white veins discovered by Gaspare Aselli during his dissection of the dog in 1622? The white substance is made up of white blood cells. Some of these are T cells and some are B cells—with other cells in the mix too.

  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.

  White blood cells are essential for your survival. They are as vital to life as the red blood that carries oxygen. 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. Within your sea of white blood cells is a match for virtually any pathogen that infects you, and a big key to your health involves the speed with which the right T cell and B cell can make contact with the disease, bind to it, and then manufacturer tens of thousands of copies of the precise defender to wipe out the offenders.

  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.

  Almost immediately, the immune system picks up an intruder, but at this point in the scientific journey—in the chronology of discovery—immunology didn’t really understand what first contact looked like. That came later.

  A T cell, central to our elegant defense. (NIAID/NIH)

  So, back to the flu and you, and T cells and B cells. 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. That is because the right B cell and T cell, with the right antibody or receptor, must be contacted, or make contact with the bug, fit lock into key, and begin generating defenders. 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.

  What we know now is that T cells and B cells find their prey in very distinctive ways, and those distinctions themselves are crucial to understanding the complex evolution of the immune system.

  A B cell, originating in bone marrow. (NIAID/NIH)

  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. They do so through an intermediary that I’ll introduce shortly in a fuller context. For now, suffice it to say, the T cells get a message alerting them of the presence of a dangerous intruder. When that happens, T cells can take on different roles. Some are foot soldiers and others are generals. The generals can dispatch other T cells to the front lines. Or they can send B cells into battle.

  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.

  Antibodies sit on the surface of B cells. They help identify pathogens by acting like a combination of an antenna and a house key.

  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. These white cells course through the body, through the raucous festival within us, and they roam and flow and jumble and can spend years of restless irrelevancy until one day—Boom!—they smack into the chemical structure that they, and only they, can attach to.

  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.

  If you get a bacterial infection, the pathogen trying to spread through your body expresses a particular antigen. Inside your body, there is a B cell that discovers the antigen, binds to it, and annihilates it. Or it sets off a cascade of other defenses.

  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.

  11

  Vaccines

  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. The right vaccine can provide your body with the power to mount a faster response to diseases that could otherwise be deadly or devastating in other ways, whether smallpox or polio.

  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. In the meantime, you might well die. That said, it’s no small thing to find the right vaccine. The lesson of this chapter is that the immune system can learn, but it’s not easy to teach.

  Among the most famous names in vaccines is Edward Jenner, the English doctor who developed the smallpox vaccine. Less well known is that the groundwork for Dr. Jenner’s discovery had been laid through various experiments aimed at stopping smallpox, the variola virus, which appears, according to the CDC, to have been around since Egyptian times (evidence: mummies with pustule scars).

  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. (I’ll save this discussion of the way diseases trick the immune system because it relates in no small way to how immunology helped save Jason.)

  Prior to the work done by Dr. Jenner, the effort to control smallpox was called variolation, the name drawn from the name of the virus. If you think vaccinations seem unpleasant nowadays, this precursor was worse. “Material from smallpox sores (pustules) was given to people who had never had smallpox. This was done either by scratching the material into the arm or inhaling it through the nose,” the CDC notes in a history of the technique. Unpleasant though it might’ve been, it did curb the likelihood of getting the disease in some people, though not enough to stop its epidemic spread.

  To physicians and scientists of the period, it showed that the immune system seemed able to develop a response that could later be called into play. The system can acquire a cheat sheet that both helps to quickly identify a problem and has the instructions on how to immediately liquidate the foe. Variolation usually didn’t work, though. In most cases, the immune system didn’t get sufficiently educated to, or stimulated against, smallpox.

  Then came a turning point for medicine.

  The setting was Gloucestershire, England, in 1796. It is hallowed ground well-trodden in the history books. Dr. Jenner noticed that the cow’s milkmaids had pustules but didn’t seem to get the deadly disease. 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!