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.
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 two 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?