by Matt Richtel
What resulted was a plaque that, viewed under the microscope, would allow the counting of antibodies.
It was a huge step. Why? When you contract a virus, your body generates antibodies to fight it. Thanks partly to Jerne, doctors regularly use tests that isolate our antibodies as a way to understand the type of bug we’re fighting, how effectively we’re fighting it, and the intensity of the fight going on between our immune system and the pathogen.
Wise man number two was César Milstein, from Argentina. He had figured out an ingenious way to create lots of antibodies for purposes of studying them. His tactic for generating antibodies involved mating a B cell with a cancer cell. This worked wonders because cancer cells, for all their evils, have an important scientific value: Cancer cells grow and grow. They are the body’s weeds. What Milstein did by fusing a B cell with blood cancer, called myeloma, was to create a lineage of B cells with cancer’s powerful reproductive cycle. Now Milstein had a petri dish filled with antibodies, which allowed science to study and experiment with huge batches of these precious defenders.
In 1973, Milstein came to Basel to give a talk on this process, and listening there was scientist number three, Georges Köhler, the German.
Long (and complex) story short (and simple), Köhler combined the techniques of Jerne and Milstein. He used mice and sheep to isolate individual antibodies and then make countless copies of them.
For the first time, scientists could isolate a cell with a particular antibody and make endless copies of it. In turn, this technology allowed researchers to begin to make distinctions between and among lots of different cell types with antibodies. This was akin to creating the most powerful microscope that cell biologists had ever seen because it let them distinguish one cell type from another, determine which had what kinds of antibodies and also how many antibodies appeared on each different cell.
As a first basic step, this began to reveal that, for instance, B cells were far more varied than people originally thought. There were thousands of antibodies on the surfaces of B cells.
Once isolated, those antibodies could be used for study. For instance, if we knew what particular antibodies responded to particular pathogens, could we then figure out how the deadly diseases attacked or how the dance between self and alien took place?
Dr. Fauci told me the change led to a profound shift for immunology, turning practical a field that had been esoteric even as late as the 1970s and ’80s. “All of a sudden, the immune system was having an impact on more diseases than you could possibly imagine,” he said. He didn’t mean that the immune system was having a new effect, but rather that it was now clear to scientists how powerful the effect was everywhere. “Cancer, autoimmunity, auto-deficiency, allergy.”
These isolated and multiplied antibodies were known as monoclonal antibodies. They are changing your life, right now. Drugs built on monoclonal antibodies have become a dominant source of drugs in the early part of the twenty-first century. The annual market for these drugs is nearly $100 billion. They work by intensifying—or dulling, as the case may be—the performance of a particular antibody so that the body does a better job of attacking a life-threatening risk, like cancer, or, alternatively, dampening our elegant defenses so that the immune system doesn’t behave so aggressively and cause autoimmunity.
The drugs have names like Humira and Remicade (which Linda and Merredith both tried in an attempt to try to slow their zealous immune systems) or ipilimumab, which has saved countless cancer patients, or nivolumab, which saved Jason. In the upcoming stories, you’ll see the development and work of some of these miraculous medicines in an intimate way. In a general sense, the aim of these drugs is a relatively precise manipulation of the immune system, a molecular-level monkeying, rather than the scorched-earth tactic of previous drugs.
As a reminder, picture the difference between two cancer treatments, chemotherapy and immunotherapy. In traditional chemotherapy, toxins that destroyed fast-dividing cells got dumped into the body, ideally killing, say, a lung tumor, but taking out lots of healthy tissue as well. This was the proverbial war of attrition. The Festival of Life had to outlive the tumor and the treatment. With nivolumab or ipilimumab, as you’ll see, the idea is to use molecular tinkering to unleash the immune system to attack cancer—using the body’s natural defenses—rather than injecting bleach into the body and killing everything that moves.
This is complex stuff. Where are we in immunology’s story?
For most of human history, infection, even modest infection, killed people with the terrifying regularity of an open wound, the ingestion of undercooked meat, the casual exhale of flu inhaled by another, pneumonia passed from hand to hand and wiped on the nose. Then over the centuries, scientists took baby steps toward understanding these infections and dipped a toe into how our bodies fought back. These scientists came from all over the world, which is worth noting because it shows the powerful, essential value to our survival of cooperation across national boundaries and cultures.
We got a big break with vaccines and antibiotics. These helped keep us alive without our really understanding how the immune system worked. More or less blindly, we squirted medicines into our bodies; they sometimes worked and often didn’t, and we frequently didn’t know why, one way or the other. But we began to chip away at the details too, particularly in the middle of the nineteenth century.
The T cell came from the thymus and seemed to play a huge role in mounting a defense, but exactly how it did so wasn’t clear.
Ditto with the B cell, which came from the bone marrow, played a huge role, and seemed to have essential interaction with the T cell.
A Japanese scientist (Tonegawa), who studied in San Diego, then made a discovery in Switzerland that explained immunology’s big bang: Our DNA rearranges itself in utero and forms millions of antibodies capable of binding to—and attacking—a trillion different antigens.
An Australian vet (Doherty) worked with a transplanted Swiss scientist to figure out that the T cell distinguished alien from self.
Then came a Russian and a final major discovery that came surprisingly late in the story of our elegant defenses. There isn’t just one immune system, but two.
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A Second Immune System
How are we able to eat food without our bodies’ attacking it as foreign? After all, a banana isn’t human, nor is bread, let alone a Philly cheese steak (which may not even be food, with all due respect to Philadelphia natives). We swallow, the food travels down into the stomach and intestines where acid breaks it down, and then nutrients are leaked into the body—tiny alien pieces but of tremendous survival value. How do our bodies know the difference between merely foreign and truly dangerous? It was a question that immunologists thought they had answered with, for instance, the discovery of the relationship between antibodies and antigens, governed by detectors like MHC.
Even in the search for AIDS, the presumption was that the action was all about this “adaptive immune system” governed largely by T cells and B cells.
Science was wrong. To answer the banana or cheese steak question, science required another foundational piece of information. Once again, the key discovery came from an international village of scientists.
Ruslan Medzhitov was born in the Soviet republic of Uzbekistan in March 1966. Eighteen years later, in college, he was living the clichéd life of a dutiful, freedom-starved Communist citizen.
“Every fall we had to go to the cotton fields for a couple of months. This was compulsory. You’d get kicked out of college if you didn’t do that. It was primitive conditions. One time I was ‘caught’ by our department chair for reading a textbook in the field.”
It was a biochemistry text.
“He said, ‘I’m going to take away your stipend.’”
That was the bad news. The worse news was war. In the second semester of his freshman year, Medzhitov was called to military service. His head was shaved and he went to a plaza, where the recruits were di
vided into platoons of thirty and the groups essentially chosen at random to determine which would go to Afghanistan, which the Soviet Union had invaded in 1979. “The two groups before me and two groups after went to Afghanistan,” he told me. “Many didn’t come back. The ones who did come back weren’t normal.”
As he looks back at the fateful war in Afghanistan, the hostility of the crumbling Communist regime to anything foreign now looks to him a bit like an autoimmune disease. “You’re trying to destroy what you perceive as nonself, and you destroy a lot of self,” he said. “It’s sort of like autoimmunity,” he added. “It’s exactly what’s happening in the Middle East.”
Political and cultural defense systems run amok, hypersensitive, reacting without checks such that they can no longer tell what will spare and preserve them—what keeps them in homeostasis—and what will be their undoing at their own hands.
After Medzhitov’s military service, he returned to college, interested broadly in the sciences, not particularly in immunology, and got what appeared to be a huge break. He was selected, after multiple interviews, to go to the United States to study. “It was an unbelievable miracle,” he gushes.
“I couldn’t believe my luck. There was just one last step.” He got a phone call one day from a man who told Medzhitov he needed to go through an orientation and asked to meet the young scientist in a park. “In retrospect, I always think: How did I not know how fishy this sounded?”
The man whom he met wore a suit and a tie. He “looked very vague. When I try to remember, there is no face. There’s everything else without a face.”
They talked about this and that, and the man asked to meet again a few days later. The next time they saw each other, the official appealed to the student’s patriotism, saying, “You want to help your country, right?” Medzhitov recalled. “I’m thinking to myself: ‘Oh, shit.’ That’s when I realized he was from the KGB.”
The man knew everything about Medzhitov—his grades, his love of basketball. But the man didn’t overtly threaten. He just explained that Medzhitov would be asked to gather classified information in the United States and transmit it back home. He was going to be a receptor for the Soviet Union’s overheated immune system. He would be a T cell, doing surveillance in the United States. “‘We’re going to teach you to sneak into buildings at night,’” he recalled being told. That part sounded a bit like James Bond. “That was exciting. Everything else about it stunk. I tried to explain my point. ‘I want to study and not be a spy.’
“The very next morning, I got a phone call from the Office of International Affairs. They said, ‘Your documents got lost. You’re not going anywhere.’”
He had stayed true to himself. It had cost him, dearly.
Then came another stroke of luck, or if you prefer, one of those random moments, a veritable random mutation in time and space, that led to scientific evolution. The spark was set off thousands of miles away from Medzhitov, on the north shore of Long Island.
In 1989, Yale immunologist Dr. Charles Janeway Jr. gave a speech at a symposium in Cold Spring Harbor, New York. In the lecture, he audaciously proposed to illuminate “immunology’s dirty little secret.”
The secret he was referring to was that the immune system was built fundamentally—essentially exclusively—around the dominance of the T cell and the B cell. This was the adaptive immune system, and I won’t belabor or repeat here its deeply rooted history in immunology.
But Dr. Janeway was troubled by a crucial question, one so simple that it had until then been overlooked. How did the T cells and the B cells know which cells to attack?
You might think, once again, at this point, that the question had already been answered. After all, antibodies and antigens had been discovered and their interactions had been widely studied. The dendritic cell was understood to present information to the T cell. The presumption was that T cells and B cells know what to attack because they recognize antigens. Remember these? They are markers on pathogens—tags.
Dr. Janeway was vexed by a question his students had asked him: Aren’t there antigens on non-harmful foreign substances? What about the nutrients from a banana we eat? What about a bacteria we inhale that is innocuous? After all, there are billions of bacteria around us, and many are not deadly. Presumably, these cells or organisms have antigens. Our elegant defenses must be assessing them, and rather than attacking them, leaving them alone or even integrating them.
“What was known was how the immune system sees the antigen. What was not known is how it sees an infection. Antigen and infection are not the same thing,” Medzhitov said as he explained the simple logic to me. He told me this story because Dr. Janeway passed away in 2003 of cancer. (His New York Times obituary noted he was “often referred to as the father of the understanding of innate immunity.”)
At the Cold Spring Harbor symposium, Dr. Janeway proposed the idea that the T cells and the B cells recognize antigens, lots and lots of antigens, but they don’t on their own know which ones to attack.
“They say: I got something, but I don’t know what it is. Is it your own pancreas or a vicious virus?” Medzhitov explains. Is it nutrients from a digested banana or HIV? “They cannot see the nature of the antigen. It could be coming from our own cells, from food, something that came in contact with our skin. But not all of that is infectious or pathogenic.”
The T cells and B cells, he says, “detect something with exquisite specificity, but at the cost of not knowing what it is.”
Medzhitov borrows an analogy from Pavlov’s dogs to describe the nature of the problem that Dr. Janeway identified. Pavlov understood that his dogs would immediately salivate if they smelled food. They didn’t do anything if they heard the ring of a bell. Then Pavlov paired the sound of the ringing bell with the smell of the food. The dogs associated the bell with the food and salivated.
Dr. Janeway had discovered that our adaptive immune cells don’t attack only if they hear the proverbial ring of the bell (the antigen); they need another signal.
When Dr. Janeway proposed this notion, “he was largely ignored,” Medzhitov recalls. “People thought this is just another crazy idea.”
It didn’t help that Dr. Janeway offered no proof. What exactly was telling the T cells and the B cells that the antigen they had identified belonged to something that deserved annihilation? What told them to leave the good stuff alone?
In a generic sense, Dr. Janeway proposed the idea of a “co-stimulatory” signal. This would be an agent, a message of some kind—from someplace—that would inform the T cell or B cell what it was looking at.
Back in the former Soviet Union, Medzhitov was in a Moscow library reading various papers when, while pursuing another subject, he came across Dr. Janeway’s theory. He had more than a passing interest in immunology by this time, and when he read this paper, it had the extraordinarily powerful impact on Medzhitov of crystallizing a question that had long vexed him about how the human body dealt with the outside world.
“Just completely by accident, I read his paper. I thought: This is it. This explains everything,” Medzhitov says. Prior to this, he’d realized, immunology was fascinating, “but it was a collection of stuff with no logic behind it.”
Medzhitov paid a full month’s college stipend to make a copy of the paper so he could study and read it over and over. It was 1991, and he had become obsessed.
Medzhitov typed up a message to Dr. Janeway on a big floppy disk. It essentially said: I’m fascinated by your theory, and here are some implications.
“After a week, he sent a response. It was a really memorable moment. He started discussing the theory with me. I was a nobody student from Moscow, and he was a very famous scientist!”
The Soviet Union was imploding. Amid the “vacuum of laws” that followed the Soviet collapse, Medzhitov made his move, securing a fellowship in San Diego. By early 1994, he wound up in New Haven, working for the man he’d come to idolize.
The pair were determined to prove
that the T cells and B cells don’t go into action until they get two pieces of information. While they recognize an antigen (a foreign substance, be it food or a virus), this information is largely meaningless without a second piece of information, which is a co-stimulatory signal that says “kill.”
Where did that second signal come from?
In seeking an answer, researchers in the 1990s were acquiring their own supertools, in the form of computing power and programs that allowed a much deeper analysis of the seemingly invisible, such as wider mapping of the immune system at a molecular level. Among the tests that Medzhitov now had at his disposal was the ability to identify segments of individual genes. He couldn’t see the entirety of most genes because the human genome—the whole of its sequence—hadn’t yet been mapped. But the technology allowed him to map portions of individual genes. Here’s how Medzhitov puts it: if you imagine a gene as a person, you might be able to map the foot and then make some inferences about the leg. Bit by bit, you could build a genetic profile of the whole person.
Or a fly. It was a fly that led Medzhitov and Janeway to their breakthrough.
They’d been searching in the dark for a way to prove the existence of a co-stimulator, a signal to push the T cells and B cells into action. Then they heard a lecture related to a discovery made in the mid-1980s in fruit flies. The finding was that flies with a mutation of a certain gene couldn’t control fungal infections. The gene was named Toll.
The first time I heard Toll receptor, I assumed it was some metaphorical term related to a booth on a highway. In actuality, it comes from German, and means amazing or wild or great. (According to one history, this was because a German scientist, upon grasping the results of the study, exclaimed, “Das war ja toll”: That was amazing.) It often goes by the name Toll-like receptor.
Medzhitov and Janeway thought it sounded, if not amazing, at least promising. They figured this Toll-like receptor may be responsible for helping the adaptive immune system discern what to attack and what to leave alone. What if it helped explain why our bodies don’t attack a banana or our own spleen? The Yale scientists started looking for fragments of DNA that would be the human analogue to the fly’s Toll receptor.
