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 divided 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.
First, they found the gene, or fragments of a gene that looked like the human version of the one in the fly. Then they did experiments to see if they could show that the gene was not just instrumental but essential in causing the T cell to act upon a pathogen. One night in February 1996, Medzhitov was checking the lab results on his computer. This is one of those experiments that is too technical to describe and, in its own way, not the stuff of Hollywood; first there were some mixtures, or assays, and then the data was crunched digitally and the results came over the computer.
But those results? Now that part is the stuff of Hollywood.
Medzhitov and Dr. Janeway had found the fundamental mechanism that allowed the body to determine if it was dealing with a pathogen, a bad guy such as a harmful virus or bacteria.
This was the discovery of what happens at first contact. The Toll-like receptor is as elemental a concept as in all of our survival and in the science of immunology, and it had taken years to uncover.
“It was Holy Grail at the time, the dream result, to find something that provided evidence for a hypothesis that at the time only two people cared about,” Medzhitov says. “It was eight o’clock at night and it was well known that Dr. Janeway didn’t like to be bothered at home. I couldn’t even contain myself and wait until the next day. I called him and told him the result: ‘I saw induction in the genes.’ He knew what that meant.”
The discovery became the basis for our understanding of the concept of a second kind of immunity. It is called innate immunity.
The innate system shows up, discovers a pathogen, and mounts an initial but generic attack, meaning the attack is not specific to the pathogen. It can hold off the evildoers but often cannot kill them completely. That requires specific attacks from a particular T cell or B cell armed with the receptor or antibody that matches the antigen on the surface or inside the bacteria or virus or parasite.
The innate system informs the adaptive system: I need help. Bring the heavies.
The innate immune system scans organisms for the presence of one of a handful of key identifying markers that are shared by viruses and bacteria. For instance, most bacteria have wiggly tails. Toll-like receptors scan for these. Or they look for a particular variety of large molecules—called lipopolysaccharides—that characterize a class of bacteria called gram-negative bacteria (such as E. coli); or they look for nucleic acids associated with viruses.
Compare now several scenarios, one in which you get bitten by the cat, another in which you ingest a banana. In the first scenario, the cat’s saliva trickles into the wound on your hand, setting off the cascade of immune cells, carried through opened blood vessels, bringing redness and heat. Among the cells at the scene are macrophages and dendritic cells with Toll-like receptors on the surface. The receptors can instantly determine whether the foreign substance entering the body has the hallmarks of a major pathogen. If a pathogen presents itself—say, a noxious bacteria—not only does the immune system unleash a first-line attack but also the dendritic cells, now aware of the pathogen, begin their journey to find the T cell and B cell necessary to provide a more specific defense.
By contrast, when you eat a banana, the food travels down into your stomach and intestine. The gut breaks down the food, and nutrients leak into the body. Those nutrients, by the time they are broken down, may look much like “self” and thus not attract attention from the immune system, or our elegant defenses may identify the scraps of nutrients as foreign but not see any of the hallmarks of a pathogen. They have been accepted into the body, permitted to survive in the Festival of Life.
The role of the Toll-like receptor represents a relationship between human beings and the outside world that is as ancient as our existence. It was cultivated through epochs of evolution so that the human genetic code has developed the ability to scan for the ancient markers shared by hundreds of thousands of pathogens.
In a 2002 paper, Dr. Janeway and Medzhitov described it like this:
The innate immune system is a universal and ancient form of host defense against infection. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious non-self from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses.
Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens.
To break the findings down further: We are born with primitive detection mechanisms that can discern not only what is alien but what is pathogen. As a first-line defense, the molecules of the innate immune system recognize a large class of pathogens and signal the T cells: That thing you just identified as alien is bad—go kill it.
With this discovery, the major pieces of immunology had been put into place. Much was still to be discovered. But immunology suddenly faced a crisis that crystallized much of the science into a very practical threat.
A plague was afoot.
The greatest modern challenge to immunology and the immune system happened in the 1980s. Or rather, that’s when it became clear the apocalypse lurked. AIDS led to a turning point in the story of immunology. The study had been so much about the lab and the mice, about inscrutable language and piecemeal science. Then came this crucible.
So our story turns too, moving more and more out of the lab and into the clinic, into the lives of patients, and into a new era of research. While basic immunology continued, there was an exciting new emphasis on applying the decades of hard-earned knowledge to more practical things, like the interaction of the immune system with sleep, stress, allergy, cancer, or nutrition, and like poorly understood symptoms that were actually autoimmunity. Various medical specialties—heart, lung, muscular, skeletal, and on and on—began to put to work the tools and knowledge of the 1970s. In that respect, what followed was an expansion of immunology.
It was spawned by the scariest disease modern medicine had ever seen.