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Kindle Notes & Highlights
by
Matt Richtel
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December 2 - December 6, 2020
When the molecule disappeared, Dr. Dinarello realized the fever-inducing molecule was so purified it only looked absent. Of equal importance, he’d discovered that the amount of that molecule could be virtually nonexistent and still light the body on fire. The importance of this is hard to sufficiently emphasize. It takes very little of this thing to cause a major reaction in the body.
Dr. Dinarello called it a leukocytic pyrogen—a fire starter born of the white blood cells, the leukocytes.
In fact, in Ermatingen in 1979, Switzerland hosted the Second Lymphokine Workshop. The assembled, having accepted the notion, decided to give a new name to these so-called mediators. Henceforth, a leukocytic pyrogen would be known as an interleukin.
Broadly, the leukocytic pyrogen was a kind of mediator, communicator.
To measure the reaction, they then went into the “counting room,” where the machine that measured the radioactive labeling would click, like a Geiger counter, when measuring a particular molecule or cell. “We’re watching every two counts to see if the T cells are activated. All of a sudden, the counter went berserk. Ba-bid-a-ba-bid-a. It was like a science fiction movie,” Dr. Dinarello related. Another scientist in the room was the one who had been working with the mice and T cell stimulation. As they watched the clicker go wild, indicating a massive increase in T cells, “Lanny says to me:
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it looked like the macrophage was prompting the T cell, not the other way around.
In a 1960s Flash Gordon comic, doctors on a spaceship used a wonder drug called interferon to cure a patient on the verge of death. Flash Gordon was fictional. The drug was not.
The scientists’ theory was that the healthy cells had picked up a signal from the inactivated virus that deterred growth. Did this mean that some message had been sent blaring: This is an inhospitable environment, so don’t waste resources here? It wasn’t clear how interferon worked, or even exactly what it was.
Also, in the 1970s, it became clear that interferon, identified by now as a protein, had several subtypes.
The interferon bolsters the body’s own defenses by sending a message to the immune system to attack the virus.
It took four years, but in 1980 they released a paper describing the pure form of interferon, allowing the substance to be manipulated, tested, and turned to medicine. Eventually researchers would identify three types of interferon: alpha (A), beta (B), and gamma (G), and then much later, lambda (L).
the immune system has multiple overlapping, sometimes redundant first lines of defense, and second lines too. This festival—our take-all-comers cocktail party—is nothing if not chaotic and multifaceted.
The invader interacts with a healthy cell. That cell detects molecules consistent with a foreign agent. Within that tiny cell, a kind of supercomputer-like process starts that leads to changes in proteins and, in turn, the secretion of alpha, beta, and lambda interferons.
Other surrounding cells pick up the presence of interferon. “This starts a chain reaction,” Zoon explained. It can cover an isolated region—say, an organ—or spread through your entire body within just a few hours. Cell after cell begins to pick up the signal and create interferon and other proteins that protect the cell. Once it does so, the interferon, true to its namesake, induces the manufacture of proteins that interfere with the ability of the virus to reproduce itself.
“When interferon is secreted, you feel sick. It causes aches and pains; you feel terrible,” Zoon explained. Your behavior is being modified—not by the virus directly, but by the response.
You are slowed down, and this can have the very beneficial impact of diverting your body’s resources to fighting the virus and not, say, focusing on your job or going for a jog. Your defense system needs your limited energy.
Your immune system takes care of you partly by making you take care of yourself. And it would be tempting to say without reservation that your feeling rotten is a sign to withdraw and let your body heal. But it turns out the practical side of this is much more complicated. This is where the forthcoming stories of autoimmune sufferers Linda and Merredith become instructive.
Sometimes the immune system overreacts, while other times, it is beneficial to push through feelings of sickn...
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Interferon belongs to a broader set of chemicals that prompts immune system action. This set of chemicals informs virtually all of disease, including how we respond to it.
A cytokine is a secretion from a cell that prompts action by other immune cells. It is a messenger.
This puts a fine point on a major concept in the understanding of the immune system: It has a telecommunications network. Full stop. Our defense network is sending signals across the body.
It’s worth pausing to think about how far immunology had come since the late 1950s when Dr. Miller discovered that the thymus wasn’t just a waste of space, or God’s throwaway line. The thymus makes T cells. The bone marrow is the origin of B Cells.
The T cells, when alerted by dendritic cells, behave as soldiers and generals, spitting out cytokines; the B cells use antibodies to connect to antigens as if they are keys in search of a lock. Macrophages, neutrophils, and natural killer cells roam the body, tasting and exploring, killing. These networks get connected by signals, chemical transmissions, or processes; are spurred on by interferon and interleukin; and can induce powerful side effects, like fever.
The stage was set, through science and the technology that supported it, to discover lots of different molecules and cytokines. Once there were only T cells and B cells, and then suddenly, there was a laundry list of molecules monitoring and policing the Festival of Life.
IL-1 induces fever. IL-2 causes T cells to grow. There’s IL-6. That causes B cells to grow. IL-2 and IL-6 are powerful ones, with a twist. The problem with these interleukins is that they can become too abundant, their signals too aggressive.
you’ve surely in your own life felt the impact of your immune system firing too aggressively, causing you, for instance, to feel fatigued when you’d be better off getting off the couch and walking, or to experience pain that has no apparent external cause or a hint of fever.
That’s why our immune system has evolved to have its own system of checks and balances. In fact, many interleukins are designed to be anti-inflammatory. They are immune system brakes, not accelerants.
How do the cytokines know to turn off? What happens if they don’t turn off? “If you fail to make anti-inflammatory cytokines, you die of mild inflammation.”
Mild inflammation, wholly unchecked, can kill.
At its core, what the immune system was doing wasn’t simply seeking and destroying. Instead it was looking for a balance—between attacking and neutralizing real dangers and showing sufficient restraint such that its potency didn’t destroy the body.
The story of the immune system became the story of homeostasis—a state of harmony or stability. This is what makes our defense so elegant.
The pieces are coming together, the exploration leading to application, to real-world solutions. None, arguably, was as significant as the discovery of the monoclonal antibody.
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.
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.
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.
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?
“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.”
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.
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.
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).
Dude you're gonna die
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.
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.”
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.
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.
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.”
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.
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.
