"An Elegant Defense"

[fiefoe]

Matt Richtel's book is organized in a way that makes me wish for a clearly diagrammed textbook instead. Do not recommend.

• Jason and his mother, Catherine, alternately cherished each other and fought with vicious visceral passive-aggressive dialogue that would make Arthur Miller melt.
• The immune system’s policing job gets complicated by the porous nature of our bodies’ borders. Just about every organism that wants to get inside us can do so. Our body is a take-all-comers bash,
• Together, autoimmunity is the third most common disease category in the United States (after cardiovascular disorders and cancer). Diabetes, the leading killer in the country, is caused by the immune system’s going to war against the pancreas.
• On July 23, 1622, an Italian scientist named Gaspare Aselli dissected a “living well-fed dog,” recounts one history of this seminal surgery. In its stomach, he observed “milky veins.” This observation wasn’t consistent with an understanding of a circulatory system carrying red blood. Instead, these milky veins looked like they contained white blood. Aselli’s dissection set off a period of exploration that the history calls lymphomania, a fascination with a little understood bodily fluid called lymph, along with the dissection and vivisection of hundreds of animals. The role of the milky veins wasn’t clear for many years.
• fetched from it a few rose thorns and introduced them at once under the skin of some beautiful star-fish larvæ as transparent as water. I was too excited to sleep that night in the expectation of the result of my experiment, and very early the next morning I ascertained that it had fully succeeded. Indeed, a bunch of these wandering cells swarmed around the splinter. They appeared to eat away at the offending or troubled tissue.
• The word phagocyte is taken from the Greek and can be roughly translated as “devourer of cells.” Phagocytosis is the process by which the devouring happens. (And congratulations, reader! You’ve been introduced to the language of immunology, at times one of the most maddening and even counterintuitive lexicons ever contrived.)
• In other words: At the moment of invasion, the body has an initial reaction that involves the swarming of eater cells, and the experience is not always pleasant. This is what we call inflammation. Know this about Metchnikoff: The man was way ahead of his time.
• Then about 500 million years ago, a split occurred, resulting in what would evolve into two major immune system lineages. One lineage belongs to non-jawed vertebrates, such as the lamprey and the hagfish. They developed a defense network that is both fundamentally different from ours and nearly as sophisticated. By comparison to ours, theirs is like an ancient language with different lettering, an alternate scripting of the genetic code that confers many of the same defense advantages... In the most fundamental sense, we share an immune system with sharks and other jawed vertebrates.
• These pathogens, unlike the healthy cells in our own bodies, don’t like to stay in a particular area. They are built to cross borders, push into virgin tissue, spread, eat, and replicate.
• What makes T cells and B cells so remarkable is that they are extremely specific. Each one of the billions of them in your body is tailored through a quirk of genetics to recognize a very specific infection. Once a T cell or B cell finds its evil mate, its infection doppelgänger, it can set in motion a powerful defense, following hard on the innate reaction, bringing defenders trained specifically to bounce out
• Arguably, the most famous virus of our time is the human immunodeficiency virus, or HIV. It belongs to a special category called retroviruses. These organisms have the ability to invade a cell and then integrate themselves into our DNA. They mix with us. Imagine how vexing that is for the immune system, trying to discern alien from self. Meanwhile, there’s another twist: About 8 percent of our genetic material was formed from retroviruses.
• 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.
• 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.
• A truism emerged: If a researcher took one organism’s genome and cut precisely the same segment over and over again, the resulting fragment of genetic material would match each time. This might sound obvious, but it was key to defining the consistency of an organism’s genetic structure. Then Tonegawa found the anomaly... when he compared the segments to identical regions in mature B cells, the result was entirely different. This was new, distinct from any other cell or organism that had been studied.
• As the B cell matured into a fully functioning immune system cell, much of the genetic material dropped out. And not just that: In each maturing B cell, different material dropped out. What had begun as a vast array of genetic coding sharpened into this particular, even unique, strand of genetic material.
• Our bodies have come stocked with keys to the rarest and even unimaginable locks, forms of evil the world has not yet seen, but someday might. In anticipation of threat from the unfathomable, our defenses evolved as infinity machines.
• That’s because skin doesn’t have as many blood vessels and as much blood flow as, say, kidneys or other internal organs. It would take time for the immune system cells, carried in the blood, to assess and reject the skin.
• In other words, the immune system was able to discern a cell that was self and had been infected from a cell that was not self. The immune system killed only the infected ones that were self. An individual’s elegant defense didn’t care simply about the infection; it cared about the infection when it attacked its own personal habitat.
• MHC is the single most varied or polymorphic of all human genes. Every human being has roughly the same MHC genes, but they are all slightly different. They are the immune system’s fingerprint. This is one of the key markers that differentiate an individual from everyone else in the world.
• Say you step on a splinter. Virtually instantly, your body recognizes the need for a response. As a preparatory step, the blood vessels in the area open, or dilate. This allows more defenders to reach the action, and it leads to redness and heat in the region. More blood, more cells, more oxygen. The blood vessels go through a second change, becoming more permeable. Now other defenders can move into the tissue, along with clotting agents. These are different kinds of proteins, and as their numbers grow, the region experiences swelling. All this activity can lead to pain.
• So the macrophages are big (macro) eaters. These cells are like the love child of a janitor and a cop who eats first and asks questions later. They attack cells in the region that might be damaged or infected by consuming them and then chemically blitzing the devoured particles.
• when your body is invaded by an alien organism, the dendritic cells take a piece of the organism and display it to soldiers and generals to determine if attack is warranted.
• T cells and B cells, together known as lymphocytes, make up only as much as 40 percent of the white blood cells. The monocytes comprise 5 percent, give or take. The biggest chunk is made up of cells known as neutrophils. They are both spies and assassins.
• The neutrophils might dip into tissue or an organ for a bit, look for pathogens and, finding none, then return to the bloodstream, to continue monitoring and smelling. They can pick up scents, or chemical releases, of pathogens.
• In the Festival of Life, neutrophils are first responders. “If you scrape your hand right now, and get an infection, the first cell there would the neutrophils. The macrophage comes soon thereafter,”
• It was from digging around down there with the rabbit rectal thermometer. “I’m joking,” he told me. Sort of. “But the reality is that I did have rabbit feces under my fingernails for twenty years.”
• It had been put there to experiment with a new technology that involved giving blood platelet transfusions to cancer patients being treated with chemotherapy. The provision of all these platelets involved using a lot of blood. The white cells weren’t of interest to the folks in the trailer. “I’d go there every late afternoon and salvage these cells. Just take them, in a blood bag.”
• “It is perhaps the most important statement of my career,” he said. In technical terms, he’s referring to the discovery that it requires an amount as little as ten nanograms per kilogram of this substance to start fever. <...> At the most basic level, it meant that the interleukin-1 was inducing not just fever but also a T cell response.
• once the IFN was pure, Zoon and her colleagues, including collaborators at Caltech, sequenced the interferon. It took four years, but in 1980 they released a paper describing the pure form of interferon,
• Or maybe the cell dies from the invasion, but before it succumbs, it manages to go through the protein changes to create interferon. Other surrounding cells pick up the presence of interferon. “This starts a chain reaction,” Zoon explained.
• A cytokine is a secretion from a cell that prompts action by other immune cells. It is a messenger. It can be sent by an interferon or any of a number of other immune system actors. In the Festival of Life, when a foreign agent bursts into the party, immune cells might send lots of cytokines to one another—pulses of communication.
• 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.
• 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.”
• 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.
• 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.
• 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.
• 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.
• In a retrovirus, the RNA turns viral; it has contracted a virus. The viral RNA is equipped with a special enzyme that causes a process called reverse transcriptase, which turns the RNA into DNA. In other words, the virus causes the process to go in the opposite, or reverse, direction from the typical genetic process by which DNA instructs RNA. Here RNA has become DNA, ... DNA integrates into the nucleus of the cell and into an organism’s own DNA. Thus this virus has essentially co-opted the organism to make copies of itself—copies that are hard to detect. It squirts out of the cell as viral RNA, infects another cell, and the cycle goes on.
• The earliest researchers of this deadly plague, not yet even called AIDS, had their first clue. It had a characteristic shared by a recent discovery of a human retrovirus. “People argued: It attacks CD4 positive T cells. Something is killing them. Maybe it’s another form of retrovirus,” Dr. Fauci said.
• Bob reflected. This was his experience of the mid- to late 1990s: inspecting his body for purple spots and his mouth for white fungus. He couldn’t make sense of what was happening, and his confusion was combined with mounting survivor’s guilt. “I would meet people and it was just unbelievable, they all died. I’d make new friends and all those guys died.”
• There was a third key discovery. It now appeared that Bob and the other elite controllers had survived likely due to a very specific moment in the interaction between their immune systems and HIV: the first point of contact. “The evidence is pointing us to what we call the prime—the priming event.
• Dr. Migueles said that intensive study of HIV has helped develop “a flow chart of the multiplicity of relationships” in how the immune system cascade works. “That’s where the treasure chest is.”
• the discovery of monoclonal antibodies in the seventies. The ability to isolate and replicate individual antibodies was allowing drugmakers to develop medicines constructed around very specific molecules. These antibodies, injected into the body, would theoretically attach to and react with only very specific cells in the body.
• With Enbrel and other drugs that act on TNF, the idea is to get the cells that are causing problems to commit suicide. Obviously, getting malignant cells to off themselves can be useful in cancer. In the case of rheumatoid arthritis, it’s also advantageous to have overzealous immune cells commit apoptosis. Instead of attacking Linda’s body, the cells would kill themselves. (Heady stuff, and even weirder given another bit of trivia: The monoclonal antibody used in Enbrel is produced in hamster ovaries.)
• were what was helping, and minocycline was either *not* helping or making it worse? What came to my brain, unexpectedly unburied, was this line from Yeats’s poem, “Among School Children”: How can we know the dancer from the dance?
• This philosophy is increasingly widely held. It is called the hygiene hypothesis, and the broad idea is that we are starving our immune systems of training and activity by an excessive obsessive focus on cleanliness.
• These four factors are sleep, stress, the gut, and hygiene.
• The British Journal of Homeopathy, volume 29, published in 1872, includes a startlingly prescient observation about hay fever: “Hay fever is said to be an aristocratic disease, and there can be no doubt that, if it is not almost wholly confined to the upper classes of society, it is rarely, if ever, met with but among the educated.”
• At a core level, we have created a mismatch between our immune system—one of the longest surviving and most refined balancing acts in the world—and our environment. Thanks to all the powerful learning we’ve done as a species, our immune system isn’t getting the regular interaction with germs that helped to teach and hone it—that “trained” it. It doesn’t encounter as many bugs when we are babies. This is not just because our homes are cleaner, but also because our families are smaller (fewer older kids to bring home the germs),
• The paper from Boulder notes that human beings have virtually the same set of genetic material—you and I are 99.9 percent similar in our underlying genetic building blocks. But the microbiome—the underlying genetic material of the bacteria in our gut or hand—can differ by 80 to 90 percent.
• That evolutionary perspective plays out on an individual stage. Each of us develops a working relationship with our environment. It’s a social contract of sorts with the bacteria in our midst, and the contract is highly personalized and highly variable.
• Broadly, Mazmanian’s work also shows that the microbiome plays a key role in dampening the immune system, in addition to helping it to attack foreign invaders.
• It is in the microbiome’s self-interest to keep the body from attacking itself, so the bacteria contribute to helping keep the immune system in check.
• Also, once a person is infected, the virus does something else that makes it challenging for the immune system. Herpes essentially lies dormant. For instance, the oral version tends to hang out in cells inside the roots of nerves at the base of the skull (or in other nerve roots near and around the spine).
• Cell receptors for steroids are outside their nucleus (the innermost part). But when the steroid reaches them, a reaction begins that moves the steroid into the nucleus. There it begins a process by which it interacts with the cell’s DNA to change the proteins made by the cell. Chief among the influences made by these steroids is that “you repress expression of a lot of genes important for an immune response to occur,” Dr. Ashwell explained.
• It might come as little surprise that a healthy immune system helps promote or mediate sleep, with various studies showing that several key cytokines—those immune-system signals—can promote sleep. This happens when you’re healthy but also when you are sick, or getting sick; then, your immune system sends stronger signals creating a feeling of fatigue, telling your body to rest, and creating more resources to fight infection. All of this means the relationship between sleep and the immune system is a tight and circular one.
• Stress and lack of sleep, Dr. Irwin believes, make it tougher to fight viruses but easier, or at least less difficult, to fight bacteria. His theory makes perfect sense from historical and evolutionary standpoints. Picture your forebear facing an acute threat—say,
• Hodgkin’s lymphoma. It’s a cancer of the immune system. The word lymphoma refers to the lymphatic system, the network of nodes where the immune cells gather. In Hodgkin’s—named for the nineteenth-century English doctor who discovered it—B cells have mutated into malignancy.
• The chemotherapy drugs target cells that are fast dividing, which is a marker of cancer. The malignant alien cells reproduce quickly, just like those healthy cells in a wound that are being fed by blood and protected by the immune system itself. The evil malignancies co-opt the system, and in an odd way, they get treated to the privilege of dividing quickly. There are other cells in the body that also divide quickly, including hair follicles and cells in the gut and mouth.
• The term for one of the key cell types stimulating regeneration of our tissue is fibroblast—highly versatile and hearty cells that proliferate and migrate to the site. These cells are drawn by signals sent by macrophages. This is of note in that it shows a different side of the macrophages.
• But as is true of many construction projects, permits must be obtained. The body must accept that what is being built is approved of as “self.” Anything seen as alien to the point of being pathogenic will be destroyed, and the site will not be rebuilt. There is a dangerous corollary. Once permission is given, once the new cells being nourished are deemed “self,” the construction can go on with zeal. The trouble is, the new cells aren’t always self. Sometimes they are cancer. And so the factors that promote growth of healthy tissue also appeared to promote the growth of tumors. This was an idea that had been floated since 1863, when Rudolf Ludwig Carl Virchow, a German scientist, observed: “Chronic irritation and previous injuries are a precondition of tumorigenesis.”
• What she and others discovered begins to explain why things like smoking or coal mining or sunbathing are so carcinogenic. Each activity injures the tissue and damages the DNA.
• When a wound occurs—an insult, as it is known in scientific circles—cells divide. Of course they do. New tissue is needed. But when new cells divide, there is always a chance something can go wrong. Each cell division is an opportunity for a mistake, a mutation.
• “This stunning tolerance mechanism is a way for the host to decide: ‘This fight is too big. It’s a fight that will kill this person.’ So it settles for a less robust response. It cohabits with the virus, thinking, ‘At least it’ll kill me slowly.’ What this research has taught me,” Dr. Migueles continued, “is when you study autoimmune disease or cancer, how many similarities there are.” The immune system is making trade-offs to keep the peace, to maintain homeostasis, to let the individual live as long as is practical. It’s just math.
• “Generally, you have to give broadly nonspecific suppressors of the immune system,” Dr. Fauci said. “It comes with absolutely inevitable toxicities.” There’s a significant lesson here for society. In our quest to build a perfect and efficient world, we have overcorrected.