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Kindle Notes & Highlights
by
Matt Richtel
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December 2 - December 6, 2020
Researchers, who, eventually, sought a handy way to define the nature of the genetic change to the material of genes, labeled the key genetic material in an antibody with three initials: V, D, and J. The letter V stands for variable. The variable part of the genetic material is drawn from hundreds of genes. D stands for diversity, which is drawn from a pool of dozens of different genes. And J is drawn from another half dozen genes.
as the cell matures, a single, random copy of V remains, along with a single each of D and J, and all the other intervening material drops out.
the body has randomly made hundreds of millions of different keys, or antibodies. Each fits a lock that is located on a pathogen. Many of these antibodies are combined such that they are alien genetic material—at least to us—and their locks will never surface in the human body. Some may not exist in the entire universe. 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.
Humans must be incredibly similar and also fundamentally diverse. The similarity is necessary to allow us to work together, communicate—share resources, ideas, food. But we must be different enough to provide diverse talents, including the innate ability to fight off different threats.
“Transplant is the parent and sibling of immunology,” Dr. Markmann told me when we spoke about the history. Transplantation and immunology are siblings because a transplant—whether of skin or an immune system—can’t work if the body rejects the transplant as “alien.” And transplantation is also immunology’s parent because the failure of the body to accept human or animal tissue was one of the clearest, earliest signs that something in our bodies was rejecting and attacking tissues that seemed so similar.
Peter Medawar—eventually Sir Peter Medawar—was a zoologist from Oxford who had been called upon during World War II to help a plastic surgeon treat burn victims. Sir Medawar tried in vain to graft skin from donors onto the charred victims of shelling and bombing. The results were cruel. Even the failed grafts looked for several days or weeks like they were succeeding. 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.
Often, great discoveries have been made on the cusp of death through experimentation on a patient. The patient would be complicit, usually agreeing to take a chance at living through a Hail Mary. Revelation had the deeply perverse quality of being born of desperation, not just from science’s grand yearning to save lives, but from the excruciating intrapersonal despair that allows a human to become a guinea pig.
Presumably, immune systems would be less likely to reject tissue with related genetics, like that of siblings. Would you believe, though, it sometimes made matters worse?
In other words, the immune system was more deliberate the first time around in rejecting a sibling’s tissue, but once the skin was determined to be “alien,” the rejection came more quickly. This underscored the ability of the immune system to learn; the first time the elegant defense took a while to assess the skin as foreign and build the machinery to reject it, but the second time, with the machinery in place, judgment was fast and merciless.
a key contribution to transplant science was being made in the 1950s, also in cows—specifically thanks to the story of one very lusty Hereford bull. The bull lived in Wisconsin, where, feeling its oats, it escaped its confines and mated with a cow that had already been impregnated by a Guernsey bull. The cow in turn had fraternal twins, each from a different father.
Despite having different dads, they had profound similarities in their blood. In fact, each actually carried blood from the other’s father. It appeared that when the calves were in utero, they had shared cell types in an unexpected way.
In 2017, in the United States, there were nearly 35,000 transplants of lungs, hearts, kidneys, intestines, and other organs, according to the United Network for Organ Sharing, and by no means were the transplants done between identical twins, let alone siblings. The best possible matches are made on a number of bases, including blood type and the similarity of antigens. Even after a successful transplant, though, the recipient can need a lifelong regimen of immunosuppression.
Work by a French immunologist, and others, isolated in human beings the first antigen that reacted against other human beings. These are called isoantigens—antigens within the same species. If two people are a poor fit for bone marrow, the isoantigens in one will provoke an antibody response in the other, setting off a defensive attack.
The T cells weren’t just killing free-floating infection; they were targeting mouse cells that were infected, meaning the cells that were being annihilated were part alien and part self. This was very interesting but maybe obvious. It meant the T cells were diagnosing illness inside the cell, not merely identifying freestanding viruses.
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.
The T cells first determine if you specifically have come under attack. The concept is called the major histocompatibility complex, or MHC—another immunological term that goes down like cold lemonade on a freezing day.
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.
Studies have shown the MHC gene gives off a scent. The scent is used as a factor in how people choose their mates. If one person’s MHC is too similar to another’s, the MHC will act as a repellent. The scent of MHC that is sufficiently different will act as a magnet.
it also creates the possibility that the immune system originated not just to keep us away from pathogens but also to help us choose mates that are sufficiently self but not too much.
Even as evolution led creatures to walk onto land, turned them (or us) bipedal, saw the transformation of our communications, and enabled the development of modern tools, the immune system remained largely the same.
This tells us that, while the immune systems are different, certain defense functions seem essential for survival. One such function is redundancy. There are multiple molecules and cells in both systems, including some proteins that seem to do virtually the same thing—whether it be attacking, inducing attack, or slowing it.
what is a fever? You think you know, right? I did too. The body heats up. But it’s a much more profound question than I had realized, one that would illuminate a new level of understanding of the immune system, namely, that it has a vast, virtually unmatched telecommunications system.
In the late 1960s, a woman showed up at Yale University Hospital with a sky-high fever, peaking more than once at 104 degrees. In her mid-twenties, originally from the Caribbean, the woman was shaking with chills, miserable. It didn’t make any sense. That’s because the woman suffered no infection. It was true that she suffered from an autoimmune disorder called lupus.
It wasn’t clear where fever came from or what its purpose was—to kill the infection, or was something else going on? This is not at all a simple question. The body, for instance, doesn’t have a central furnace. It doesn’t have a thermostat or an organ that produces heat. But somehow, when provoked, the body—the immune system—sends its internal temperature soaring.
Interestingly, body temperature was at its peak at around six P.M. each day. These temperatures Dr. Dinarello referred to as low-grade fevers that are likely not representative of disease.
A definition of inflammation written by the Institute for Quality and Efficiency in Health Care, a group funded by the German government, sums up the sheer breadth of the concept: “Inflammation is—very generally speaking—the body’s immune system’s response to stimulus.”
inflammation is the reaction of the body to an event that challenges our well-being. This can be the inhalation of a virus, the poke of a splinter, the ingestion of noxious bacteria, the claw of a bear or a cat, or even a noise loud enough to cause injury to our hearing.
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. In that way, the
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there can be more tissue damage twenty-four hours after the insult takes place than there was at the moment it happened. During that period, the elegant defenses are examining, cleaning, and rebuilding enough of a physical space to make sure that no danger is left behind and that they can rebuild healthy new tissue seamlessly in the region around it.
When an insult, like the splinter, happens, it might seem like a fender bender from the outside, but our elegant defenses need a lot of information to make that call and to repair the area of the insult, however small it may be, and this brings multiple cells into the fray.
The technical term for one cell eating another is phagocytosis. That word derives from the Greek word phageîn, which means to eat. 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.
If you’re surprised to hear there are any more cells in the immune system, you’re in good company. In fact, the more that immunologists over the previous century explored inflammation, the more they realized that our defenses are broken down into many different cells and receptors with widely varied functions.
For instance, I mentioned that macrophages are a kind of cell called a monocyte. Then in the mid-1970s, Ralph Steinman threw a wrench into science by discovering a sibling monocyte.
Dr. Steinman and a collaborator surmised that these cells played a key role in the immune system, and then proved it. Through a series of experiments, they showed that these cells, when presented with a foreign cell or organism, could stimulate or induce a powerful response from T cells and B cells.
In practical terms, 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. The dendritic cells roam the Festival of Life, brushing up against guests at the packed affair, and presenting their identities to the T cells. If an antigen were perceived as foreign, it would stimulate a heavy response, what is known as a mixed leukocyte reaction, or MLR, a major inflammation of T cells and B cells and other immune cells.
In fact, T cells and B cells, together known as lymphocytes, make up only as much as 40 percent of the white blood cells.
The neutrophil is the cell that Metchnikoff had observed and had himself eventually better understood. The neutrophils represent more than half of our white blood cells—50 to 60 percent. Their work in the body, we now know, is a bit like that of a cold war spy—a deadly agent but one who is often quietly looking and listening for trouble and then occasionally getting drawn into violence.
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 much smaller concentration in the body are two other defenders, the eosinophil (less than 5 percent of the white blood cell population) and the basophil (less than 2 percent). Combined, they are known as granulocytes. This name reflects their function. These cells contain tiny enzymatic granules that digest and destroy pathogens.
quite oddly, the attack didn’t involve any B cells or T cells. The response was less specific than the targeted nature of B cell and T cell attacks. These “new” cells swarmed instantly in a kind of raw, generic manner that seemed more consistent with a knee-jerk attack than the specified, deliberate nature postulated by clonal selection theory.
One reason scientists had trouble absorbing the new information was that, just as the human body itself struggles with the alien, science can have trouble making peace with ideas that seem foreign.
Ideas, memes, can elicit a kind of autoimmune response, an overreaction that feels protective initially but can ultimately prove counterproductive and make it harder to find truth.
Dr. Dinarello dates the relevant research to 1943, when a Russian scientist who had relocated to the United States found that he could induce fever in rabbits by injecting them with pus. Pus, it turns out, is the detritus of neutrophils, the cells that rush into action at the first sign of insult. They kill what is around them and die in the process. When you observe pus oozing from your body, you’re seeing these dead cells.
Through the 1950s and ’60s, more evidence was added about the process. For instance, the rabbits conserved heat during fever by constricting blood vessels, such that their ears became cold. (Have you ever felt clammy when you have a fever?)
A paper published in The New England Journal of Medicine reported evidence of a pyrogen—a fire starter—in a blood cell different from the neutrophil. Rather than coming from a first-responder killer, the chemical that seemed associated with fever derived from a monocyte, which is a kind of macrophage.
Dr. Dinarello went for research and wound up working at the National Institutes of Health. Not only that, he earned his way into a remarkable place and time: Building 10 at the NIH, a hall of truly great science, a Willy Wonka factory of experimentation and discovery.
Seeds of salvation for sufferers of cancer, AIDS, autoimmune diseases, flu, and other killers were planted in Building 10. The work done here speaks to the power of a broad field called basic science, defined as science that is aimed at understanding core concepts and isn’t directed at developing, say, a particular medicine to attack a specific disease.
Dr. Dinarello was easy to pick out. He was the one with rabbit shit under his fingernails. It was from digging around down there with the rabbit rectal thermometer.
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.”
