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February 18 - July 16, 2023
English, they were called platelets—small plates.
platelets were found to be the central component of a clot.
researchers discovered that there was a second, intersecting system in the blood to stop bleeding. This involved a cascade of proteins that float in the blood, sense injury, and also assist in congealing into a dense mesh to stabilize the platelet clot and stanch bleeding. The two systems—platelets and clot-making proteins—communicate with each other,
key clotting protein called, appropriately enough, von Willebrand factor (vWf).
Platelets carry receptors that bind to vWf and thus have the capacity to “sense” when a wound has exposed the vessel, and they begin to gather around the site of injury.
Ultimately, the cascade leads to the conversion of a protein called fibrinogen into a mesh-forming protein called fibrin. Platelets, trapped in the fibrin mesh, like sardines in a net, ultimately form a mature clot.
Verve Therapeutics, has proposed an audacious strategy for reducing blood levels of LDL cholesterol.
they hope to use gene-editing technologies to inactivate the genes that encode for these cholesterol-related proteins in human liver cells—and
catheters will deliver gene-editing enzymes, loaded inside tiny nanoparticles, to the organ. Once these particles off-load their cargos inside the liver cells, the gene-editing enzymes will change the scripts of genes that aid and abet cholesterol metabolism, thereby drastically decreasing the amount of circulating cholesterol in the blood—in essence, activating the LDL metabolizing pathways. It’s a one-and-done infusion. Once the genes have been altered, they are altered for life.
Metchnikoff noted that the immune cells moved toward the site of inflammation autonomously as if impelled by a force or an attractant. (Later, these attractants would be identified as specific proteins, called chemokines and cytokines, released by cells upon injury.)
The human versions of the phagocytic cells that Metchnikoff discovered—macrophages, monocytes, and neutrophils—are among the very first cells to respond to injuries and infections. Neutrophils are produced in the bone marrow.
It is as if they are maniacally driven to reach sites of infection and inflammation—in part, because they so keenly perceive the gradient of cytokines and chemokines released by injury. They are lean, energetic, mobile machines built for immune attack.
this wing of the immune response—neutrophils, macrophages, among other cell types, with their attendant signals and chemokines—began to be termed the “innate immune system.”II Innate, in part, because it exists inherently in us, with no requirement to adapt to, or learn, any aspect of the microbe that caused the infection. (We will come to the adaptive wing of the immune response, with B cells, T cells, and antibodies, in the next chapter.)
Vaccination, as we will soon learn, generally works by inciting specific antibodies against a microbe. The antibodies come from B cells, and they are retained in the cellular memory of the host because some of these cells live for decades—long after the initial inoculum was introduced.
Our bodies produce B cells primarily in the bone marrow (thankfully, another B), which then mature in the lymph nodes.
The locus of immunological memory, in summary, is not a protein that persists, as Ehrlich may have imagined. It is a B cell, previously stimulated, that bears the memory of the prior exposure.
Ultimately, the B cell matures into a cell so single-mindedly dedicated to antibody production that its structure and metabolism are altered to facilitate the process. It is now a cell dedicated to making antibodies—a plasma cell. Some of these plasma cells also become long lived and retain the memory of the infection.
A drug typically works by binding its target—as Paul Ehrlich had pointed out, like a key to a lock—and inactivating or, occasionally, activating its function. Aspirin, for instance, jams itself into the lock cyclooxygenase, an enzyme involved in blood clotting and inflammation.
But if B cells generated antibodies to kill microbes, what did T cells do?
Although a CD8 T cell could recognize a cell from the same body, it killed only infected cells from the same body. No viral infection, no kill. It was as if the T cell was capable of asking two independent questions. First: Does the cell that I am surveying belong to my body? In other words, is it self? And second: Is it infected with a virus or a bacterium? Has the self been changed? Only if both were true—the self and infection—would a T cell kill its target.
cells of the innate immune system—macrophages, neutrophils, and monocytes—are constantly surveying the body to find signs of injuries and infections. Once such an infection is detected, these cells swarm to the infected site to ingest, or phagocytose, bacterial cells or the viral particles. They devour the invaders, internalize them, and route them to special compartments. These compartments—lysosomes, among them—are chock-full of enzymes to degrade the virus into smaller fragments, including those bits and pieces of proteins known as peptides.
the CD4 cell is not so much a helper as it is the master machinator of the entire immune system, the coordinator, the central nexus through which virtually all immune information flows. Its functions are diverse. Its work begins, as we read before, when it detects peptides from pathogens, loaded on class II MHC molecules, and presented by cells. Then it jump-starts the immune response, activating it, sending alarms, enabling B cell maturation, and recruiting CD8 T cells to sites of viral infection. It secretes factors that enable cross talk between the various wings of the immune response. It
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“There appears to be a fork in the road to immunity to Covid-19 that determines disease outcome,” Iwasaki told me. “If you mount a robust innate immune response during the early phase of infection [presumably via an intact type 1 interferon response], you control the virus and have a mild disease. If you don’t, you have uncontrolled virus replication in the lung that […] fuels the fire of inflammation leading to severe disease.”
Some signal, or impulse, must move between cells, informing them of the global “state” that the body is inhabiting. The signals move from one organ to the next, carried by blood. There must be a means for one part of the body to “meet” a distant part of a body. We call these signals “hormones,” from the Greek hormon—to impel, or to set some action into motion. In a sense, they impel the body to act as a whole.
A heart cell, a neuron, a pancreatic cell, and a kidney cell rely on these commonalties: mitochondria to generate energy, a lipid membrane to define its boundaries, ribosomes to synthesize its proteins, the ER and Golgi to export proteins, membrane-spanning pores to let signals in and out, a nucleus to house its genome.
Genes, by themselves, are strikingly incomplete explanations of the complexities and diversities of organisms; we need to add gene-gene interactions and gene-environment interactions to explain organismal physiology and fates.
He died on September 5, 1902. Virchow continued to work on his understanding of cellular physiology and its converse, cellular pathology, right until his moment of death. The many seminal ideas sparked by his work, and their many offshoots over the ensuing decades, are his lasting legacy and the lessons of this book.
To some degree, being a good parent, athlete or performer is about accepting and cherishing the raw material you’ve been given to work with [italics my own]. Strengthen your body, but respect it. Challenge your child, but love her. Celebrate nature. Don’t try to control everything […]
genes are lifeless without cells. The real “raw material” of the human body is not information, but the way that information is enlivened, decoded, transformed, and integrated—i.e., by cells.
in the 1840s and ’50s, Virchow would revolutionize the idea of medicine and physiology. Virchow argued that cells were the basic units of all organisms and the key to understanding human illness was to understand the dysfunctions of cells. His book Cellular Pathology would transform our understanding of human disease.
