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October 26, 2022 - February 5, 2023
These organelles, later renamed mitochondria, were found to be the cell’s fuel generators; the furnaces that glow and burn constantly to produce the energy needed for life. There is some debate about the origin of mitochondria. But one of the most intriguing, and widely accepted, theories is that more than a billion years ago, organelles were, in fact, microbial cells that developed the capacity to produce energy via a chemical reaction involving oxygen and glucose. These microbial cells were engulfed or captured by other cells and entered into a working partnership of sorts, a phenomenon
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Mitochondria possess their own genes and their own genomes, which, suggestively, bear some resemblance to the genes and genomes of bacteria—again supporting Margulis’s hypothesis that they were primitive cells that were engulfed by other cells and then became symbiotic with them.
The fast route occurs mainly in the protoplasm of the cell. Enzymes serially break down glucose into smaller and smaller molecules, and the reaction produces energy. Because the process doesn’t use oxygen, it is called anaerobic. In terms of energy, the end product of the fast pathway is two molecules of a chemical called adenosine triphosphate, or ATP.
The deeper slow burn of sugars to produce energy occurs in mitochondria. (Bacterial cells, lacking mitochondria, can use only the first chain of reactions.) Here the end products of glycolysis (literally, the chemical breakdown of sugar) are fed into a cycle of reactions that ultimately produce water and carbon dioxide. This cycle of reactions involves the use of oxygen (and is therefore called aerobic) and is a small miracle of energy production: it generates a much larger harvest of energy, again, in the form of ATP molecules.
Over the course of a day, we generate billions of little canisters of fuel, to fire a billion little engines, in the billions of cells in our bodies. “Should all the billions of gently burning little fires cease to burn,” the physical chemist Eugene Rabinowitch wrote, “no heart could beat, no plant could grow upward defying gravity, no amoeba could swim, no sensation could speed along a nerve, no thought could flash in the human brain.”
Palade launched crucial collaborations with Porter and Claude. The lab would soon become the intellectual basement for the field of subcellular anatomy and function, the plinth on which the towering discipline would be constructed.
Just as Robert Hooke and Antonie van Leeuwenhoek, peering down a microscope, revolutionized cell biology in the seventeenth century, Palade, Porter, and Claude discovered a more abstract way of “looking” inside the cell. First, they burst cells open and spun the contents in a high-speed centrifuge along a gradient of densities. As the centrifuge spun with dizzying velocity, pulling down the cell’s heaviest subparts to the bottom and leaving lighter subparts above, different components of the cell appeared at different gradients along the length of a tube.
The whole process can be imagined as an elaborate postal system. It begins with the linguistic code of genes (RNA) that is translated to write the letter (the protein). The protein is written, or synthesized, by the cell’s letter writer (the ribosome), which then posts it to the mailbox (the pore by which the protein enters the ER). The pore routes it to the central posting station (the endoplasmic reticulum), which then sends the letter to the sorting system (the Golgi), and finally brings it to the delivery vehicle (the secretory granule). There are, in fact, even codes appended to proteins
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The Belgian biologist Christian de Duve, yet another Rockefeller Institute scientist, discovered an enzyme-laden structure called a lysosome. Like a cellular “stomach,” it digests worn-out cellular parts, as well as invading bacteria and viruses.
Plant cells contain structures called chloroplasts, the sites of photosynthesis, the conversion of light into glucose. Chloroplasts, like mitochondria, carry their own DNA, again suggesting an origin in microbes that were engulfed by other cells.
There is a membrane-bound structure called a peroxisome, another of de Duve’s discoveries, where some of life’s most dangerous reactions—for instance, the oxidation of molecules—is sequestered, and where hydrogen peroxide, an intensely reactive chemical, is generated. Were the peroxisome to open up and release its internal poisons, the cell would be attacked by its own reactive contents. It...
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The process of switching genes on and off is vital, giving the cell its identity. The set of on/off genes instructs a neuron to be a neuron, and a white cell to be a white cell. During the development of an organism, genes—or rather proteins encoded by genes—tell cells about their relative positions and command their future fates. Genes are turned on and off by external stimuli such as hormones, which also signal changes in a cell’s behavior.
“We can only hope that what the geneticist J. B. S. Haldane posited on the cosmos will prove not to be true for the nucleus: “ ‘Now, my suspicion is that the universe is not only queerer than we suppose, but queerer than we can suppose. If we appropriately bear in mind that the nucleus may be more complicated than we may have once thought, and yet just may be knowable, then this very belief may empower us and our students and successors to penetrate the subject’s awaiting depths, the next of which now beckon. There is every reason to believe in this program. So let us be of good cheer.’ ”
a cell’s autonomy lies in its anatomy.
There is no such thing as reproduction…. When two people decide to have a baby, they engage in an act of production. —Andrew Solomon, Far from the Tree: Parents, Children, and the Search for Identity
In humans and multicellular organisms, the process for the production of new cells to build organs and tissues is called mitosis—from mitos, the Greek word for “thread.” In contrast, the birth of new cells, sperm, and eggs for the purpose of reproduction—to make a new organism—is called meiosis, from meion, the Greek word for “lessening.”
The third phase is perhaps the most mysterious and least understood: a second resting phase, called G2. Why stop a cell from dividing once it has synthesized a duplicate chromosome? Why waste a freshly synthesized strand of DNA? G2 exists as a final checkpoint before cell division because cells cannot afford chromosomal catastrophes such as translocations, broken arms of DNA, drastic mutations, deletions. This is a time when the cell checks and double-checks the fidelity of DNA replication, guarding against damage to DNA, or a devastating event in a chromosome. A cell showered with
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Let us begin with a fact that is both strikingly self-evident to a cell therapist and startling to someone outside the field: in vitro fertilization (IVF) is cell therapy. It is, in fact, among the most common cell therapies in human use. It has been a reproductive option for more than four decades and has produced roughly eight to ten million children. Many of those IVF babies are now adults with children of their own—typically produced without any need for in vitro fertilization. It has become so familiar, indeed, that we don’t even imagine it as cellular medicine, although, of course, it is
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In the mid-1950s, an unorthodox, secretive professor who taught obstetrics and gynecology at Columbia University, Landrum Shettles, launched a project to create an in vitro fertilized human baby. He wanted to cure infertility. Shettles, who had seven children, rarely went home to rest. His lab was furnished with a large, overgrown fish tank and a series of clocks. He slept on a makeshift cot amid the constant ticktocking, and the medical residents would often find him, in his wrinkled green scrubs, wandering the halls late at night.
The paper by Edwards, Steptoe, and Bavister, “Early Stages of Fertilization in Vitro of Human Oocytes Matured in Vitro,” was published in the journal Nature in 1969. Unfortunately, Jean Purdy, who had performed the experiment, was not credited, consistent with the conventional practice of cutting women out of science. Later, both Edwards and Steptoe made several attempts to acknowledge her contributions, for IVF was born in Purdy’s hands. In the lab, she created the first human embryo produced through IVF; in the hospital, she would later cradle the first IVF baby. In 1985, she died of
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IVF is thus learning the vocabulary of Cyclins and CDKs. Why, for instance, is it sometimes tough to harvest eggs from some women, despite hormonal stimulation? In 2016, a group of researchers demonstrated that the very molecules that Nurse, Hartwell, and Hunt had discovered—Cyclins and CDKs—are involved. As long as one such combination, CDK-1 and a Cyclin, remains inactive in egg cells, the cell remains dormant. Quiescent. In G-zero. Release these molecules and activate them, and the egg cells begin to mature. If the eggs mature “prematurely,” as it were, they are progressively lost over
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single cell zygotes into hollow, multicellular embryonic balls called blastocysts—an early sign of a healthy, viable embryo. The blastocyst is made of two parts. Its outer shell gives rise to the placenta and the umbilical cord, the developing baby’s support system, while the inner mass of cells, hanging on to the wall of the fluid-filled cavity, becomes the embryo. Both the outer shell and the inner mass form out of the first fertilized cell, through the rapid division of cells, mitosis upon mitosis.
the Stanford group identified just three factors that were predictive of future blastocyst formation: the duration of time that it takes the first cell to divide for the first time; the time between that first division and the second; and the synchronicity of the second and third mitosis. By relying on this trio of parameters, the odds of predicting blastocyst formation (and, subsequently, the chance of viable implantation) increased to 93 percent. Imagine IVF performed with a single embryo—no high-risk pregnancies with twins and triplets—and with a 90 percent success rate.
But perhaps the most astonishing feature of multicellularity is that it evolved independently, and in multiple different species, not just once, but many, many times. It is as if the drive to become multicellular was so forceful and pervasive that evolution leapt over the fence again and again. Genetic evidence suggests this incontrovertibly. Collective existence—above isolation—was so selectively advantageous that the forces of natural selection gravitated repeatedly toward the collective. The transformation from single cells into multicellularity was, as the evolutionary biologists Richard
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To some extent, the “minor major transition” from unicellularity to multicellularity can be studied and reproduced in the laboratory. In one of the most intriguing attempts, carried out at the University of Minnesota in 2014, a group of researchers led by Michael Travisano and William Ratcliff made a multicellular being evolve from a unicellular organism.
“All happy families are alike; each unhappy family is unhappy in its own way.”
Travisano and Ratcliff worked with yeast. And so, in December 2010, over Christmas break, Ratcliff set up one of the most magnificently simple evolutionary experiments. He allowed yeast cells to grow in ten separate flasks and then let the flasks stand for forty-five minutes such that single-celled yeast remained afloat, while heavier multicellular aggregates (“clusters”) fell to the bottom.
Evolutionary scientists have performed variations of this experiment for a number of different unicellular organisms—yeast, slime molds, algae—and a general principle emerges from them. Under the right evolutionary pressure, single cells can become multicellular aggregates over a mere few generations.
Pause, for a moment, to consider the birth of a human zygote. A sperm swims its wayI across a seemingly oceanic distance and penetrates an egg. A special protein on the surface of the egg and its cognate receptor on sperm clicks the two cells together. Once a single sperm has penetrated an egg, a wave of ions diffuses out from within the egg, initiating a host of reactions that prevent other sperm from entering. We are, after all, monogamous in the cellular sense.
It was a wholly incorrect scheme, but it contained a kernel of truth. Aristotle broke from the ancient idea of preformation, which proposed that the mini-human, called a homunculus, came already premade—eyes, nose, mouth, ears intact—but shrunk into microscopic size and folded tight in the sperm, like a toy that expands to full size when you add water. The preformation theory would preoccupy many scientific minds from ancient times all the way up to the early eighteenth century.
The next series of events represents the true marvel of embryology. The tiny cluster of cells hanging from the walls of the cellular balloon, the inner cell mass, divides furiously and begins to form two layers of cells—the outer one called the ectoderm, and the inner called the endoderm. And about three weeks after conception, a third layer of cells invades the two layers and lodges itself between them, like a child squeezing into bed between her parents. It’s now the middle layer, called the mesoderm. This three-layered embryo—ectoderm, mesoderm, endoderm—is the basis of every organ in the
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The embryo is now ready for the final sequence of activities. Within the mesoderm, a series of cells assemble along a thin axis to form a rodlike structure called the notochord, which spans from the front of the embryo to its back. The notochord will become the GPS of the developing embryo, determining the position and axis of the internal organs as well as secreting proteins called inducers. In response, just above the notochord, a section of the ectoderm—the outer layer—invaginates, folding inward and forming a tube. This tube will become the precursor of the nervous system, made up of the
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physician Lewis Thomas wrote in his collection of essays The Medusa and the Snail: More Notes of a Biology Watcher, “at a certain stage there emerges a single cell which will have as all its progeny the human brain. The mere existence of that cell should be one of the great astonishments of the earth.”
Frances Kelsey likely saved tens of thousands of lives by standing, like the final regulatory bulwark, against the relentless onslaught of a pharmaceutical giant. In 1962, she was awarded the Presidential Medal of Honor. This chapter serves to memorialize her service and tenacity. If this book is about the birth of cellular medicine, it must also mark the birth of its demonic opposite: the birth, and death, of a cellular poison.
The cell… is a nexus: a connection point between disciplines, methods, technologies, concepts, structures, and processes. Its importance to life, and to the life sciences and beyond, is because of this remarkable position as a nexus, and because of the cell’s apparently inexhaustible potential to be found in such connective relationships. —Maureen A. O’Malley, philosopher of microbiology, and Staffan Müller-Wille, science historian, 2010
“Divide the main cellular components of blood. Red cell. White cell. Platelet. Examine each cell type separately. Write what you observe about each type. Move methodically. Number, color, morphology, shape, size.”
Normal white cells come in two main forms: lymphocytes and leukocytes.
blood speaks to everyone and everything: it is the central mechanism of long-distance communication, of transmission, in humans. Be it hormones, nutrients, oxygen, or waste products, blood delivers and connects—talks—to every organ and from one organ to the next. It even speaks to itself: its three cellular components, red cells, white cells, and platelets, in particular, engage in an elaborate system of signaling and cross talk. Platelets band together to form a clot. A single platelet, in isolation, cannot congeal into a clot, but millions of platelets, in conjunction with proteins in the
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melancholia or depression (melan-cholia literally means “black bile”)—a
Serum differs from plasma: it is the fluid that’s left over after blood has been clotted. It contains proteins, including antibodies, but no cells.
megakaryocytes (massive, multi-nuclear-lobe-carrying cells),
platelets were found to be the central component of a clot. Activated by signals from an injury—a wound, say, or a broken blood vessel—they swarmed to the wound site and began a self-perpetuating loop to plug the bleeding. It was a healing cell (or, more accurately, cell fragment).
Von Willebrand’s factor circulates in blood and is also strategically located right under the cells that line blood vessels. Injury to the blood vessel exposes 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.
But the formation of a clot is a much more complex process. Proteins secreted by the injured cells send out further signals to summon platelets to the site of injury, amplifying their activation. And clotting factors floating in the blood use yet other sensors to detect the injury. A cascade of changes is launched. 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.
The most prominent among these was aspirin. Its active ingredient, salicylic acid, originally found in willow extract, had been used by the ancient Greeks, Sumerians, Indians, and Egyptians to control inflammation, pain, and fever.
In the 1960s, deeper investigations into the biology of platelets revealed how aspirin works to prevent clots. Platelets, in concert with some other cells, produce chemicals to signal injury and get activated. Aspirin, at low doses, blocks the key enzyme that produces these injury-sensing chemicals, thereby decreasing platelet activation and subsequent clots. As a prevention mechanism for heart attacks, aspirin may well rank among the most important medicines of the past century.
Scientists at Verve have devised ways to insert catheters into the arteries leading to the liver. (The dexterity that Sek learned from decades of practice in cardiology helped.) These 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
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these receptors come in two classes: those that recognize “damage-associated molecular patterns” (substances released upon cellular damage) and those that sense “pathogen-associated molecular patterns” (components of microbial cells). In short, they sniff around the body looking for patterns of injury and infection—substances that signal invasion and pathogenicity.
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.) Innate, also, because it is the most ancient wing of the immune system and therefore innate to our ancestors. Starfish have it, as Metchnikoff first
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Despite the centrality of the innate immune response, or perhaps because of its centrality, innate immunity has proven difficult to manipulate medically. But, unknowingly, perhaps, we have been playing with innate immunity for longer than a century. This age-old instance of manipulating innate immunity is vaccination—although, of course, when vaccines were first invented, the vocabulary of innate immunity did not exist, nor was the mechanism of protection known. Even the word vaccine would be coined centuries after vaccination itself was being practiced widely across China, India, and the Arab
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