The Song of the Cell, Siddhartha Mukherjee
"The discovery of cells, and the reframing of the human body as a cellular ecosystem, also announced the birth of a new kind of medicine based on the therapeutic manipulations of cells. A hip fracture, cardiac arrest, immunodeficiency, Alzheimer's dementia, AIDS, pneumonia, lung cancer, kidney failure, arthritis--all could be reconceived as the results of cells, or systems of cells, functioning abnormally. Ad all could be perceived as loci of cellular therapies."
"What is a cell, anyway? In a narrow sense, a cell is an autonomous living unit that acts as a decoding machine for a gene. Genes provide instructions--code, if you will--to build proteins, the molecules that perform virtually all the work in a cell. Proteins enable biological reactions, coordinate signals within the cell, form its structural elements, and turn genes on and off to regulate a cell's identity, metabolism, growth, and death. They are the central functionaries in biology, the molecular machines that enable life."
"What do cells do? Well, they build organisms. Gradually, as the reach and generality of their claim became evident, Schleiden and Schwann proposed the first two tenets of cell theory:
All living organisms are composed of one of more cells.
The cell is the basic unit of structure and organization in organisms."
"Cellular Pathology detonated through the world of medicine. Generations of anatomic pathologists had thought about diseases as the breakdown of tissues, organs, and organ systems. Virchow argued that they had missed the real source of the illness. Since cells were the unit blocks of life and physiology, Virchow reasoned, then the pathological changes observed in diseased tissues and organs should be traced back to pathological changes in the units of the affected tissue--in other words, to cells. To understand pathology, doctors needed to look for essential disruptions not just in visible organs but in the organ's invisible units."
"These two paragraphs--the first proposing the cell as a unit of life and physiology, and the second proposing the cell as the unit locus of disease--are pinned on a board in my office. In thinking about cell biology, cellular therapies, and the building of new humans out of cells, I inevitably return to them. They are, as it were, the twin melodies of that ring throughout this book."
"The nucleus is the command center; the captain's bridge of the cell. It is the place that both receives and then disseminates most of life's signals. RNA, the code to build proteins, is copied from the genetic code here and then exported out of the nucleus. We might imagine the nucleus as the center of the center of life."
"In biology, there is rarely a more poignant moment than when a structure of a molecule melds with its function: what a molecule looks like, and what it does, fall into perfect union. Take DNA, the iconic double helix. It looks like an information carrier--a string of four chemicals, A, C, T, and G, with a unique sequence (ACTGGCCTGC) just like a four-letter Morse code. The double helix also allows us to understand how replication occurs. The strands are complementary, yin and yang: the A on one strand is matched with T on the other, and C matched with G. When a cell divides to make two copies of DNA, each strand serves as a template to make the other. The yin dictates the formation of the yang; the yang shapes the yin--and two new yin-yang double helices of DNA are formed."
"But there are potent lessons, and open questions, in Brown's story that are relevant for vaccine and antiviral drug development. First, altering the cellular reservoir of HIV in the blood can potentially cure the disease, or at least achieve deep permanent control on viremia. In the wake of Timothy Brown's HIV cure, a second, patient, in London, was also cured of HIV with a bone marrow transplant. Unless, these two cases are anomalies, it is unlikely that there is a "secret" reservoir, beyond blood, where HIV might hid and get reactivated when the drugs are discontinued--a potential problem that has concerned researchers for decades. (Note that I specified blood, not just CD4 T cells. Macrophages, also derived from blood, for instance, are known to act as reservoirs for HIV.)"
"The basis for this tolerance was that T cells that reacted against "self" cells--immune cells that attacked our own (i.e., pieces of proteins derived from our own cells and presented on our own MHC molecules)--were somehow deleted or removed from the immune system during infanthood or prenatal development. Immunologists called the self-reactive cells "forbidden clones"--forbidden because they had dared to react to some aspect of a self peptide and were therefore deleted from existence before they could be allowed to mature and attack the self. Burnet likened them to "holes" in immune reactivity. It is one of the philosophical enigmas of immunity that self exists largely in the negative--as holes in the recognition of the foreign. The self is defined, in part, by what is forbidden to attack it. Biologically speaking, the self is demarcated not by what is asserted but by what is invisible: it is what the immune system cannot see. "Tat Twam Asi.""That [is] what you are."
"I have sketched the skeletal outline of how a neuron functions, and how that function relates to the building of the brain. But this is the barest of sketches. Of all cells in the body, the neuron is, perhaps, the most subtle and the most magnificent. The pared-down principle is this: we should imagine the neuron not just as a passive "wire" but as an active integrator. And once you think of each neuron as an active integrator, you can imagine building extraordinarily complex circuits out of these active wires. Those complex circuits, you might surmise, could be the basis for building even more complex computational modules--those that can support memory, sentience, feeling, thought, and sensation. A collection of such computational modules could coalesce to form the most complex of machines in the human body. That machine is the human brain."
"What general principle can one draw out of these experiments? One of the most unusual conundrums of cell biology is that while the early genesis of organs seems to follow a relatively ordered pattern, the maintenance and repair of tissues in adulthood seems idiosyncratic and peculiar to the tissue itself. If you cut the liver in half, the remnant liver cells will divide and grow the liver back to nearly its full size--even in adults. If you fracture a bone, osteoblasts will deposit new bone and repair the fracture--although the process slows down dramatically in older adults. But there are other organs where damage, once down, is permanent. Neurons in the brain and the spinal cord, once they've stopped dividing, don't divide to regenerate neurons (they are "post-mitotic"--i.e., no longer able to divide). When certain kidney cells die, they don't come back."
"Many readers might read the word song as metaphorical. But in my reading, it's far from a metaphor. What the young man laments is that he hasn't learned the interconnectedness of the individual inhabitants of the rain forest--their ecology, interdependence--how the forest acts and lives as a whole. A "song" can be both an internal message--a hum--and, equally, an external one: a message sent out from one being to another to signal interconnectedness and cooperativity (songs are often sung together, or to one another). We can name cells, and even systems of cells, but we are yet to learn the songs of cell biology."