The Language of Life How Cells Communicate in Health and Disease (2005) / Chapter Skim
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5 "The Scenario-Buffered Building"
5 "The Scenario-Buffered Building"
Pages 185-240
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From page 185... ...
-- Stewart Brand, How Buildings Learn W e moved a closet, tore out a vanity, and added a bathtub because the previous owners of our house had installed a dressing room instead of a master bathroom. Across the street, a couple with three growing children bumped out the back wall to extend their kitchen and family room.
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From page 186... ...
186 THE LANGUAGE OF LIFE Unfortunately, most architects, says Brand, prefer to think of their creations as everlasting. The buildings they design resist change.
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From page 187... ...
What's more, the signaling mechanisms constructed from these patterns were themselves powerful agents for change. Through the use of structural motifs like interaction domains, organisms could revamp the regulation of conserved biochemical functions, link signaling pathways, and control the timing and location of developmental events.
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From page 188... ...
But hormonal conversations are promiscuous -- it doesnt' matter which islet cell responds to insulin as long as one does -- and conversations coordinating stimulus and response had to be precise. After all, if an animal wants to move its right hind leg, the message must get to the right hind leg muscles, not the muscles of the left hind leg, the right front leg, the jaw, the ribcage, or the tail.
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From page 189... ...
Much as current flows through a wire, these impulses, known as action potentials, travel down the axon from its origin near the cell body to its terminal. Axons and ion channels solved the problems posed by distance; a new appliance, developed especially for conversations between neurons, met the need for precision and solved the problem of translating the action potential into a format suitable for cell-cell communication.
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From page 190... ...
190 THE LANGUAGE OFLIFE many as 100 different signaling molecules (neuroscientists call them "neurotransmitters") , but their conversations utilize the same principles and the same signal-receptor-relay syntax pioneered by the simplest organisms, long before the existence of language, thought, or emotion.
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From page 191... ...
To further his study of the literature, he learned German. Applying his newfound skills, he published monographs on the ultrastructure of the epithelium and the muscle fibers of insects and wrote and illustrated a histology textbook.
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From page 192... ...
Based on the limited amount of detail revealed by the few available dyes, many argued that the processes of each neuron were fused to those of its neighbors, forming an unbroken network, or reticulum, rather than a conventional tissue composed of discrete cells. In 1887, Cajal was summoned to Madrid to administer the examinations for doctoral candidates in descriptive anatomy.
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From page 193... ...
A few iconoclasts had already begun to question the reticular theory, to criticize the possibility that of all the body tissues only the brain and spinal cord were not made up of discrete cells. Surely Golgi's stain would shed light on the matter, everyone thought.
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From page 194... ...
Since the full-grown forest turns out to be impenetrable and undefinable, why not revert to the study of the young wood, in the nursery stage, as we might say? Using a modified, more dependable version of Golgi's silver stain, Cajal probed the "young wood" in the brains of the immature and found that if he applied the technique before the myelin sheath formed, "the nerve cells, which are still relatively small, stand out complete in each section; the terminal ramifications of the axis cylinder are depicted with the utmost clearness and perfectly free." In the cerebellum he not only observed the plump bodies of Purkinje cells described by earlier investigators but also described axons that split and wove baskets around them, as well as axons that climbed the cell body and insinuated themselves throughout the dendritic arbor like "ivy or lianas to the trunks of trees." He observed long processes of sensory neurons coursing into the brain from the retina and olfactory bulb.
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From page 195... ...
Like all architectural innovations, the neural synapse evolved to solve problems, in this case the problems associated with distance, preci * Cajal was an odd houseguest.
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From page 196... ...
By definition the neural synapse is asymmetric. On the presynaptic side the axon terminal is specialized to meet the challenges of directed secretion.
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From page 197... ...
Some vesicles have already redocked at the plasma membrane before the action potential ever arrives; a few have even begun to fuse, poised to expel their neurotransmitter at a moment's notice. Behind these first responders, backup vesicles wait in a grid anchored to the presynaptic membrane, like racehorses
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From page 198... ...
Actually a tightly woven matrix of protein, this postsynaptic density, as it's called, locks neurotransmitter receptors in place directly opposite the secretory apparatus of the presynaptic neuron. Some it even arranges like flowers in a centerpiece.
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From page 199... ...
With their axons traversing the brain and coursing through the spinal cord, neurons allow one part of the nervous system to talk directly to another, no matter how far apart they are. And where axon and dendrite meet, the architectural features of the synapse direct the release of neurotransmitter, focus the attention of receptors, maximize precision, and guarantee clear, high-fidelity conversations.
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From page 200... ...
Cajal favored the latter. The free ending of the axon, he noted, "appeared as a concentration of protoplasm of conical form," a structure he called a "growth cone." He imagined this growth cone to be
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From page 201... ...
Lines on the pavement will mark out lanes, the median, and the shoulder of the road. Overhead and on either side are signs that tell me "Go here": the green exit signs for the Vine Street Expressway and I-76, street signs for Chestnut Street and Walnut Street, and the white sign at the entrance to the parking garage.
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From page 202... ...
A, the adhesion proteins known as laminins, which bind to integrin receptors on axonal growth cones, act as "lane markers" to keep axons on the correct path without straying. B, chemoattractants, exemplified by the netrins that direct commissural neurons in the spinal cord to the midline, are the neural equivalent of exit or street signs.
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From page 203... ...
Signal Axon of neuron Growth cone C Ephrin Ephrin receptor Growth halted in direction of ephrin Repellent ("do not enter")
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From page 204... ...
Already loitering around the floor plate after it's finished the task of patterning the ventral spinal cord, it's understandable that Sonic hedgehog would take up a new career as a guide to migrating axons, supplementing the efforts of the netrins. Overhead, BMPs have nothing to do either; they might as well busy themselves pushing any errant axons away from the dorsal half of the spinal cord.
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From page 205... ...
Receptors in the growth cones of retinal axons adhere to the laminin in the matrix, much as your finger might stick momentarily to the tacky surface of not-quite-dry paint. Laminin is no ordinary glue, however.
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From page 206... ...
To ensure that temporal axons stay on their side of the optic tectum and find anterior partners, posterior tectal neurons have posted "Do Not Enter" signs -- signs that can only be read by the temporal axon growth cones. Like Delta (of Notch and Delta fame)
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From page 207... ...
During synapse formation, proteins that neurons have already made -- the docking mechanism for vesicles or calcium channels, for example -- are being put together." What's more, Sanes notes, the assembly of synaptic proteins doesnt' really require formal neurotransmission, although the two neurons certainly talk to each other during the process. Once the two neurons pair off, the presynaptic neuron will install the secretory apparatus it has constructed, stock it with a supply of vesicles, and begin releasing little trial balloons of neurotransmitter.
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From page 208... ...
Finally, when the big day arrives and the motor neuron starts firing action potentials in earnest, the acetylcholine it lobs at the muscle fibers shuts down any illicit receptor making or gathering. The muscle fiber and the intervening basal lamina have had a few choice words for the axon as well.
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From page 209... ...
Conversely, on the presynaptic side, a recent study has demonstrated that the adhesion molecule neuroligin tells axon terminals it's time to assemble synaptic vesicles. When neuronal migration and synapse formation are done, the young brain can feel a real sense of accomplishment -- it's wired about 1015 individual connections.
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From page 210... ...
In other words, you could build only the proper synapses. Or you could build extras, stabilize the proper ones, and let the others fall away." Neural synapse formation can take place in the complete absence of neural activity.
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From page 211... ...
But the nervous system that coordinates behavior also includes mechanisms to facilitate continuity, to enable considered responses as well as allowing for novel ones. Taking advantage of the ability to link the binding of chemical signals to changes in proteins and gene expression afforded by the syntax of cellular language, neurons have exploited synaptic transmission to devise methods of generating connections between behaviors and outcomes -- learning -- and to store important associations for future reference -- memory.
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From page 212... ...
Shaped like tiny clubs, with a bulbous head seated on top of a narrow shaft, spines are hot spots for synapses, particularly so-called excitatory synapses, in which the word spoken by the axon terminal stimulates the postsynaptic cell to action. The precursors of spines are mobile, actin-rich fingers, or filopodia, that grasp at incoming axon terminals in the earliest stages of synapse formation.
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From page 213... ...
Within the cell, changes in calcium concentration triggered by events like the opening of NMDA receptor channels are detected and relayed to other signaling proteins by dedicated calcium-binding proteins. The most ubiquitous of these go-betweens, found in all eukaryotic cells, is called calmodulin.
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From page 214... ...
The exchange between the interneuron and the siphon sensory neuron results in the activation of protein kinase A The kinase, in turn, phosphorylates calcium channels and proteins of the secretory apparatus, enabling the
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From page 215... ...
A human being needs to remember more important things-the names of co-workers, how to log on to the new office computer system, how to care for a newborn baby, the dates and battles on tomorrow's history test, lists of signaling proteins. This sort of memory, the one we associate with "book learning" or factual information, is called "explicit memory," and for that you need a part of the brain known as the hippocampus.
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From page 216... ...
Being excitatory neurons, the terminals of cells that make up LTP-sensitive pathways broadcast glutamate, which binds to AMPA and NMDA glutamate receptors on dendritic spines. Everyday low-frequency conversations engage only AMPA receptors, with no lingering aftereffects.
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From page 217... ...
And he found that the answer lies in some unusual furnishings of dendrites: mRNA transcripts, shipped and stored in an inactive form prior to all the excitement, and the machinery to carry out local protein synthesis. All the synapses have these materials.
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From page 218... ...
And the fear wouldnt' go away. A brain that can remember the birth of a child, how to play the piano, multiplication tables, the names of dozens of business associates, and the rules for filing an expense account can also learn to be afraid -- and remember this lesson even longer than a sea slug remembers a series of electric shocks.
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From page 219... ...
Joseph Le Doux, an expert on the neurobiology of emotional memory, and others have demonstrated that fear conditioning induces long-term potentiation in the amygdala much as highfrequency electrical stimulation induces LTP in the hippocampus. The development of ultrasensitive neural responses correlated with the emergence of the fearful response and, much like the animal's anxiety at the sound of the tone, the sensitivity of amygdala neurons persisted long after the training period.
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From page 220... ...
As a result, they cant' stop taking drugs, even in the face of profoundly negative consequences. Their predicament stems from the fact that cells communicate in chemicals, meaning that cellular communications, including discussions between neurons, are accessible to outside influence.
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From page 221... ...
A nervous system built to adapt gives us the flexibility to cope with a wide range of contingencies. But when traumatic experiences or addictive drugs muscle into the signaling pathways at the heart of this
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From page 222... ...
222 THE LANGUAGE OF LIFE flexibility, the brain can also be waylaid by its ability to change. Or in Steven Hymans' words, "Not all adaptations are good for the organism." Memories engraved in the fabric of the brain cannot be willed away, ignored, or rationalized.
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From page 223... ...
"THE SCENARIO-BUFFERED BUILDING" 223 we may not be able to unlearn, but we can relearn, replacing memories that have outlived their usefulness with new and better ones. THE ART OF WAR The phone rings as you pause to hand your secretary a draft of the new proposal en route to your 11 o'clock meeting.
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From page 224... ...
In addition, the macrophages collaborate with platelets, fibroblasts, ketatinocytes, and endothelial cells to issue a call for reinforcements. Known collectively as chemokines, these "come here" signals bind to G proteincoupled receptors on other macrophages as well as neutrophils, carnivorous white blood cells packing an arsenal of toxic chemicals that enable them to poison any invaders they dont' swallow.
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From page 225... ...
The area surrounding the cut will be warm and red -- the handiwork of mast-cell missives that order blood vessels to dilate-and swollen as well thanks to signals that weaken the connections between endothelial cells to facilitate the migration of phagocytes, allowing fluid to leak into the tissue in the process. Immunologists call these artifacts of battle "inflammation," the cells that engineer it, the innate immune system.
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From page 226... ...
Every phagocyte displays the same battery of receptors, but each lymphocyte (immunologists' name for the white blood cells of the adaptive immune system) is an individual; together, these antigen receptors can distinguish millions of bacterial and viral features.
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From page 227... ...
The antigen receptors of T cells are similar to antibodies, but they are not immunoglobulins. Embedded, never secreted, they resemble other transmembrane receptors, with an external binding site and an internal segment on friendly terms with a gaggle of kinases and other signaling proteins.
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From page 228... ...
Carpet bombing the invaders with antibodies, confronting them in handto-hand combat, and overwhelming them with additional reinforcements, the adaptive immune forces seek to end the enemy's quest for total domination once and for all. Agile, discerning, and ruthless, the adaptive immune system gives vertebrates one more disease-fighting advantage over creatures armed only with innate immune defenses: once it's fought a particular pathogen, it remembers the experience.
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From page 229... ...
Patrolling the site of an incipient infection along with the phagocytes and straddling the gap between adaptive and innate immune systems is yet another representative of the immune system. In contrast to the stout, rather homely lymphocyte, these cells are resplendent with spines and tentacles that reminded immunologists of the dendritic arbor of neurons, hence their name: dendritic cells.
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From page 230... ...
"The dendritic cells tell them. They give the lymphocytes context, so they can choose the appropriate response." But to realize these benefits, a naïve T cell must first locate a dendritic cell displaying the antigen that matches its receptors.
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From page 231... ...
Mature synapse The immunological synapse. T cells are activated by intimate discourse with professional antigen presenting cells known as dendritic cells, an exchange regulated by an orderly arrangement of T cell receptors, antigen-MHC complexes, costimulatory signals and their receptors, and adhesion molecules known as the immunological synapse.
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From page 232... ...
As a consequence, the phrase "immunological synapse" began to creep into the literature to describe these intimate conversations between T cells and their partners, as well as speculation that the "immunological synapse" might be the basis of the T celldendritic cell interactions that initiated T cell activation. By labeling proteins thought to be involved in immune synapse formation with fluorescent tags, scientists, including Dustin, demonstrated that the immunological synapse is assembled on the spot when the T cell contacted its signaling partner.
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From page 233... ...
So there is something useful in stable interactions." That is, the immunological synapse is more than a platform for directed secretion -- it is a stable environment in which participants can exchange critical information needed to regulate rather than initiate T cell signaling. For example, in 2003, he and collaborator Andrey Shaw demonstrated that receptor segregation within the synapse may be important for the fine-tuning of T cell activity to match the level of antigen.
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From page 234... ...
During the initiation phase of the adaptive immune response, for example, signals released by mast cells and macrophages, particularly tumor necrosis factor (acting through the death-defying NF-B pathway rather than the death-promoting FADD pathway; see Chapter 4, page 163) , attract dendritic cells and warn them that the antigens they're consuming are likely to be pathogenic, while chemokines lure newly activated lymphocytes to the infection site.
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From page 235... ...
Many, for example, are sent to their deaths during development, when their unnaturally high affinity for an illegal antigen gives them away. Others are caught and disarmed when they bind antigen in the absence of the costimulatory signal they need to start dividing and attacking or snagged and eliminated by dendritic cells that have picked up self antigens during their travels.
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From page 236... ...
Myelin contains both lipids and proteins, the best known of which are myelin proteolipid protein, myelin-oligodendrocyte glycoprotein, and a complex of seven closely related proteins known collectively as myelin basic protein. So-called autoreactive T cells that recognize myelin proteins, particularly myelin basic protein, can be found in the blood of even normal healthy people, part of the contingent of malcontents that body has chosen to ignore.
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From page 237... ...
Spewing cytokines and chemokines that bring ravenous macrophages and more autoreactive-turned-autoaggressive T cells running, they precipitate an inflammatory immune reaction that annihilates the cells responsible for myelin production in the brain, spinal cord, and optic nerves. Without myelin, nerve conduction slows to a crawl.
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From page 238... ...
Half-chewed myelin generated by the attack provides a fresh infusion of myelin antigens, while the relentless battle cries of T cells draw even more recruits to the site of damage, perpetuating or exacerbating the autoimmune response. Once scientists learned the secret words traded by cytokine-inspired T cells and endothelial cells willing to pull them out of the bloodstream, they could interrupt the conversation with a word of their own -- "natalizumab." An antibody to the integrin receptor VFA-4, found on the surface of active myelin-reactive T cells, "natalizumab" sounds so much like "V-CAM1," the endothelial cell adhesion molecule that matches VFA-4, it's no wonder T cells confuse the two.
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From page 239... ...
"`Change is suffering' was the insight that founded Buddhism," writes Stewart Brand. "We hate change.
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