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From page 139... ...
4 LIFE IN THE BALANCE T he weather report called for snow, followed by freezing rain, but, hey, that's why you bought an all-wheel-drive vehicle in the first place. Still, you hadn't counted on leaving the office so late, adding poor visibility to your difficulties.
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From page 140... ...
Once the crisis has passed, however, there's no need for internal organs to work so hard. Now the body puts on the brakes, setting in motion mechanisms to slow heart rate, reduce blood pressure, and conserve energy.
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From page 141... ...
In the signaling pathways responsible for such mundane functions as the upkeep of tissues and the disposition of nutrients, scientists have not only discovered how "the unstable stuff of which we are composed .
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From page 142... ...
Some jobs are carried out by cells with good memories, able to recall and repeat words they learned during development: the endothelial cells lining the blood vessels, liver hepatocytes, fibroblasts. Others may have retired their cell-cycle machinery, but these journeymen, fed the right combination of growth factors or embryonic signals, can still duplicate their DNA and divide to yield two identical daughters.
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From page 143... ...
But in contrast to drudges like fibroblasts, the progeny of stem cells are not always identical twins. On average, about half the daughters of stem cells leave the niche and complete the task their mothers abandoned, differentiating into replacements for cells lost by mature tissues.
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From page 144... ...
Meanwhile, in the basal layer of the epidermis, epidermal growth factor (EGF) and TGF- (the patriarch of the family that includes bone morphogenetic proteins)
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From page 145... ...
Blood contains at least 10 different kinds of cells: erythrocytes, the red blood cells that ferry oxygen; three types of phagocytes, white blood cells eager to devour bacteria and scavenge the corpses of fallen cells; B cells that secrete antibodies and T cells that kill damaged or infected cells and nurture B cells; natural killer cells; platelets and the megakaryocytes that spawn them. All are born in the bones, and all are the handiwork of a single cadre of uniquely versatile stem cells.
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From page 146... ...
Some of the same signals that controlled cellular fate and drove cell division in the embryo can be found in the mature organism cooing at stem cells. Wnt, for example, can keep even hematopoietic stem cells transferred from their precious niche to a culture dish dividing and replenishing.
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From page 147... ...
Cavities and alleyways serve as classrooms, and instructional materials are provided by the stromal cells in the bone marrow, the endothelial cells of capillaries, or mature blood cells. Cells that graduate earn the right to a job in the blood, with a guarantee of lifetime employment.
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From page 148... ...
A freshman precursor cell of the myeloid (red blood cell/macrophage) lineage signs up for the introductory course "Commitment 101." Required reading: the cytokines stem cell factor (known colloquially as "Steel")
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From page 149... ...
Even in times of crisis, when stem cell reservoirs are churning out replacements to repair some catastrophe, it maintains homeostasis and prevents unnecessary clutter. Finally, suicide offers cells a way to atone for any errors made during the course of cell division -- an important safeguard when continuous transit through the cell cycle is a way of life.
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From page 150... ...
No matter how long we live, the cells set aside to repair body tissues will never grow up, never stop dividing. Conversely, part of us is always dying.
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From page 151... ...
In animals treated with cyclopamine, the Hedgehog pathway is constantly suppressed, even if Sonic hedgehog is present, because the drug disconnects Smoothened from the transcription factor complex." Gorlins' syndrome, also called basal cell nevus syndrome, causes a constellation of birth defects that are the mirror image of cyclopia. Instead of a single eye, patients with this heritable condition have abnormally wide-set eyes and a broad, flat nose.
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From page 152... ...
The pathway is full-on, even in the absence of Sonic hedgehog, because there's no repressor." Some cells just seem to be looking for trouble. Basal cell carcinomas originate in the basal layer of epidermis that includes skin stem cells and their immediate progeny, still immature and capable of dividing.
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From page 153... ...
Expansions, deletions, or rearrangements in genes that encode growth factors and developmental signals, their receptors, or components of their intracellular signaling pathways replace normal counterparts with hyperactive imposters that encourage cells to thumb their noses at their neighbors and divide as often as they please. The genes src and fps, encoding the kinases that led to the discovery of interaction domains and adaptor proteins, are examples of such oncogenes, tricksters that cells mistake for legitimate growth signals.
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From page 154... ...
Amy Wagers, referring specifically to hematopoietic stem cells, suggests that longevity is precisely why stem cells may be "hot spots" for tumor initiation: "They are the only cells in the blood that live long enough to accumulate all the hits. Even if you get two or three mutations in progenitor cells, those progenitors are going to die." The evolution of colorectal cancer is a well-studied example of how such a succession of small genetic errors can add up to one lifethreatening malignancy.
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From page 155... ...
A steady stream of intact active -catenin molecules chant "go, go" at genes, as if a steady stream of Wnt messages were bombarding the cell. What cells wouldnt' divide manically under such pressure?
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From page 156... ...
But to Gerard Evan of the University of California San Francisco Cancer Center, cancer cells, like the white-tailed deer eating my neighbors out of house and home, are out of control because chance and circumstance have upset the balance of nature. Proliferation is only one side of the equation; after all, Evan points out, "our cells divide by the zillion every day": during embryonic development, as the egg expands into a multicellular newborn, and in adulthood, to replace the cells we lose in the course of a long, active life.
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From page 157... ...
You need the key that flips them all." Similarly, he argues, cells discourage illicit building programs by placing growth under lock and key. The pins of this lock are a network of intermeshing signaling pathways that link cell division and cell survival.
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From page 158... ...
"Cancer cells, by and large, dont' do anything normal cells wouldnt' do following injury or during development," he says. "What's different is how they regulate -- or dont' regulate -- that behavior.
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From page 159... ...
LIFE IN THE BALANCE 159 1 Mitogenic signals from neighboring cells Normal DNA (genes) 2 Mutation in oncogene Intact p53 p53 and Myc Cell division increases, Cell division but so does cell death 3 Mutation in oncogene and mutation in p53 or Myc Cell division increases, cell death decreases Myc 4 The result is cancer The "cancer platform." Mutations in oncogenes stimulate abnormal proliferation but are not by themselves sufficient to cause cancer because interlocking signaling mechanisms that oversee cell growth and voluntary cell death, or apoptosis, ensure that any signal triggering an increase in growth will trigger an increase in cell suicide as well.
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From page 160... ...
"When you pick up the proliferation program, you pick up the death program as well," Gerard Evan explains. The most notorious two-faced double-dealer of all is the transcription factor biologists call "Myc," activated when growth factor sentences take a 90 degree turn at the level of Ras, opting for the clause with the second messenger PIP3 as its direct object.
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From page 161... ...
A cancer cell obeys no social conventions, accepts no limits, acknowledges no authority. Bad, mad, and out of control, even a direct command to commit suicide may no longer contain its pathological rebelliousness.
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From page 162... ...
The decision to die is not one that cells take lightly. They would prefer to wait for an explicit command, from p53, say, or from a signal like tumor necrosis factor, one of a family of signaling proteins that apoptosis researchers call "death ligands." When Dixit began his quest to learn how tumor necrosis factor persuaded cells to kill themselves, the scientific community knew that this death ligand, like other signaling molecules, transmitted its sinister message to its victims by way of specific receptors that spanned the cell membrane.
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From page 163... ...
Yet when the smoke clears, you are left with this work of art." Actually, recent evidence suggests that tumor necrosis factor signaling is not quite as simple as it first seemed. Just as Myc can promote cell division or call for cell death, this death ligand, it turns out, can also be a life ligand.
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From page 164... ...
But one little mutation is all it takes to override the voice of reason. Addle the tumor necrosis factor receptor or one of the adaptor proteins and apoptosis drops off the list of options.
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From page 165... ...
I looked forward to snacking on them during the drive home. Then my cell phone rang.
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From page 166... ...
Yet despite my best efforts to destabilize my internal milieu, my blood glucose levels have remained high enough to keep me from fainting and low enough to keep my doctor happy. More impressively, my body has juggled supply and demand well enough over the long term that I can still wear the Armani jacket I bought before I had children and began to live on Pop Tarts and pasta.
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From page 167... ...
"Insofar as the constancy of the fluid matrix is evenly controlled," Cannon noted, "it is not only a means of liberating the organism as a whole from both internal and external limitations, but it is an important measure of economy, greatly minimizing the need for separate governing agencies in the various organs." Keeping cells well fed is one of the most important duties of the homeostatic mechanisms regulating the composition of the fluid matrix. Mammals, supporting large brains as greedy as a gasguzzling SUV, must satisfy a relentless demand for fuel.
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From page 168... ...
Released in response to rising blood glucose levels (for example, immediately following a meal) , insulin titrates the concentration of glucose by suspending the mobilization of glucose reserves and commanding muscle, liver, and fat cells to clear the excess and store it as glycogen or fatty acids.
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From page 169... ...
Once under exquisite control, blood glucose levels spiral higher and higher, with devastating consequences for the health and well-being of the body. INSIDE THE BLACK BOX Herophilus of Chalcedon might have made it into the history books even if he hadnt' discovered the pancreas.
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From page 170... ...
Indeed, when a test was finally developed to measure blood insulin levels in 1960, these
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From page 171... ...
In an attempt to restore balance, it secretes more and more insulin -- in effect, trying to get the receptor's attention by shouting. Instead, glucose levels keep rising, glucose homeostasis deteriorates, and clinical symptoms of diabetes emerge.
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From page 172... ...
And with that we created a mechanism to get the signal inside the cell." Like other receptor tyrosine kinases, the insulin receptor has a split personality. In fact, it's actually two proteins in one, a pair of subunits that constitute the binding site, and a pair of subunits that constitute the kinase.
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From page 173... ...
So if you just look at the metabolic pathways and you consider the receptor, the various receptor substrates, the various isoforms of PI3 kinase, and the molecule Akt, there are literally over a thousand potential combinations of signaling molecules." The challenge, he continues, is to select the right combination for each task. Just as stem cells must have a key to liberate cell division from apoptosis, cells responding to insulin must unlock a signaling pathway before they can use it.
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From page 174... ...
All the steps have to work together to control the process." Just freeing the transporter-laden vesicles from their tethers-the step regulated by insulin -- is complicated. In contrast to the average signaling assignment, this job requires two combinations, each opening a distinct insulin-signaling pathway.
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From page 175... ...
Researchers now believe that the attention deficit at the heart of type 2 diabetes is almost certainly the result of a subtle defect downstream of the insulin receptor, a disaffected adaptor or inept kinase that alters the meaning of the sentence just enough to render it unintelligible to the GLUT4 and its vesicles. However, cautions Kahn, it doesnt' have to be the same defect in every patient.
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From page 176... ...
As a consequence, their plasma glucose levels stabilize, and their chances of developing serious complications like blindness and kidney failure decrease. That's why doctors emphasize the importance of weight loss and exercise, and educators like Barbara Reynolds spend so much time teaching about portion sizes and "carb choices." Reynolds doesnt' like the word "diet." "It makes me think of deprivation," she says.
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From page 177... ...
Despite an estimated $30 billion to $50 billion spent each year on diets, drugs, and exercise programs in this country, most overweight individuals trying to lose weight fail; of those who do succeed, about 90 percent will eventually gain it all back. Dieting is so often an exercise in futility because body weight, like glucose levels, is controlled by homeostatic mechanisms.
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From page 178... ...
Moreover, it was made neither in a gland nor a stem cell niche but in that bloated repository of unspent calories, the lowly adipocyte, or fat cell. Fat cells talking?
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From page 179... ...
There are other molecules out there," Lazar says -- other fat cell hormones. One, adiponectin, increases sensitivity to insulin, promotes the uptake and breakdown of fatty acids by muscle, and reduces blood glucose levels.
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From page 180... ...
With the exception of a handful of individuals with a genetic deficit in leptin production (human equivalents of the ob/ The defense of body weight. Signaling mechanisms linking the fat cell and brain regions central to appetite control and eating behavior strive to maintain body weight within 15 to 20 percent of a set point that may be biologically predetermined.
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From page 181... ...
B Increased body fat levels 2 Hypothalamus releases POMC and CART Increased weight 3 Eat less decreases fat mass Leptin Fat droplet 1 High leptin levels (many fat cells)
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From page 182... ...
Our fat cells worry as much about our weight as we do, and they share their concerns with a most unlikely confidant: the brain, in particular, a collection of cells in the hypothalamus known as the arcuate nucleus. The arcuate nucleus takes a leadership role in the control of feeding behavior, couching its directives, as is the custom in the hypothalamus, in peptides.
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From page 183... ...
Type 2 diabetics cant' seem to win. If diet and exercise dont' restore glucose levels to an acceptable value, most doctors add an oral medication.
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From page 184... ...
It's enormously frustrating," he says. The human body has evolved to weather catastrophes, to strive for balance by preparing for contingencies.
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