Cell Talk

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by Neil Caudle

In most cases, disease represents failure to communicate, not in the brain but down in the trenches, in cells. Sure, the brain thinks it’s in charge, and it does indeed command and control many processes necessary to life. But the signals in our bodies don’t stop at the ends of our nerves. They are everywhere, in every cell, moving messages along: go, stop, grow, change, die.

Cell signaling is the way a cell interprets information, not only from its environment but from its own genetic code. Cell signaling mediates our response to odors, to light, and to other kinds of stimulation. It also controls the enzymes of metabolism, controls how genetic information gets put to work (gene expression), and controls the cell’s shape and movement. Simply put, it controls the choices—the decisions cells make.

Many signals originate outside the cell and must negotiate their way through its defenses. Steroid hormones such as testosterone and estrogen melt their way through the cell membrane. But other kinds of signals have to dock onto the surface and push the right buttons. Consider a familiar example: adrenaline, that rush that comes with excitement or fear and gets our bodies ready for action.

"What happens when you encounter a grizzly bear or a shark?" Harden asks. "What do you want your body to do? You want your pupils to dilate. You want your bronchial smooth muscle to relax. You want your blood flow to be redistributed to tissues that are important for dealing with stressful situations. You want to break down glycogen so that you have glucose for energy.

"All of that occurs because there are cell-surface receptors that recognize adrenaline in a specific way, and these receptors coupled with two other proteins transduce the signal across the cell membrane to start cascading events inside the cell. So a lot of drugs that are used in everything from the treatment of glaucoma to all kinds of heart disease to the common cold interact with these sets of receptors for adrenaline, either by mimicking the effect of adrenaline or by blocking the effect of adrenaline."

For years, Harden and his colleagues have been working out the signaling pathways associated with adrenaline and its cousins. Histamine, for instance, is involved in allergic reactions. Dopamine, a neurotransmitter, influences moods and addictions. And serotonin, which, among other things, constricts blood vessels, is associated with migraines and depression.

"All of these act in one way," Harden says. "They all have a G-protein coupled receptor (see How to get through to a cell)."

Basically, the receptor is a biological switch. When it’s on, the signal flows. When it’s off, the signal stops. Many drugs or druglike compounds, natural or synthetic, work by turning these switches on or off. In fact, more than half of all drugs target the cell-signaling machinery. A well-publicized, recent example involves a molecule that signals the smooth-muscle relaxation that promotes blood flow. By tapping into its signaling pathway, pharmacologists and drug makers gave the world Viagra.

And then there’s caffeine, which gives us that wide-awake buzz. Normally, cell-signaling responses for adrenaline and serotonin and their like close down as enzymes called phosphodiesterases break down cyclic AMP, which is the "on" side of the switch. By inhibiting phosphodiesterases, caffeine keeps the switch open.

Each of the various enzymes involved in such pathways is a potential target, a place where a chemical nudge could, as Harden puts it, "restore a balance or reroute a hell-bound train."

Not every signal originates outside the cell. Very often, the trouble that ends a life begins with a mistake, an internal error. Let’s say a random mutation strikes a molecule associated with cell growth. Suddenly, the cell is firing off the message to multiply, and unless another signal arrives to shut it down, the runaway cells become cancer.

This isn’t news. We’ve known this story for decades. But today, we know that the story was incomplete. For one thing, cells have the ability to correct some kinds of mistakes the way editors correct typos.

"We get damage to our DNA all the time," says Shelton Earp, director of the Lineberger Comprehensive Cancer Center, "from our environment and from mistakes when DNA are replicating. There is a special set of genes that proofread the DNA. If they find mistakes, they can repair them. If they can’t repair them in a timely fashion, then they send a signal out to stop the cell cycle, paralyzing the cell at one stage so it will then have the time to repair that damage. And if that still doesn’t work, then it has to send a signal for the cell to die, to commit suicide."

Cell suicide is not just a way of erasing mistakes. It can also be a necessary step in normal development. Earp holds his hand up, fingers together, mittenlike. "When you’re an embryo and your limbs are formed, you’re undifferentiated like this," he says. "The way you get fingers is that the cells between the fingers die, and they die because of what is called ‘programmed cell death.’ In the genetic code there’s a program that leads to a set of signals that say, ‘Okay, these cells die,’ and you get digits."

Since cell suicide is intimately involved with the arrangement of cells in our body plan, Earp wonders why it took researchers, himself included, so long to realize that cancer wasn’t just a problem of cell growth but was also a problem of cells’ failure to die.

"Some cancers do begin with a mutation in a cell-signaling molecule that signals for growth," Earp says. "And when these mutations occur, they’re referred to as oncogenes. But that’s only a part of the picture. Most leukemias, for example, or lymphomas, are diseases that occur when a cell fails to differentiate or fails to die on time."

Earp’s lab, working with Carolyn Sartor of radiation oncology and Ben Calvo of surgery, studies tyrosine kinases, a class of signaling molecules that, among other things, drives the growth of breast-cancer cells. By understanding the signaling pathways involved, the researchers find possible targets for drugs that could someday stop the cancer by flipping a biochemical switch. This kind of high-precision editing is very different from conventional cancer treatments. Chemotherapy is designed to attack, without discrimination, rapidly proliferating cells. Unfortunately, we also have normal cells that proliferate rapidy, such as the cells in our hair follicles and our bone-marrow, so chemotherapy attacks those, as well.

"If you look at cancer treatments before 1990," Earp says, "you would say that almost none of the therapies, with the possible exception of hormonal therapies like Tamoxifen, involved cell signaling pathways. We’ve seen that change over the last ten years. But the next ten years will be the era in which cell signaling comes to the fore."

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