Understanding how cells self-destruct, a technique employed by the human body to discard dangerous or damaged cells, could mean big things for the treatment of everything from cancer to brain disease to hair loss. Stanford scientists have shone the light on one kind of programmed cell death and watched on as the path of destruction was formed, with the speed on show offering vital clues as to the mechanics at play.
Apoptosis is one of the better understood types of natural cell death, yet even it is pretty poorly understood. We lose billions of cells each day to apoptosis, both in good ways and in bad. It plays a vital role in killing off dangerous cells that might be associated with cancer, for example, but can also cause the decline of healthy cells and onset of neurodegenerative diseases like Alzheimer's.
So better understanding how exactly it plays out could open up new ways to manipulate it for our benefit. In the last few years, scientists have discovered olive oil ingredients that promote apoptosis to kill cancer cells, proteins that do so in mice to reverse symptoms of aging, and other proteins that kill off scarred heart cells that hinder the organ's function.
The Stanford scientists set out to learn more by putting apoptosis under the microscope ... in a figurative sense. They carried out their research using Xenopus frog eggs, each of which is a single cell, and an enormous one at that, making it possible to observe the spread of death with the naked eye.
They began by extracting fluid, or the cytoplasm, from the egg, inserting it into teflon tubes measuring a few millimeters long and then triggering apoptosis with a molecular "death signal." Using a form of fluorescence microscopy already known to enable observation of apoptotic signals, the scientists watched on as a bright green glow made its way down the tube.
They then watched a similar process play out with complete, intact frog eggs, where the fluorescence microscopy approach was problematic due to the opaque nature of the sample. Instead of a glow, the scientists observed a wave on the egg's surface when apoptosis was triggered, which made its way through the egg as a curved line in a similar fashion to the green glow.
These waves moved through the sample at a speed of 30 microns per minute, which is around a millimeter every 33 minutes. That might sound awfully slow, but it was the speed with which death swept through the cell that served to enlighten the scientists. They say the rapid and constant speed is too fast to be driven by another form of cellular movement, such as diffusion, and could only be explained by what are known as trigger waves.
"This work is another example of how nature makes use of these trigger waves – things that most biologists have never heard of – over and over again," says James Ferrell, professor of chemical and systems biology at Stanford. "It is a recurring theme in cell regulation. I bet we'll start to see it in textbooks soon."
Trigger waves can be thought of as a line of falling dominoes. One falls onto the other and passes along its momentum, but only if a threshold of force is surpassed and forces each to topple into the next, rather than wobbling momentarily and remaining upright. When apoptosis is triggered, it activates killer proteins in the cells called caspases. You could think of activated caspases as the "force" in the falling dominoes, leaping down the chain and activating other caspases as they go until the entire cell is done for.
"It spreads in this fashion and never slows down, never peters out," Ferrell says. 'It doesn't get any lower in amplitude because every step of the way it's generating its own impetus by converting more inactive molecules to active molecules, until apoptosis has spread to every nook and cranny of the cell."
Trigger waves have been observed elsewhere in biology, such as the spread of viruses and the division of frog eggs, but the team says this is first time they have been identified in cell death. Looking to build on the discovery, the team is now aiming to uncover other processes where it might be the underlying mechanism, such as the spread of an immune response from cell to cell.
"We have all this information on proteins and genes in all sorts of organisms, and we're trying to understand what the recurring themes are," Ferrell said. "We show that long-range communication can be accomplished by trigger waves, which depend on things like positive feedback loops, thresholds and spatial coupling mechanisms. These ingredients are present all over the place in biological regulation. Now we want to know where else trigger waves are found."
The research was published in the journal Science.
Source: Stanford University
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