In apoptosis, cell death spreads through perpetuating waves, study finds

August 9, 2018, Stanford University Medical Center

Inside a cell, death often occurs like the wave at a baseball game.

What starts with two hands flung skyward prompts another, and another, until the wave has rippled far and wide across the whole stadium. This kind of a rolling surge, spurred by the activity of one or a few things, is known as a trigger wave. A new study out of the Stanford University School of Medicine has found that this phenomenon guides one of the most well-known and widespread forms of cell death: .

It's not the first time trigger waves have been identified in the microcosms of life. The cell cycle, a cornerstone of cell biology in which cells divide to make new cells, regulates production via trigger waves, too. So do neuronal action potentials, which allow neurons to pass signals via electrical impulse. And it likely doesn't end there.

"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," said James Ferrell, MD, Ph.D., professor of chemical and systems biology and of biochemistry at Stanford. "It is a recurring theme in cell regulation. I bet we'll start to see it in textbooks soon."

One of the better-understood forms of cell death, apoptosis still manages to mystify scientists. "Sometimes our cells die when we really don't want them to—say, in neurodegenerative diseases. And sometimes our cells don't die when we really do want them to—say, in cancer," Ferrell said. "And if we want to intervene, we need to understand how apoptosis is regulated."

The study will be published in Science Aug. 10. Ferrell is the senior author. Postdoctoral scholar Xianrui Cheng, Ph.D., is the lead author.

Apoptosis spreads through cytoplasm without slowing down or petering out. This left end of this tube of cytoplasm was dipped in an apoptotic extract. Apoptosis then spread across the tube at constant speed. Apoptosis is monitored with a fluorescent probe. Credit: Xianrui Cheng and James E. Ferrell, Jr.
Spreads like wildfire

Trigger waves require two main elements: a loop and a threshold think—falling dominoes. One domino collapses on another and triggers that domino to topple onto the next. The threshold is the force necessary to completely knock the tile over; a domino just shy of its threshold would teeter and rock back into a vertical position, whereas one that's reached the threshold would fall. Trigger waves in an apoptotic cell are governed by that same phenomenon. Once cell death is initiated, by way of disease or something else, specific killer proteins in the cell, called caspases, activate. These proteins then float to other caspases and activate them; those follow suit until the entire cell has to pack it in.

"It spreads in this fashion and never slows down, never peters out," Ferrell said. "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."

To see how death takes over a single cell, Cheng and Ferrell used Xenopus frog eggs. One egg is a single cell, and as cells go, these are enormous, making them a prime candidate to observe how death spreads from one end of the cell to the other, which can be done with the naked eye.

To start, the two scientists took fluid from the egg and inserted it into Teflon tubes, which were several millimeters long, and initiated apoptosis through a molecular "death signal." By using a fluorescent technique linked to the activation of apoptosis, Ferrell and Cheng could watch as the bright green glow moved its way down the tube at a constant speed, indicating that apoptosis was spreading via trigger waves, as opposed to some other more rudimentary mechanism, such as diffusion, which slows down as it moves.

The question was, did apoptosis also spread like that in as they naturally occur?

Turning to fluorescence microscopy here proved more difficult, as intact frog eggs are quite opaque. However, Cheng and Ferrell noticed that when frog eggs die, a sort of ripple of pigmentation occurs at the egg's surface. The scientists saw that during death, a dark ripple moved like a curved line across the egg at a constant speed from one side to the other. The speed of this surface wave, which was constant and did not slow down, tipped them off to trigger waves here too. So to further confirm, they analyzed individual dying eggs: Every egg that had undergone this surface wave contained activated caspase, whereas the that had not yet undergone the waves did not —more evidence that trigger waves propagate cell in an intact cell too.

A wave of trigger waves

So far, apoptosis is the only form of in which trigger waves have been identified, but Ferrell is investigating other processes in biology to see if the continual waves might play a role.

Now, they're looking into whether trigger waves might be responsible for how our innate immune response spreads from cell to cell. Viruses spread from cell to cell through trigger waves, so it makes sense that our initial line of immune defense might employ the same tactic.

"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."

Explore further: Why does making new egg cells require so much cell death?

More information: X. Cheng el al., "Apoptosis propagates through the cytoplasm as trigger waves," Science (2018). … 1126/science.aah4065

Related Stories

Why does making new egg cells require so much cell death?

July 19, 2018

A highly detailed study of how the roundworm C. elegans forms oocytes suggests that the egg-making process leads to the formation and subsequent destruction of cells with an extra nucleus, but that some cellular materials ...

Cell death proteins key to fighting disease

October 31, 2014

Melbourne researchers have uncovered key steps involved in programmed cell death, offering new targets for the treatment of diseases including lupus, cancers and neurodegenerative diseases.

Scientists find a way to postpone cell death

March 6, 2018

A team of scientists from MSU and the Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences (located in Pushchino) have studied the mechanisms of interaction between the Fas-ligand protein that ...

Recommended for you

The Trojan horse of Staphylococcus aureus

November 21, 2018

Staphylococcus aureus causes different types of infections in humans, some of which are lethal. One of its most powerful weapons is α-toxin, which destroys host cells by forming pores in their membranes. Researchers at the ...

Tropical tree mortality—new study reveals why trees die

November 21, 2018

A study by scientists at UNSW Sydney, Macquarie University, data61 and the Smithsonian Tropical Research Institute has shown why some tropical tree species die and others survive, revealing new insights into the processes ...

Scientists study puncture performance of cactus spines

November 20, 2018

Beware the jumping cholla, Cylindropuntia fulgida. This shrubby, branching cactus will—if provoked by touching—anchor its splayed spines in the flesh of the offender. The barbed spines grip so tightly that a segment of ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Aug 10, 2018

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.