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The key to speed? Inside a cell, it's trigger waves

Think of what you see in this video as a message going viral, only it's spreading not in cyberspace but in cytoplasm. The video shows a trigger wave, an under-appreciated chemical phenomenon that can help cells get things done fast. Stanford graduate student Jeremy Chang and professor of chemical and systems biology Jim Ferrell, MD, PhD, published a video of this scene as part of their recent paper (subscription required) in Nature. The August 29 paper describes several lines of evidence all pointing to the conclusion that in frog eggs the dramatic dance of mitosis - in other words, the process of the egg dividing and forming two new eggs - is launched by trigger waves.

At the end of this post I'll explain in more detail what's happening in the video. But first I'll answer the question: Why study how frog eggs divide? It's not as odd as it sounds.

The eggs of these frogs (African clawed frogs or Xenopus laevis) are popular cells to study because, as cells go, they're huge - about 1 millimeter in diameter - which makes them relatively easy to manipulate and observe. But of particular relevance for this study is a mystery Ferrell and Chang wanted to solve concerning mitosis. Mitosis in a frog egg happens way too fast than would be possible if it were orchestrated merely by proteins randomly diffusing hither and thither - which is how most people assume things work most of the time in cells. If only random diffusion were in play, mitosis in a big cell like this would take several hours, Ferrell said. But in reality it takes just 10 minutes. So something more is going on and that something, as Ferrell and Chang have shown, is the cell's equivalent of going viral: trigger waves.

"It's a physical process that takes place in lots of settings," Ferrell told me. "The spread of a fire in a forest is an example of a trigger wave. The spread of an action potential from the body of a nerve to its axon is an example. Or a joke spreading through YouTube. The main ingredient you need for a trigger wave is positive feedback. It's an autocatalytic process."

To learn more about mitosis in the frog egg, Chang and Ferrell looked at the master regulator of mitosis, a protein called cyclin-dependent kinase 1, or CDK1. Activated molecules of CDK1 not only start mitosis, they turn inactive CDK1 molecules into active ones. In other words, there's positive feedback, and the result is a trigger wave spreading CDK1 activity across the cell.

To scale up the trigger wave to make it easier to see, Chang whipped up an extract from the guts of many frog eggs mixed together. He also figured out how to get the nuclei in the extract to undergo mitosis over and over again - in this video, seven rounds, and sometimes up to 15. (Ferrell said Chang is legendary in Xenopus research circles for engineering such a massive multiplicity of mitoses. Chang said it was sheer luck: Switching from a glass tube to Teflon to hold the extract did the trick.)

The flashing green spots in the video are the nuclei undergoing mitosis: They disappear when the cell pulls itself apart and reappear when the division is complete. You can see trigger waves traveling from both the top and the bottom of the tube. Take a look at the topmost nucleus and you'll see it blink off, shortly followed by its neighbor and so on down the line. The same happens if you follow the nuclei from the bottom up. The first cycle is a little messy but later rounds are clearer.

Ferrell and Chang suspect that trigger waves are behind many biological events assumed until now to be made possible by simple diffusion or by the circulatory system.

"We think it's a third general mechanism for long-distance biological communication," said Ferrell.

And in case you're wondering, it's not normal for frog cell nuclei to glow green. Chang engineered them to look this way so they'd be easier to see.

Video by Jeremy Chang. Images were obtained at a rate of one image per minute and are shown at a rate of 15 frames per second.

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