Over the past decade, biologists have discovered an ever-increasing number of phenomena that exhibit wave-like behavior. Everything from the firing of neurons to the spread of a virus through a population can show a similar pattern: they emanate from a central source and spread without a reduction in speed or amplitude, a feat known as a travelling wave. In two recent studies in Developmental Cell, cell biologist Min Wu of the National University of Singapore shows that cells can also use travelling waves to control their shape and the specific location of mitosis.
“Biologists tend to think of reactions as being linear: you have an input, and you have an output. Dose-responses are deeply ingrained in our thinking,” Wu says. “But what’s really interesting about these waves is that they are due to feedback mechanisms in the system. Waves and oscillations are quintessential examples of nonlinear responses.”
Living systems need to be able to be able to transmit information quickly and reliably. Over small distances, chemical diffusion can do the job. But over larger distances—millimeters and greater—this process can be too slow.
Take cell division. James Ferrell, a chemical and systems biologist at Stanford University, studies mitosis in the giant, millimeter-long eggs of the African clawed frog, Xenopus laevis. If random diffusion orchestrated the process, it should have taken hours for the cells to divide. Instead, it takes ten minutes.
The cause, Ferrell discovered, was a type of traveling wave called a trigger wave. A protein called cyclin-dependent kinase 1 (CDK1) controls mitosis by catalyzing activation of its own activator and switching off its deactivator. A wave of CDK1 activation sweeps across the cell, triggering mitosis. Ferrell published his results in 2013. The CDK1 itself doesn’t need to move, Ferrell notes, as long as it can spark other, nearby CDK1 proteins to activate. Although this work demonstrated the role of waves in giant Xenopus eggs, no one knew whether waves would also help normal-sized cells divide.
Wu wasn’t thinking about waves when she began her work on how the plasma membrane gets its shape. Work by other researchers had shown that a protein called actin assembles in waves in the cell cortex, the layer just beneath the outer plasma membrane. But as she began focusing on a process called clathrin-mediated endocytosis, Wu noticed something unusual. During clathrin-mediated endocytosis, the binding of a protein to a receptor causes the plasma membrane to fold inward, after which spherical clathrin proteins coat the area. The clathrin-coated vesicle then buds off from the plasma membrane.
Using live cell imaging, Wu found that waves of clathrin assembly set off a series of events that led to cortical waves of actin assembly. Curvature-generating F-BAR proteins such as FBP17 and the actin-regulating proteins Cdc42 and N-WASP linked these two processes, according to Wu’s first paper in Developmental Cell.
FBP17 and Cdc42 don’t just regulate endocytosis—they also play a major role in mitosis. In the second study, Wu observed circular waves of activated Cdc42 and FBP17 at the earliest onset of cell division in a subset of cultured mast cells, a type of white blood cell that can secrete large amounts of histamine. Importantly, the geometry of the wave differed depending on whether the cell was in interphase or actively dividing. Wave geometry during metaphase also predicted the site of furrow formation, where the cell pinches in two as it divides. Not only that, their wavelengths are scaled according to the size of the cell. The fact that waves could coordinate cell division not only in giant cells like Xenopus eggs but also in normal-sized mast cells suggest it is not really about the absolute size of the system when such mechanisms are invoked.
“My gut feeling, as a scientist, is that this is an historically important discovery,” says Stanford University theoretical physicist Robert Laughlin via email; he was not involved with the research. “One of the most dangerous things you can do as a theorist is accept an experimental result because it agrees with your theory,” Laughlin notes. “But, as of this moment, my best guess is that the effect described in these papers will be found not only correct but pervasive in biology, with many thousands of such waves operating in different chemical reaction circuits at different scales in a higher organism such as ourselves.”
“What’s interesting about these dynamics is that they are so diverse,” Wu adds. “At different cell states, they actually do different things, which means they probably contain information about the state the cell is in, and by studying their differences, we can really learn something about the cell.”