Q: Why Do Animal Cells Stay So Small? A: Gravity
Cutting-edge technology leads to a big discovery.
The typical animal cell measures about 10 microns, or 0.001 centimeters, in diameter. Which is unsurprising—cells are small! that's sort of the point!—and, at the same time, curious. Animals exhibit nothing if not biodiversity, yet the building blocks we all share are, with very few exceptions, astoundingly similar in size. So: Why? Why do cells stay so small? Why don't they generally, across the vast majority of animal life on Earth, become any larger than a hundredth of a millimeter?
Biologists have generally attributed the limit to the difficulty that large-volume cells face in obtaining nutrients. But researchers at Princeton are now offering another answer, one that has nothing to do with food and everything to do with force: gravity. Clifford Brangwynne, an assistant professor of chemical and biological engineering and the scientist who led the research, has put bioengineering techniques to use to suggest that it's gravitational force that imposes the size limit on cells. The rare cells that are larger than 10 microns in diameter, his work has found, seem to be the exceptions that prove the rule: They have evolved as they have in part to support their contents against gravity.
Which is a major finding. Size, biologically, matters: The forces of nature are scale-dependent, which means that different forces become relevant—and essentially irrelevant—at different length scales. So the quantum effects that exert themselves on matter at microscopic scales average out as you move up to larger length scales. And gravity's force, in turn, becomes negligible at a certain smallness of scale. Biologists have long assumed that animal cells fall below that point—that they are simply too small to be affected by gravity. So while, at a tissue level, sure, cells are subject to gravity, at the level of the tiny individual, the thinking went, gravity wasn't one of the forces that cells are subject to. In microbiology, "we really have never, in my experience, worried about gravity—or thought about it," Brangwynne told me.
Brangwynne's work, published in Nature Cell Biology, may change that. And it may offer, as well, an answer to a longstanding mystery about where that line may be drawn: At what point, exactly, does gravity stop mattering to matter?
Brangwynne came to his findings with the help of some fairly ingenious technology. He also came to them somewhat unexpectedly. His previous work had shown that certain large particles within cells act essentially like water droplets, merging as they contact each other. In cells' nuclei, however, something seemed to be keeping them from fusing. To follow up on that observation, Brangwynne and his co-author, graduate student Marina Feric, studied egg cells of the African clawed frog, which are, like other eggs, anomalous in that they can reach sizes of 1 millimeter in diameter. The pair were studying, in particular, how the eggs are engineered: They wanted to explore why the nuclei of those larger cells contain, compared to smaller cells, a significantly higher concentration of actin, the protein that forms microfilaments in eukaryotes.
To do that, they turned to engineering of a more mechanical variety: microrheology, a technique that allows for the examination of viscosity within cells. They first tested whether the nuclei had a kind of mesh scaffolding that would allow smaller particles to move through the mesh but cause larger particles to get trapped—which would explain why those nuclei wouldn't fuse. Feric injected the frog egg nuclei with microscopic, Teflon-like beads of varying sizes. She then used microscopic imaging to observe the results. As she and Brangwynne predicted, the small beads diffused throughout the nucleus ("we watched them, basically, dance around," Brangwynne puts it) while the larger ones got stuck. A scaffold did, as they suspected, seem to be in place in the larger cells.
Feric then tested whether that scaffolding could be made up of actin. (Actin is known to form a kind cytoskeleton outside cells' nuclei, but its structural role in the nucleus has been largely unclear.) They treated the cells' nuclei with anti-actin drugs, disrupting their scaffolding stuctures. And when they did that, something more unexpected happened: The organelles that are naturally suspended throughout the nucleus of the cell ... fell. It was, as Brangwynne says, "exactly like what you would see if you took a marble and dropped it into a bucket—it's going to plop right down to the bottom."
Which suggested, in turn, that the elastic network in the cells' nuclei was what had kept the organelles suspended—allowing the organelles, essentially, some resistance against gravity's forces. Remove that scaffolding, and the particles fall.
"It was completely surprising to us that gravity really mattered," Brangwynne told me. But gravity did, indeed, seem to matter. That the actin mesh that spans the nuclei of larger cells—and that it doesn't seem to do the same in small cells—suggests that it's there because of the size of the cells. It's a deduction, but one that makes sense: Larger cells have the actin mesh to protect against gravity. As cells grow larger than 10 microns, they have to bolster their contents against gravity. But if cells stay under that 10-micron threshold—as the vast majority of animal cells do—they can essentially escape gravity's forces. The building blocks of life are small, essentially, because gravity keeps them that way.