For Cells, Consider the Raindrop

Sometimes it’s useful to picture cells as microscopic machines with organelles such as the mitochondria and the Golgi apparatus serving as spinning cogs and gears. But the vision falls short when it comes to explaining how the internal structure of cells forms in the first place.

For that, a better image might be a raindrop.

“Non-living matter, like raindrops, form by molecules switching between different phases, or states, of matter – solid, liquid and gas,” Brangwynne explains. “Certain types of organelles within living cells also assemble by the transition of biological molecules between different phases.”

Phase transitions – the change in form caused by an alteration of molecular organization – are common in nature. Examples include water vapor condensing to form dew on grass or the surface of a puddle freezing to form a sheet of ice in winter. The water is chemically identical in each of these phases, but the ordering of the molecules creates a totally different form.

Brangwynne’s lab studies the role of phase transitions in organelle assembly, and how phase transitions are involved in fundamental biological processes. Stephanie Weber, a post-doctoral researcher in the lab, explained that Brangwynne proposed this idea in earlier studies on a class of organelles called P. granules – assemblies of RNA and protein that have no distinct membranes to separate them from the cytoplasm that makes up the cell interior.

“Twenty years ago, the assumption was that cells were bags of enzymes and aqueous solutions with no internal structure,” she said. “It was assumed that outside of the membrane-bound organelles everything is a homogenous aqueous solution.”

But, in fact, molecules do have “specific localization patterns” within the cytoplasm that fills the cell’s interior, Weber said. One of the reasons that membrane-less organelles are so fascinating is that they do not have any boundary.

“There is no barrier that separates what is in the droplet from what is cytoplasm; yet they are different,” Weber said.

The interior of a cell is not homogenous; it consists of different types and concentrations of proteins, RNA and other materials.

“The cytoplasm consists of thousands of different types of protein molecules,” Weber said.  Brangwynne’s work has shown that the physicochemical rules underlying phase transitions of nonliving matter may play a similar role in organizing these biomolecules in cells. When some of these molecules are present within the cell at concentrations exceeding a critical level, they condense to form droplet-like organelles, similar to the condensation of water vapor.

Brangwynne’s lab studies these intracellular phase transitions, and the way in which they are coupled to the size of growing cells. In a recent paper, Brangwynne and grad student Marina Feric showed that gravity plays a key role in regulating the overall size of cells – gravity has almost no effect at the average cell size, but when cells grow too large, gravity begins to disrupt the cell’s internal organization, and causes the organelles to all coalesce into a single large droplet.

Brangwynne’s group is particularly interested in a membrane-less organelle known as the nucleolus. The nucleolus plays a well-known role in cell growth; nucleoli are large and hyperactive in fast growing cancer cells. Brangwynne’s previous work has shown that the nucleolus behaves as a liquid phase droplet. Current work in the lab suggests that the nucleolus also assembles by a phase transition, which links the assembly and function of the nucleolus to cell size.

“I find the work very exciting because it is based in really fundamental physics and engineering, but we’re applying these fundamentals to address a biomedically critical problem: cell growth,” Brangwynne said. “We’ve been fortunate to make some important findings, but we are really just at the very beginning. There is an enormous amount to still figure out – what are the molecular players, how does a cell control the concentration of molecules, what role do non-equilibrium dynamics in the cell play, and what does this all mean for cell growth diseases like cancer? It’s clear we are going to be working on this problem for decades, and I’m looking forward to every minute of it.”