Joel Berry, PhD

The interior of living cells is a very complex but very well-organized environment. Many distinct structures or compartments called organelles assemble within cells and perform different biological functions. These structures are often roughly micron-scale in size and are commonly enclosed by membranes that provide a selective barrier between the organelle and the surrounding cytosol or nucleoplasmic fluid. Prominent membrane-bound organelles include the nucleus and mitrochondria.

​

There is another important class of organelles in living cells that have no enclosing membrane. Such membraneless organelles include the nucleolus, stress granules, and Cajal bodies. Many organelles of this type are liquid-like bodies rich in RNA and protein that spontaneously assemble and perform functions in a wide variety of biological processes. Abnormalities in the assembly and maturation of some of these bodies have recently been linked to a number of aging-associated and neurodegenerative human diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Much effort is currently being devoted to understanding how cells assemble membraneless organelles and how these bodies function and age.

​

A formative and fascinating concept in this area is the idea that cells use phase transitions to control the assembly and disassembly of membraneless organelles. Instead of requiring some complex sequence of tightly-controlled biological processes to occur in specific places at specific times, the cell simply modulates global concentrations of a few key molecules and induces liquid-liquid demixing above certain threshold concentrations. Imagine droplets of oil demixing from a water-oil solution. Here the oil is a mixture of various proteins, RNA, etc that spontaneously condense into droplets that allow specialized functions to be performed in their interiors. In this way, relatively small responses to stimuli can be amplified into dramatic changes in internal structure and subsequently function. With mounting experimental and theoretical support, this concept is rapidly becoming well-established.

​

My research with Mikko Haataja and Clifford Brangwynne’s experimental biochemistry group at Princeton has focused on developing and quantitatively applying modern field-theoretic modeling approaches to membraneless organelle assembly kinetics. We have shown that some classes of membraneless organelles (nucleoli and various “optoDrops”) do in fact assemble in very much the same way as passive demixing fluid droplets. Classical theories of domain growth and coarsening from condensed matter and materials science are sufficient to quantitatively describe their assembly kinetics. Effects of nonequilibrium biological activity in these cases can be straightforwardly absorbed into space-dependent effective thermodynamic interaction parameters, time-dependent average molecular concentrations, and/or space-dependent chemical reaction rates.