30 THE SCIENTIST | the-scientist.com

I

t was a simple but insightful experiment.

At the turn of the 20th century, Ameri-

can biologist Edmund Wilson squashed

starfish eggs under a microscope and

watched what happened as cellular

material spilled out between two glass

coverslips. He noted that the cellular goo

contained spherical globules that fused into

larger globules—behavior characteristic of

liquid droplets suspended in another, chem-

ically distinct liquid. Wilson also observed

that only droplets of the same type (which

he judged by their color or apparent density)

fused upon contact with each other.

These observations led Wilson to con-

clude that “the living protoplasm” contains

numerous liquid droplets that vary in their

“chemical nature.”^1 Despite having been

overlooked for the last century, this has

turned out to be a prescient description of

the interior of eukaryotic cells.

In addition to membrane-encased

organelles—the nucleus, mitochondria,

and Golgi apparatus, to name a few—

eukaryotic cells harbor a variety of com-

partments that lack a casing. These

protein-based liquid globules, called

membraneless organelles, selectively per-

mit entry of enzymes and substrates to

carry out various cellular functions that

would be less efficient or not possible at

all in the cytoplasm. The structures are

highly dynamic, and range in size from

0.1–3 micrometers in diameter, far big-

ger than just a few molecules clustered

together or than multi-component molec-

ular machines such as ribosomes (which

are about 0.03 micrometers in diameter).

Globules can even occur within other

organelles. The nucleolus, the largest and

most prominent compartment lacking

a membrane, is found in the nucleus of

almost all cells. First described nearly 200

years ago, this globular structure is now

known to play critical roles in ribosome

formation. Other membraneless organelles

are found only in certain cell types, where

they have more-specialized functions.

In the past decade, researchers have

learned that a well-known phenomenon

known as liquid-liquid phase separa-

tion governs the formation and function

of several of these large membraneless

structures. The emerging picture of the

inside of the cell is that the cytoplasm

and nucleoplasm are complex fluids that

can stably segregate, like a cruet of oil

and vinegar. Borrowing knowledge from

fields such as physical chemistry and soft

matter physics—where theories explain-

ing liquid-liquid phase separation have

informed the development of products

ranging from stabilizers in processed

foods to cosmetics, from therapeutic

ointments to paints—biologists are now

developing a new understanding of the

nearly two dozen types of membraneless

structures characterized so far.

Seeing the internal cellular environ-

ment as a fluid that contains multiple liq-

uid droplets functioning as membraneless

organelles marks a turning point in our

understanding of cell biology. The concept

is young, and how and why liquid-liquid

phase separation organizes the intercellular

space remain open questions. But already,

it is clear that the phenomenon underpins

the formation and functionality of a grow-

ing number of long-observed membraneless

organelles. And researchers are now learn-

ing that it could play a role in the aggrega-

tion of proteins associated with disease. (See

sidebar on page 34.) As details of the influ-

ence of phase separation on cellular features

emerge, the biological community will come

to see the cell in a new light.

Like oil and water

As in vinaigrette left on the countertop,

segregation of droplets of different com-

positions appears to be a natural char-

acteristic of a cell’s innards. But the var-

ied droplets in a cell’s cytosol or nucleus

VOCABULARY LESSON

Membraneless organelles, defined

as subcellular compartments that

lack a surrounding membrane and

perform a specialized biochemical

role, are also referred to as

membraneless compartments,

cellular bodies, and, most broadly,

biomolecular condensates.

As in vinaigrette left

on the countertop,

segregation of

droplets of different

com positions

appears to be a

natural charac teristic

of a cell’s innards.