32 THE SCIENTIST | the-scientist.com
© ISTOCK.COM, JOSE LUIS CALVO MARTIN & JOSE ENRIQUE GARCIA-MAURIÑO MUZQUIZpolymer to form a separate droplet state that
largely excludes the solvent, and this typi-
cally occurs when the polymer concentra-
tion surpasses a defined threshold. If more
polymer chains are then added, they join the
existing droplets. As a result, the concentra-
tion of polymer chains outside the droplet
(in a dispersed state) remains constant.
For the droplet to retain liquid-like
properties, the polymer chains inside it must
be able to rapidly move past each other. To
achieve this, the chains must be highly flex-
ible and capable of engaging in multiple,
weak interactions with one another. Longer
chains undergo phase separation more read-
ily than shorter chains of a similar mono-
mer composition, as a longer chain can
engage with more molecules. In sum, poly-
mer phase separation depends on polymer
chain length, chain flexibility, the number
and strength of interactions the polymer
can make, and the overall polymer concen-
tration with respect to the solvent. The phys-
ical properties of these polymers also dictate
whether other molecules are permitted into
or excluded from these structures.Polymers are common in biology and
include carbohydrates, nucleic acids, lipids,
and proteins. Of these, proteins have the
greatest variety of sidechain chemistries—
through amino acid sequence variation as
well as posttranslational modification—
and therefore provide the greatest range of
polymer flexibility and interactions. Protein
chain length and monomer sequence are
genetically encoded, and the overall con-centration of a protein is regulated at three
levels: transcription, translation, and deg-
radation. This high level of control makes
proteins ideal components to promote
regulated liquid-liquid phase separation.Indeed, proteins form the basis of almost
all known membraneless organelles.
The notion that highly flexible pro-
teins perform important biological roles
goes against the long-held dogma that,
in order to be functional, a protein must
adopt a defined three-dimensional struc-
ture. Until the late 1990s, scientists
thought that such highly flexible proteins
were extremely rare. Since then, research-
ers have identified more of these so-called
intrinsically disordered proteins (IDPs)—
which likely account for approximately
30 percent to 40 percent of proteins in a
human cell. IDPs have also proven to be
functionally important in contexts such
as cell signaling, transcriptional regula-
tion, and, consequently, cancer. Over the
past decade, IDPs that undergo liquid-
liquid phase separation in living cells have
emerged as an important subset of these
flexible proteins. Such IDPs appear to
form the bulk of phase-separated mem-
braneless organelles, and are likely to have
a major influence on the physical and bio-
chemical properties of these structures.Membraneless organelles house
cellular reactions
Like their membrane-bound counter-
parts, membraneless organelles allow
cells to compartmentalize their interior,bringing compounds together to control
reaction rates and cordoning off toxic
agents. Cajal bodies of the nucleus, for
example, play important roles in process-
ing messenger RNAs, and germ granulesLIQUID NEOPLASM: The nucleolus (pink dots
within the purple nuclei of these liver cells)
hosts ribo some biogenesis in a series of liquid
droplets that form due to phase separation.The nucleolus consists of at least three
distinct phase-separated layers—droplets
within droplets within droplets.