No one saw the blob takeover coming. In 2009 a team of biophysicists led by Anthony A. Hyman of the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, were studying specklelike structures called P granules in the single-celled embryo of a tiny, soil-dwelling worm. These specks were known to accumulate only at one end of the cell, making it lopsided so that, when it divides, the two daughter cells are different. The researchers wanted to know how that uneven distribution of P granules arises.
They discovered that these blobs, made from protein and RNA, were condensing on one side of the cell like raindrops in moist air, and dissolving again on the other side. In other words, the molecular components of the granules were undergoing phase transitions like those that switch a substance between liquid and gas.
That was a weird thing to be happening in cell biology. But at first it seemed to many researchers little more than a quirk and didn’t excite much attention. Then these little blobs—now called biomolecular condensates—began popping up just about anywhere researchers looked in the cell, doing a myriad of vital tasks.
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Biologists had long believed that bringing order and organization to the chaos of molecules inside a cell depended on membrane-bound compartments called organelles, such as the mitochondria. But condensates, it turns out, offer “order for free” without the need for membranes. They provide an easy, general-purpose organization that cells can turn on or off. This arrangement permits many of the things on which life depends, explains biophysicist Petra Schwille of the Max Planck Institute of Biochemistry in Martinsried, Germany.
These little blobs inside living cells now appear to feature across all domains of the living world and are “connected to just about every aspect of cellular function,” says biophysical engineer Cliff Brangwynne, who was part of the 2009 Dresden team and now runs his own lab at Princeton University. They protect cells from dangerously high or low temperatures; they repair DNA damage; they control the way DNA gets turned into crucial proteins. And when they go bad, they may trigger diseases.
Biomolecular condensates now seem to be a key part of how life gets its countless molecular components to coordinate and cooperate, to form committees that make the group decisions on which our very existence depends. “The ultimate problem in cell biology is not how a few puzzle pieces fit together,” Brangwynne says, “but how collections of billions of them give rise to emergent, dynamic structures on larger scales.”
These ubiquitous specks have “completely taken over cell biology,” says biophysicist Simon Alberti of the Technical University of Dresden. The challenge now is to understand how they form, what they do—and perhaps how to control them to devise new medical therapies and cures.
Initially researchers studying condensates thought they formed by coalescing as one liquid phase became insoluble in another—like vinegar droplets in the oil of salad dressing. But condensates aren’t always simply phase-separated liquids.
In 2012 biophysicist Michael Rosen of the University of Texas Southwestern Medical Center in Dallas and his coworkers showed that various proteins and RNA molecules could phase-separate from a solution into dense liquid droplets, which then congealed into viscoelastic substances. They seem to span the range from gloppy liquids such as mucus to almost solidlike gels such as Jell-O. Or, as biophysicist Rohit Pappu of Washington University in St. Louis describes it, “all condensates are Silly Putty.”
The umbrella term “biomolecular condensates,” proposed by Hyman, Rosen and their colleagues in 2017, distances these ubiquitous blobs from the early notion that they are all liquids.
Condensates now seem to be a key part of how life gets its countless molecular components to coordinate.
Condensates can look messy compared with the precise molecular unions that biochemists and molecular biologists are used to studying. They are not a static form but molecular meeting places, often loose collections of several different components, some of which can move into or out of the blobs. Some of these ingredients, called scaffold molecules, are essential to the fabric, sticking together into gel-like networks. Others, sometimes referred to as client molecules, merely hang out in the network. Both types, however, seem able to come and go from the condensate without it falling apart.
Typically the gels contain proteins and RNA molecules. The archetypal image of a protein is an enzyme, made from a chain of amino acids tightly folded into a globule. But many of the proteins in condensates have parts that are more open and floppy (like cooked spaghetti), or what biochemists call intrinsically disordered regions.
Such condensate-forming proteins often appear to have sticky patches, for example, where the chains carry electrical charges that can attract one another, joined together by disordered and flexible spacer segments. Unlike the conventional view that proteins, like enzymes, bind other molecules tightly and very selectively, the interactions of intrinsically disordered proteins can be rather weak and promiscuous: they aren’t too choosy when it comes to what they bind.
Another ingredient of many condensates is RNA molecules, which are also long chains studded with electrical charges. RNA was long considered to serve mostly as an intermediary that carries information from a gene to the machinery of the ribosome, which translates it into the amino acid sequence of a protein’s chain. But condensate-forming RNAs are generally members of a different family: noncoding RNAs, which are not mere messengers for making proteins but are ends in themselves.
Some of the proteins in condensates, meanwhile, belong to a family whose job seems to be to bind RNAs. By tuning protein and RNA sequences and structures to alter their binding propensities, biology has dials for altering the functions of condensates or the conditions under which they form.
Proteins, for example, might be switched into condensate-forming mode when enzymes decorate them with other chemical groups such as electrically charged phosphates, altering their shape and stickiness. Or these blobs might be summoned when a cell starts synthesizing the constituent RNA. That seems to be what happens, for example, when our own cells make a noncoding RNA called NEAT1, the scaffold for condensates called paraspeckles that play a role in regulating genes.
Weirdly, scientists have had evidence of the existence of condensates for as long as they have known about living cells—they just didn’t know what to make of them. Way back in 1830 mysterious specks were seen by early microscopists inside the cell nucleus. Then called nucleoli, they were later found to be where the ribosome is made. But it wasn’t until 2011 that Brang-wynne, Hyman and veteran cell biologist Tim Mitchison of Harvard Medical School clarified what nucleoli actually are: phase-separated liquidlike droplets.
These particular blobs have many jobs. It seems they help to keep all the many steps of ribosome assembly—made of many proteins along with pieces of RNA—under control. Brangwynne and others have shown that the liquidlike nucleoli (a type of condensate) are subdivided into several concentric layers with different compositions, like the shell, white and yolk of an egg. “This layered condensate allows for spatial segregation of the different processing steps,” he explains.
Besides the nucleoli, condensates are associated with other long-recognized compartments and organelles of the cell. One of them is called the Golgi: a set of stacked ribbonlike lipid membranes near the nucleus that acts as a kind of sorting hub for proteins and other molecules. Yiyun Zhang and Joachim Seeman of University of Texas Southwestern Medical Center in Dallas have shown that, when cells are stressed, these ribbons are maintained or repaired by a condensate formed from a protein called GM130.
The protein creates a matrix on a Golgi membrane and then gathers RNA and RNA-binding proteins into a liquid phase that helps to glue the membranes into a stack. Under stress conditions, however, the protein and RNA dissociate, the condensate comes apart, and the ribbon starts to disintegrate. Then the freed-up GM130 gathers with RNA into condensate “stress granules,” which store it ready for gluing the membranes back together when the stress has passed.
That’s just one example of how condensates help to sustain cells through difficult times. One common stressor is heat, which can cause folded proteins to “denature,” or unravel. Many cells make heat-shock proteins when they get uncomfortably warm, which can act as molecular chaperones that guide denatured proteins back to their folded state. That’s important not just so the proteins work properly but so unfolded proteins do not stick together in a gloppy mess.
But according to biochemist D. Allan Drummond of the University of Chicago, there was always something a bit screwy about this picture. It implies that if cells are becoming too hot and need to make heat-shock proteins, they can sense it only if the damage has already happened. “It just doesn’t smell right,” he says.
Instead Drummond suspects the way cells sense temperature—and other forms of stress—is by condensate formation. In 2017 he and his coworkers found that stress granules, blobs that appear in yeast cells, contain condensates made of an RNA-binding protein called Pab1. When this protein gets bound up in a condensate, it loses most of its ability to bind messenger RNA molecules that encode chaperone proteins needed to protect against heat shock.
When the researchers introduced mutations into the gene that encodes Pab1, they could alter the resulting protein’s propensity to form condensates so that cells with the mutation fared poorly when warmed. Thus, Drummond thinks condensate formation—a phase transition that happens abruptly at a particular threshold (in temperature, say)—is itself the stress sensor that alerts the cell to the problem and provokes a response. “You add condensates into the picture, and you utterly rewire your thinking about it,” he says.
Another common threat to cells is DNA damage, caused by exposure to ultraviolet light or environmental toxins, for example. Alberti’s group has found that condensates can act as a superglue to hold damaged DNA strands together while enzymes repair them.
DNA repair has long been known to involve a protein called PARP1, and in early 2024 Alberti’s team reported that this molecule travels along DNA strands until it finds a break, whereupon it aggregates with the DNA into a condensate, shielding the damage from the rest of the nucleus. “The glue is very solid,” Alberti says. A protein called FUS then gets incorporated into the blob of glue and softens it so that other enzymes can work within the condensate to join the ends of the strand back together. Because DNA damage can be fatal to cells, drugs that target PARP1 in cancer cells and arrest DNA repair by fixing the glue in its “solid” form might kill them.
Organizing complex biochemical processes and responses to stress are two common functions of condensates. Pappu, his colleague Yifan Dai and their coworkers have recently found another: Condensates can act as catalysts for biochemical reactions, even if their component proteins do not. This is because condensates create an interface between two phases, which sets up a gradient in concentrations—of ions for example, creating an electric field that can trigger reactions. The researchers have demonstrated condensate-induced catalysis of a wide range of biochemical reactions, including those involving hydrolysis (in which water splits other molecules apart).
Condensates may also play a part in one of the most important processes in biology: how genes are regulated to determine whether or not they generate their corresponding proteins. In complex organisms such as humans, the initial process of transcription—where the gene in DNA is read to make the mRNA molecule that templates the protein—is a bafflingly complicated affair. It involves many players: DNA regions outside the gene itself such as enhancers (which are often on rather distant parts of the strand), proteins called transcriptions factors that bind to DNA, RNA-making enzymes, and more.
How all these components get together and reach a group decision to regulate transcription is still unclear. “When I was transitioning from physics into biology,” Pappu says, “I would sit there [at conferences] listening to these gene-regulation talks—this activates this, and this recruits that—and I was always thinking: ‘Are these molecules making cell phone calls to one another? What the devil’s going on?’”
It seems that condensatelike aggregates may be what bring these components together within the tangle of DNA in the cell nucleus. The DNA strand might itself act as a seed for such droplets, like the atmospheric dust particles that seed the condensation of cloud droplets. This blob can then suck in the distant enhancer regions on loops of DNA while gathering all the other molecules needed and stopping them from drifting off.
Molecular gatherings during transcription are considerably smaller affairs than those in many other condensates, and it is hard to get a clear view of them inside the nuclei of living cells. So there’s still debate about whether such “transcriptional hubs” are true liquid droplets and whether condensate formation is an essential part of the process or a side effect. Another possibility, Drummond says, is that all these molecules, once brought together into the same space, fit together into a more orderly complex to initiate transcription, but their congregation also generates condensates.
There’s much to be unraveled. “I tell people that all I know is that these [transcriptional] proteins really want to phase-separate,” Brangwynne says. “I just don’t see another plausible model. Phase separation is the most parsimonious explanation.”
Proteins aggregating into dense blobs seems to be an essential aspect of how life works. But there’s a dark side to this process.
Tangled clumps of protein have long been linked to neurodegenerative conditions such as Parkinson’s and Alzheimer’s. These solidlike knots, called amyloids, can be toxic to cells and kill off neural tissue. Some researchers suspect that such problematic protein aggregates might arise from improper control of ubiquitous, ephemeral condensates, for example, because of gene mutations affecting the constituent proteins in ways that make them apt to congeal into long-lived solid lumps.
At first the mantra among researchers was “liquid good, solid bad”—but that’s clearly too simplistic because healthy condensates have a range of material properties that can include solidlike. What really distinguishes “good” from “bad” condensates is now one of the pressing questions for the field.
The possible connection between condensates and pathological amyloids is being explored in the search for treatments for neurodegeneration. It’s possible that antisense oligonucleotides—short segments of nucleic acids that can bind to RNA—might be used to inhibit the aggregation of proteins associated with these conditions. They are also being explored for disabling condensate-forming RNA molecules.
Similarly, the importance of condensates such as paraspeckles in gene regulation means that their dysregulation might lead to all manner of diseases, including cancers. There is now an emerging field of condensate therapeutics being pursued by start-up companies such Dewpoint Therapeutics (cofounded by Hyman, biologist Richard Young of the Massachusetts Institute of Technology and Nobel laureate Phillip A. Sharp) and Nereid Therapeutics (which is building on Brangwynne’s work), both based in Boston. “There is a ton of progress being made,” Brangwynne says. “Condensate biophysics is now moving drugs into clinical trials.”
Most of the attention so far has been on treatments for neurodegenerative diseases and cancer, but there are also efforts to combat viral infection via condensates. Some viruses seem to “hijack” condensate-forming proteins to help them replicate—so targeting those condensates could thwart the virus. In 2021 researchers in France and China showed that a drug that makes virus-induced condensates called inclusion bodies more solidlike can disrupt infection by RSV, the human respiratory syncytial virus.
In 2023, when Brangwynne and Hyman were awarded the $3-million Breakthrough Prize for their work, it was surely a sign that condensates had arrived. “There’s going to be a lot of cool stuff in the next 10 years,” Alberti says. And although many questions about biomolecular condensates remain, these blobs are, in Drummond’s view, “the revolution we have been waiting for.”
It might seem odd that it took so long to see condensates for what they are. At least a part of the answer is that they don’t fit into the picture of molecular biology that has prevailed for many decades. The old paradigm was all about how molecules pass information around the cell by getting together via selective interactions tightly encoded into their structure. Condensates undermine this view. They are loose, transient and flexible, and they show that many of the cell’s key processes are conducted using molecular committees of many hundreds of members.
Schwille suspects that achieving molecular organization via condensates was probably critical in the origin of life itself, before nucleic acids and proteins had evolved to have precisely defined structures. For one thing, they show how cell-like compartments might have formed spontaneously from the progenitors of those polymeric biomolecules by liquid phase separation.
In fact, protein blobs like this were reported in 1929 by two Dutch chemists, who called them coacervates, and were invoked a few years later by Russian biochemist Alexander Oparin as the first primitive “proto-cells.” Schwille says that such compartments, by sequestering some molecules away from others, could have set up the gradients in concentration that sustain living organisms in an out-of-equilibrium state.
Pappu speculates that catalytic condensates might have been important in such proto-living entities before proteins were themselves capable of acting as enzymes. Among the big questions for the future, Alberti says, is how evolution has subsequently made use of condensates. How do the forces of natural selection act on all the molecular players to alter and tune their ability to form condensates? “It’s going to be fascinating to study,” Alberti says. “You have to bring the evolutionary biology together with the physics.”
Right now, though, condensates signal a new phase in our understanding of how life works at the molecular scale. “We now realize that [traditional] biochemistry and structural biology aren’t going to be enough to describe what’s happening in the cell, especially when we are dealing with processes that involve many components,” Alberti says. We need to understand how all those components coordinate their interactions to create the unified entity that is the cell.
The blobs reveal an important scale on which that coordination happens: somewhere between the size of multicomponent complexes such as chromosomes and the size of whole cells. It’s a scale where the molecules are no longer working like precise little machines but are instead gathering into a kind of material entity, governed by the collective physics of phase transitions yet still sensitive to the details of their molecular components. We don’t yet know the rules dictating what goes on at these scales. But it’s clearer than ever that life depends on them.
