Sunday, December 16, 2018

A ‘Self-Aware’ Fish Raises Doubts About a Cognitive Test
A report that a fish can pass the “mirror test” for self-awareness reignites debates about how to define and measure that elusive quality.
[[My sarcastic comments in double brackets.]]

Very few animals have ever passed the mirror test for self-recognition — even most primates fail it. The news that a fish seemed to recognize itself in one recent study has made psychologists and animal behaviorists wonder anew what (if anything) the mirror test proves.

December 12, 2018

A little blue-and-black fish swims up to a mirror. It maneuvers its body vertically to reflect its belly, along with a brown mark that researchers have placed on its throat. The fish then pivots and dives to strike its throat against the sandy bottom of its tank with a glancing blow. Then it returns to the mirror. Depending on which scientists you ask, this moment represents either a revolution or a red herring.
Alex Jordan, an evolutionary biologist at the Max Planck Institute for Ornithology in Germany, thinks this fish — a cleaner wrasse — has just passed a classic test of self-recognition. Scientists have long thought that being able to recognize oneself in a mirror reveals some sort of self-awareness, and perhaps an awareness of others’ perspectives, too. For almost 50 years, they have been using mirrors to test animals for that capacity. After letting an animal get familiar with a mirror, they put a mark someplace on the animal’s body that it can see only in its reflection. If the animal looks in the mirror and then touches or examines the mark on its body, it passes the test.
Humans don’t usually reach this milestone until we’re toddlers. Very few other species ever pass the test; those that do are mostly or entirely big-brained mammals such as chimpanzees. And yet as reported in a study that appeared on earlier this year and that is due for imminent publication in PLOS Biology, Jordan and his co-authors observed this seemingly self-aware behavior in a tiny fish.
Jordan’s findings have consequently inspired strong feelings in the field. “There are researchers who, it seems, do not want fish to be included in this secret club,” he said. “Because then that means that the [primates] are not so special anymore.”
If a fish passes the mirror test, Jordan said, “either you have to accept that the fish is self-aware, or you have to accept that maybe this test is not testing for that.”
[Yes, yes yes!! I have been saying this for years. Self-awareness indeed! Because it can find a spot on its own body via the mirror image.

The correct explanation may be a little of both. Some animals’ mental skills may be more impressive than we imagined, while the mirror test may say less than we thought. Moving forward in our understanding of animal minds might mean shattering old ideas about the mirror test and designing new experiments that take into account each species’ unique perspective on the world.
Reflecting on Primates
The evolutionary psychologist Gordon Gallup thought up his field-defining experiment while shaving in a mirror one day as a graduate student. When Gallup took a position at Tulane University a little later, he had access to animals at the Delta Regional Primate Research Centerhe could test his idea on.
Gallup started by showing a mirror to four chimpanzees, each alone in a cage. At first the chimps reacted as if they were seeing a stranger. But after a few days, they stopped threatening and vocalizing at the reflections. They started using the mirrors to look at themselves: They cleaned food from their teeth, picked their noses and examined their genitals. To prove that the chimps understood what they were seeing, researchers anesthetized the animals and dabbed red dye onto their eyebrows and ears. Then they returned the chimps to the mirrors. Looking at their reflections, the animals touched their fingers to the paint on their faces.
What surprised Gallup more than the chimpanzees’ success at recognizing themselves was the failure of macaques he tested at the same time. When the paper came out in Science in 1970, “it was bigger than I thought it would be,” Gallup said. “People were quite taken with the finding.”

Gordon Gallup, an evolutionary biologist now at the State University of New York, Albany, invented the mirror test for self-recognition almost 50 years ago. To him, the only animals that have definitively passed it are humans, chimpanzees and orangutans.
Courtesy of Gordon Gallup
We were speaking in his cramped office on the campus of the State University of New York, Albany, where Gallup has worked since 1975. Every surface and drawer overflowed with stacks of paper. A phone teetered atop a paper heap that covered the entire desk. Here and there, obsolete technologies peeked through the clutter: a dusty vintage computer scattered with floppy disks, VHS tapes on a rolling TV cart, a slide projector. Gallup sat on a rolling desk chair that had worn a circular hole through the carpet to the industrial floor below.
He showed me black-and-white photos of chimps studying themselves in mirrors. What the mirror test shows, Gallup said, is self-awareness, which he defines as “the ability to become the object of your own attention.”
[[Wow. “The object of your own attention.” But what is the “you” here? A person?  Who says so?]]
 And he believes this implies a certain rare intellect. Any animal that can recognize itself in a mirror, Gallup thinks, can potentially recognize that others have their own minds and even empathize with them.
[[Wow. Recognize that others have minds! Empathize!! Who says so? This is all overblown ffantasy.]]
A sense of self means a sense of selves.
Around the same time as Gallup’s initial study, the psychologist Beulah Amsterdam, at the University of North Carolina, Chapel Hill, was working on a similar experiment with babies and toddlers, in which she dotted their noses with rouge. She found that most children recognize themselves in a mirror by age two. In the following years, Gallup and his colleagues tested a range of other animals with mirrors, from primates to chickens, and found more failures than successes. Most animals never moved beyond seeing the reflection as another animal.
But a few did — or seemed to. Diana Reiss, a marine mammal scientist and cognitive psychologist at Hunter College in New York City, has done extensive research on dolphins, including mirror tests both with Gallup and other co-authors. Though the study she worked on with Gallup wasn’t conclusive, she said, later studies showed that dolphins can pass the test. In their reflections, aquarium dolphins studied their eyes and mouths, did flips and blew different kinds of bubbles. After being drawn on with black marker, the dolphins spent more time looking at the marked sides of their bodies in the mirror.

As observed through one-way glass, a dolphin playfully spins in front of its reflection. Some researchers consider dolphins to have passed the mirror test, but that conclusion is debated.
Courtesy of Diana Reiss
Monkeys, for the most part, have continued to fail mirror tests. Some rhesus macaques passed after weeks of training with their heads restrained, forced to stare at the mirror. In another experiment, researchers tried marking marmosets with chocolate to increase their motivation, with no luck. (Some of the monkeys tried to lick the chocolate in the mirror.) But Reiss and her colleagues have found mirror self-recognition in Asian elephants. Orangutans, bonobos and gorillas have all passed the test, too, Reiss said — along with one bird, the magpie.
In Gallup’s view, though, only three species have definitively passed: chimpanzees, orangutans and humans. He finds the evidence for every other species uncompelling, and thinks researchers are reading things into animals’ behavior that aren’t there. Gallup has co-authored papers critiquing others’ methods and interpretations.
One researcher whose results Gallup challenged was the Harvard University biologist Marc Hauser, who charmingly marked monkeys called cotton-top tamarins by dyeing their fluffy white hair exotic colors. Hauser and his co-authors reported that the monkeys touched their heads while looking in the mirror. Yet an attempted replication of the study failed, and in 2011 Hauser left Harvard after an investigation found he had falsified data in other studies.
Still, Gallup claimed he keeps an open mind. “I’m more than happy to consider the possibility that any other species might be capable of recognizing itself in a mirror,” he said.
Enter Jordan’s fish.
Social Enough to Be Self-Aware
Jordan is interested in the mental skills that animals lose or gain as they evolve to live in social groups. He and his co-authors wanted to explore the cognitive limits of social fish — so they thought of the mirror test. First they tested cichlids, which didn’t pass. So the researchers pondered what fish to try next. “The answer came: Of course it should be the cleaner wrasse,” Jordan said. “It is an incredibly intelligent animal, and highly social.”
Cleaner wrasse live on coral reefs and specialize in nibbling parasites and dead skin off the bodies of larger fish that could easily make a meal of them. It’s a dangerous life, and the wrasse have to be savvy to avoid being eaten themselves. In the lab and in the wild, Jordan said, the fish are inquisitive about their environments and attentive to humans, attempting to clean a person’s hands or face masks as they would a client.
In front of a mirror, cleaner wrasse seemed to pass through the same stages as chimpanzees. First they attacked their reflections. Then they performed unusual behaviors in front of the mirrors, like swimming upside down. After several days, the fish were spending extra time near the mirrors, as if studying their reflections.

Alex Jordan, an evolutionary biologist who studies behavior at the Max Planck Institute for Ornithology in Germany, was inspired to test the cognitive limits of social fish, so he administered a mirror test to the fish called a cleaner wrasse.
Simon Gingins
Next, the researchers marked the fish that seemed to be catching on. They injected a bit of brown material (or clear, for a control) under the skin of each fish’s throat. Afterward, some of the fish seemed to study the marks in front of the mirror. Then they scraped their throats against rocks or the sandy bottom of their tanks — a common fish behavior for removing irritants, Jordan said. The fish often followed this maneuver by swimming back up to the mirror. Three out of the four fish that made it this far in the study passed the mirror test, the authors concluded.
The researchers spent more than three years trying to get the paper published. Peer review is a largely cloaked process in which experts in a field respond anonymously to papers that have been submitted to journals. But Gallup signed his reviews of the cleaner wrasse paper, which were “violently anti,” Jordan said.
In Albany, Gallup chuckled at the suggestion that the fish had recognized themselves. To him, the demonstrated behavior was too ambiguous. He wrote in one of his reviews that when a wrasse scraped its throat, maybe it was pantomiming an instruction for what the mirrored fish should do — as in “You’ve got some mustard on your chin,” said Jordan, who called this alternate explanation “incredibly far-fetched.”
I think the community wants a revision and a reevaluation of how we understand what animals know.
Alex Jordan, Max Planck Institute for Ornithology
Reiss also reviewed the paper several times for different publications, she said. She wasn’t convinced that behaviors like swimming upside down showed that fish were testing how the mirror worked. She and Gallup also found it problematic that the brown mark resembled a parasite — to which wrasses instinctively react — unlike the unnatural marks on other animals. “I think for a claim like this, the evidence has to be much stronger,” Reiss said.
In response to the reviewers’ objections, Jordan and his co-authors added more control experiments to their study. Now that the paper has finally been accepted for publication, Jordan thinks the grueling revision period made the study stronger. “And, you know, I didn’t die in the process,” he joked.
Alexandra Horowitz, a psychologist at Barnard College in New York City who studies dog cognition, called the wrasse study “amazing.” She added, “I think it … challenges our presumptive notions about what fish can or cannot experience.”
Jordan wants the world to know how smart fish can be. But, he said, “I am the last to say that fish are as smart as chimpanzees. Or that the cleaner wrasse is equivalent to an 18-month-old baby. It’s not.” Rather, he thinks the main point of his paper has more to do with science than fish: “The mirror test is probably not testing for self-awareness,” he said.
[[Hooray! Finally! After decades of mindless hype, a little caution – not to say skepticism.]]

 The question then is what it is doing, and whether we can do better.
What Is Self-Awareness?
Sometimes it’s easy to tell that an animal really doesn’t understand mirrors. The writer Mary Laura Philpott has frequently been awakened in the wee hours of the morning by a loud knocking on her door in Nashville, Tennessee. When she opens the door, she finds only a small turtle. She nicknamed the prankster reptile Frank. Eventually she came to suspect that Frank might be challenging or attacking the strange turtle he sees in the reflective part of her door — night after night after night.
But just because one individual animal fails a mirror test doesn’t mean every member of its species would do the same. It’s a more meaningful positive test than a negative one. And even when animals do recognize themselves in mirrors, researchers are divided about what that implies.
“Recognition of one’s own reflection would seem to require a rather advanced form of intellect,” Gallup wrote in 1970. “These data would seem to qualify as the first experimental demonstration of a self-concept in a subhuman form.”
Either a species shows self-awareness or it doesn’t, as Gallup describes it — and most don’t. “And that’s prompted a lot of people to spend a lot of time trying to devise ways to salvage the intellectual integrity of their favorite laboratory animals,” he told me.
But Reiss and other researchers think self-awareness is more likely to exist on a continuum. In a 2005 study, the Emory University primatologist Frans de Waal and his co-authors showed that capuchin monkeys make more eye contact with a mirror than they do with a strange monkey behind Plexiglas. This could be a kind of intermediate result between self-awareness and its lack: A capuchin doesn’t seem to understand the reflection is itself, but it also doesn’t treat the reflection as a stranger.

Diana Reiss, a cognitive psychologist at Hunter College, has seen evidence of self-recognition in dolphins but she is skeptical about cleaner wrasse: “I think for a claim like this, the evidence has to be much stronger.”
Elizabeth Nolan
Scientists also have mixed feelings about the phrase “self-awareness,” for which they don’t agree on a definition. Reiss thinks the mirror test shows “one aspect of self-awareness,” as opposed to the whole cognitive package a human has. The biologists Marc Bekoff of the University of Colorado, Boulder, and Paul Sherman of Cornell University have suggested a spectrum of “self-cognizance” that ranges from brainless reflexes to a humanlike understanding of the self.
Jordan likes the idea of a spectrum, and thinks cleaner wrasse would fall at the lower end of self-cognizance. He points out that moving your tail before it gets stepped on, or scraping a parasite off your scales, isn’t the same as sitting and pondering your place in the universe. Others in the field have supported his contention that the mirror test doesn’t test for self-awareness, he said. “I think the community wants a revision and a reevaluation of how we understand what animals know,” Jordan said.
One thing on which most scientists in the field do agree is that there’s a link between recognizing yourself in a mirror and being social. The species that perform well on mirror tests all live in groups. In an intriguing 1971 study by Gallup and others, chimpanzees born in captivity and raised in isolation failed the mirror test. The chimps that passed the test had been born in the wild, in social groups. Gallup thought this finding supported the ideas of the philosopher George Herbert Mead of the University of Chicago, who said our sense of self is shaped by our interactions with others. “[T]here could not be an experience of a self simply by itself,” Mead wrote in 1934.
Gallup sees a clear connection between recognizing yourself in a mirror, understanding something about others’ states of mind, and even empathizing. “Once you can become the object of your own attention, and you can begin to think about yourself, you can use your experience to infer comparable experiences in others,” Gallup said. No species evolved looking in mirrors, but some of us can see ourselves reflected in our companions.
The Mirror as a Window
The sociality of Asian elephants helped researchers to design a better mirror test in 2006. Joshua Plotnik, a comparative psychologist now at Hunter College in New York City, worked on the study with de Waal and Reiss. In an earlier test that elephants failed, the animals had been in an enclosure, looking at a small mirror. For the revised test, the researchers used an eight-foot-by-eight-foot mirror, so the elephants could see their whole bodies at once. They also let the elephants approach the mirror so that they could stand on their back legs to look behind it or kneel to peer beneath it.

Asian elephants never seemed to pass the mirror test until experimenters made the mirrors large enough to show their whole body alongside other elephants.
Courtesy of Diana Reiss
They also tested elephants in pairs, which “gave them an opportunity to use their partner as a frame of reference,” Plotnik said. When an elephant saw a friend standing in the mirror next to a stranger, she might be able to deduce that the strange elephant was herself.
This time, one of three elephants passed the test. Plotnik said the researchers have promising results from other elephants that haven’t been published yet.
“You have to really try to take the perspective of the animal that you’re working with,” Plotnik said. For example, elephants like being dirty and might not care about marks on their bodies, unlike grooming animals such as chimpanzees. Gorillas groom, but they hate making direct eye contact with others. This might help explain why they haven’t had the same success in the mirror test as chimps or orangutans.
Plotnik thinks future experiments should take an animal’s particular motivations and perceptions into account. For example, the mirror test is visual, but elephants are more interested in what they smell and hear. “Is it fair if you test an animal that’s not a primarily visual animal and they fail?” Plotnik said. “You could make that argument for dogs.”
Dogs are lousy at recognizing themselves in mirrors. But Horowitz recently designed an “olfactory mirror test” for dogs. She found that dogs spent longer sniffing samples of their own urine when it had an extra scent “mark” added to it.
“It’s challenging for us as visual creatures to imagine ourselves into the sensory worlds of nonvisual animals,” Horowitz said. But we have to do it, she thinks, if we want to understand how their minds work.
Reiss, who calls Horowitz a friend, doesn’t think the olfactory mirror study proves dogs can recognize themselves. But she thinks the experiment is an interesting jumping-off point. “How else can we [design] tests to get glimpses into what animals know about themselves?” she said.
As empathetic as Homo sapiens is, we struggle to place ourselves in the viewpoints of other species. Yet this kind of understanding could help us not just to grasp our own place in the world but to protect the world. For example, Plotnik said, a lack of habitat for Asian elephants is driving conflict between the endangered species and humans. “I think a lot of what’s missing from the debate around how to solve this conflict is the elephant’s perspective,” he said. The kind of insight we get from putting pachyderms in front of mirrors might be a helpful window into their minds.
Several mirrors decorate the walls of Gallup’s office, partially hidden behind the towers of papers. It’s just a coincidence, he told me — the mirrors were there when he moved in. He got up from his chair to show me another coincidence born of pareidolia, our mind’s inclination to look for faces. In the black wood grain of his office door, a student had once pointed out the barely discernible face of a gorilla. Gordon traced it for me: an eye, another eye, two nostrils. He directed me to stand in front of the door and move back and forth until I saw it.
Suddenly the light caught the grain in just the right way and the gorilla’s giant face emerged. It stared back at me directly, as a real gorilla never would, like a glimpse straight into the unknowable mind of an animal. “I do see it!” I said. Gallup laughed delightedly. “Isn’t it amazing?” he asked. Then it was gone.

Tuesday, December 11, 2018

Predictions of environmental catastrophe..................

Arguable - with Jeff Jacoby
Monday, December 10, 2018

My own longstanding view is that the worldwide use of fossil fuels — oil, coal, and natural gas — is not something to be deplored, but celebrated. The carbon-based energy on which the modern world runs has generated an almost inconceivable amount of good and made human life far more comfortable, safe, and healthy than at any time in history. I don’t doubt that climate is changing — climate patterns are always in flux — but I am skeptical that climate change will lead to the world-shattering scenarios routinely described by alarmists in the media and elsewhere on the left.

At the same time, if climate change does turn out to pose serious environmental threats, wealthy societies will be best equipped to meet those threats — and without fossil fuels, no society can create the necessary wealth. A billion human beings, mostly in Asia and sub-Saharan Africa, still have no access to electricity ; millions of men, women, and children die prematurely each year because the air in their homes is polluted from burning dirty fuels such as wood and dung. What those populations desperately need is affordable fossil fuels and the higher standard of living they make possible. Only after they pull themselves out of dire poverty will they be able to concentrate on broader environmental goals. That has always been the pattern: Until there is economic progress, there can be no progress on climate.

Meanwhile, the doomsayers continue to whip up terrors of imminent environmental catastrophe.

At the opening of the UN climate change summit now underway in Poland, the celebrity naturalist Sir David Attenborough warned that mankind is on the brink of apocalypse now:

“Right now we are facing a manmade disaster of global scale, our greatest threat in thousands of years: climate change,” he intoned. “If we don’t take action, the collapse of our civilizations and the extinction of much of the natural world is on the horizon.”

Does that sound familiar? Of course it does. It’s the way environmentalists have sounded for decades, always dialing the hysteria up to 11, always pushing the worst-case scenario, always reaching for the most hyperbolic rhetoric.

This shrillness serves a purpose. Back in 1989, the late Stephen Schneider, a professor of environmental biology at Stanford and the founder of the journal Climate Science,contended that such fearmongering was justified as a means of advancing the climate agenda:

“We are not just scientists but human beings as well,” he told an interviewer.
We'd like to see the world a better place, which in this context translates into our working to reduce the risk of potentially disastrous climatic change. To do that we need to get some broad-based support, to capture the public's imagination. That, of course, entails getting loads of media coverage. So we have to offer up scary scenarios, make simplified, dramatic statements, and make little mention of any doubts we might have. . . . Each of us has to decide what the right balance is between being effective and being honest.

And so the scary scenarios and simplified, dramatic forecasts proceed without letup, even as actual facts on the ground consistently fail to bear them out. The Himalayan glaciers were vanishing, the experts declared — wrongly, as it turned out. Sea levels would rise by 20 feet “in the near future,” Al Gore famously warned in 2006 — wrongly, as it turned out. The oceans are warming much faster than previously thought, scientists claimed earlier this year — wrongly, as it turned out.

An international conference of scientists and policymakers predicted in 2005 that the planet was just a decade away from global warming’s point of no return as measured in “widespread agricultural failure,” “increased disease,” and “the death of forests.” All of that, too, turned out to be wrong: The wails of the self-anointed Cassandras notwithstanding, food today is more plentiful than everhuman beings are living longer, and forests are healthier.

Indeed, by almost any objective yardstick you choose — education, homicide rates, famine, clean air, freedom, child labor, infant mortality, leisure time, global poverty, literacy — humanity is thriving as it has never thrived before. And all this progress has coincided not with a dramatic retreat from fossil fuels, but with the steep rise in the world’s reliance on carbon-based energy . Given that juxtaposition, is it really so obvious that eliminating carbon-dioxide emissions from the atmosphere should be mankind’s most important policy goal?

Climate alarmists remind me of immigration alarmists who link undocumented aliens with surging violence and crime. During the decades that illegal immigration was reaching new heights, violence and crime were falling to unprecedented levels. Yet nativist fearmongers, against all the evidence, have kept right on warning that unless unlawful immigration is forcibly halted, more and more Americans will become victims of homicide and rape.

In similar fashion, climate doomsayers continue to insist that unless radical steps are taken to reduce CO2 emissions, life on earth will grow ever more ominous and bleak. In reality, CO2 emissions have been growing for decades — and life on earth has been become safer, richer, cleaner, and healthier.

Energy from fossil fuels has led to dramatic gains in human progress over the past few generations. Isn’t it reasonable to conclude that forcibly suppressing the use of such energy will slow or reverse those gains? Hundreds of thousands of angry French residents certainly seem to think so. Green elites may be gung-ho for the war against carbon. The people know better.

Sunday, December 9, 2018

Science headlines - designed to mislead

First read this:

and then this:

And separately, read this:

Tuesday, November 27, 2018

 ‘Lava-Lamp’ Proteins May Help Cells Cheat Death
With proteins that reversibly self-assemble into droplets, cells may control their metabolism — and harden themselves against harsh conditions.

Hibernating animals put themselves into a largely inert state to survive a hostile winter. Individual cells may do something similar to cope with stressful conditions by solidifying and lowering their metabolism with the help of phase-shifting proteins.
Rachel Suggs for Quanta Magazine

November 26, 2018

“If you make a discovery and at first people tell you that it can’t be right, and then they eventually switch to telling you ‘we knew that all along,’ then you are probably on to something.” It’s a quip that has stuck in Clifford Brangwynne’s mind. For the biophysicist at Princeton University, that is “exactly what happened with our findings on intracellular liquid phases.”
Think of liquids with different properties that don’t really mix but, under specific circumstances, cluster and separate like the shifting blobs in a lava lamp. That phenomenon, also known as liquid-liquid phase separation, was once considered to be an exclusively chemical process. But less than a decade ago, Brangwynne became one of the first to observe it happening inside cells as well, and ever since then, biologists have been trying to learn its significance.
Now scientists are beginning to understand that evolution has tuned certain proteins to act in aggregate like liquids. Through phase separation, they spontaneously self-assemble into dynamic, membrane-free, dropletlike structures that can perform needed tasks in cells.
In this ‘solidified’ state, a cell can survive starvation.
Vasily Zaburdaev, Max Planck Institute for the Physics of Complex Systems
“Somehow, no one thought that this kind of ability of molecules could be harnessed by evolution to achieve functionality or regulate functions,” said Simon Alberti, a biologist at the Max Planck Institute of Molecular Cell Biology and Genetics (MPICBG) in Dresden, Germany. “The focus was on the individual molecule and not on the collective.”
The breakthrough has big implications for our understanding of cellular organization and function, said Vasily Zaburdaev, a biophysicist at the Max Planck Institute for the Physics of Complex Systems, also in Dresden. One of the latest findings is that phase separation allows certain types of cells to cheat death when they are deprived of nutrients or otherwise put under stress. Phase separation enables the cells to turn a large part of their cytoplasm from a liquid to a solid — essentially putting themselves into a hardy condition of stasis until the nutrients return.
Organelles Without Membranes
Nineteenth-century cell biologists coined the term organelle (“little organ” in Latin) to describe the tiny components they saw inside cells. Even then, pioneers in the field such as the American cell biologist Edmund Beecher Wilson suspected that the jellylike cytoplasm filling cells might hold various liquids “like suspended drops … of different chemical nature.” That early insight found little purchase in biology for almost a century, however: Researchers simply assumed that any droplet-shaped cellular organelles must have an encapsulating lipid membrane to prevent their contents from remixing with the cytoplasm.
Still, electron microscopy by researchers such as L. Dennis Smith of the University of California, Irvine, and Edward Mitchell Eddy of the National Institute of Environmental Health Sciences in the 1960s and early 1970s showed that some organelles simply didn’t seem to have any membrane at all. More membraneless structures continued to be found, such as the nucleolus, a dense structure in the cell nucleus. Yet until 2009, how and why they were forming wasn’t clear.

While studying the distribution of membraneless organelles called P granules (green) in the cells of a roundworm, Clifford Brangwynne and his colleagues discovered that they were liquid droplets of protein, not solid masses.
Courtesy of Clifford Brangwynne/Science
That year, when Brangwynne was a young postdoc at MPICBG, he, his colleague Christian Eckmann and his supervisor Tony Hyman saw something unexpected. They were looking at the uneven and inconsistent distribution of organelles called P granules inside cells of the roundworm Caenorhabditis elegans. P granules were widely assumed to be dense pellets of RNA and protein. But Brangwynne, Eckmann and Hyman saw that the granules were not solid at all. Instead, they appeared to be droplets of liquid that were coalescingat times to form bigger drops, like oil in a well-shaken vinaigrette.
“It was a serendipitous discovery,” Brangwynne said. “When we discovered that they were liquids, a number of quantitative measurements that we had been taking suddenly made perfect sense.” It also changed biologists’ understanding of how cells work.
That initial work by Brangwynne, Eckmann and Hyman triggered an avalanche of papers investigating the assembly and dispersal of various cytoplasmic proteins under various conditions. The evidence was getting stronger that cells had evolved a fine-tuned mechanism for organizing some of their internal structure and processes through phase separation — that is, letting proteins self-assemble into structures that could perform distinct functions.
Michael Rosen, a structural biologist and chairman of the biophysics department at the University of Texas Southwestern Medical Center in Dallas, was the first to reproduce this kind of phase separation in the lab with certain proteins and RNA molecules that could coalesce into droplets. Phase separation seemed to give proteins a reversible way to align and separate again when conditions were right.
In some instances, however, researchers are learning that the process is not reversible — and that this failure represents a malfunction of proteins associated with a broad range of diseases, including neurodegenerative disorders and cancer. For example, Zaburdaev observed that several mutant forms of a protein linked to certain diseases showed abnormal phase-separation behavior.  “Instead of forming nice drops, they form very strange hedgehog structures,” he said.
Solidifying for Survival
Intrigued, Zaburdaev and several of his colleagues, including Alberti, decided to check what happens to proteins when cells are subjected to stresses such as falling temperatures and the sudden disappearance of nutrients. The surprising result they uncovered was that phase separation can be part of a cell’s survival mechanism.
The cells’ behavior could be likened to hibernation for bears. The animal lays still in a dormant state for weeks, minimizing its expenditure of energy. At a cellular level, phase separation helps the gelatinous cytoplasm make a protective transition into something more solid. “In this ‘solidified’ state, a cell can survive starvation,” Zaburdaev said.

Clifford Brangwynne, a biophysicist at Princeton University, was named a MacArthur Fellow in 2018 for his pioneering work on identifying the role that phase separation plays in cell regulation.
The researchers studied this phenomenon by depriving yeast and amoebas of nutrients. No nutrients means no energy, and yeast cells need energy to pump protons out of their cytoplasm to maintain the neutral pH essential for their biochemistry. “By starving, cells acidified,” Zaburdaev said. Under the more acidic conditions, proteins readily went from a dissolved state to a more condensed and solid one, and the well-mixed cytoplasm separated into clusters of gelatinous blobs.
Simply by varying the acidity of the cells’ environment, the scientists could induce them to switch into this survival state, even without taking away the cells’ nutrients. The cells could rest this way for hours or even days. “We found that the cells are so rigid that they keep their shape” instead of being deformable, Alberti said. They “transition into a completely different material state.”
When their normal pH was later restored, the cells returned to normal, “dividing and living happily,” Zaburdaev said.
The scientists found that they could also trigger phase separation and solidification by completely dehydrating the yeast through osmosis. Different types of stresses seem to induce slightly different solid states, however. Exactly how that works is “something we don’t yet understand,” Alberti said.
Nevertheless, the survival mechanism that the experiments revealed was very simple, Alberti said: When there is stress, extensive phase separation leads to the rigidification of the entire cytoplasm, and the cell turns off its metabolism, like a hibernating bear settling down for the winter.
The comparison to hibernation may be more than figurative. “The cells of hibernating mammals may also solidify inside,” Alberti said. “It’s a perfect way of dealing with these kinds of environmental changes because solidification comes for free. The energy comes out of the temperature change or the drop in pH.” However, the hypothesis that phase separation is involved still needs to be tested, he said.
Immobilized for Metabolic Control
Most recently, Alberti’s team has been probing the phase-separation response of cytoplasmic proteins to stress at the molecular level. Their particular interest is in how it relates to control over cellular metabolism.
The perfect way to turn something off, Alberti said, is to put it into a solid material that can reversibly immobilize it until it’s needed again. “It’s a way of protecting molecules from damage, but also turning them off, storing them for later use.”
The team found that when a protein has a certain identifiable domain or region, the protein will form easily reversible gels. In the absence of this domain, the protein forms an irreversible type of assembly — permanently removing it from further use.
It’s a way of protecting molecules from damage, but also turning them off, storing them for later use.
Simon Alberti, Max Planck Institute of Molecular Cell Biology and Genetics
In effect, this domain modifies the protein’s phase behavior and keeps it reusable. “The domain provides a new possibility, for that protein to assemble into a benign kind of gel and not something from which you cannot come back,” Alberti said.
In one test-tube experiment, the researchers took a solution containing a single type of protein and lowered its pH. They saw molecules of the protein phase-separate from the solution and form gel-like blobs. Then they brought the pH back to neutral, getting the gels to dissolve, “showing exactly what we saw in cells,” Alberti said.
Such results imply that nature has designed the domain sequences to tune the proteins’ material properties. That’s very beneficial, said Dustin Updike, a biologist at the MDI Biological Laboratory in Bar Harbor, Maine, because it gives cells “a mechanism to respond to abrupt stress, such as heat shock, pH or osmotic stress.” Regulatory mechanisms in cells often work at the genetic level, he explained, meaning that they depend on signals reaching the nucleus, initiating gene transcription and the manufacture of an appropriate enzyme. But those events take time. In contrast, phase separations are very rapid — and can provide an almost immediate response to stress.
Does It Really Matter?
Understanding the precise mechanism and effects of phase separation in cells could be highly relevant for a whole range of big biological challenges — from organ preservation and aging research all the way to space travel, according to Zaburdaev.
Recently, for example, the neuroscientist Pietro De Camilli at Yale University and his colleagues found evidence that phase separation might be involved in the controlled release of neurotransmitters at synapses. It had been observed that vesicles containing neurotransmitters routinely hover in clusters near the presynaptic membrane until they are needed. De Camilli’s team showed that a scaffolding protein called synapsin 1 condenses into a liquid phase, along with other proteins, to bind the vesicles into these clusters. When the synapsin is phosphorylated, the droplet rapidly dissipates and the vesicles are freed to spill the neurotransmitters into the synapse.

Lucy Reading-Ikkanda/Quanta Magazine
It’s still early days, though. When Brangwynne and his colleagues published their paper a decade ago, biologists reacted with either total incredulity or hope for a brand-new direction of research. As Updike noted, it can be hard for cell biologists to go from thinking about a phenomenon in terms of protein aggregation to the more complex problem of liquid phase separation, which requires fluid dynamics to describe.
“To me, Cliff’s work was a huge advance that better described the nature of P granules and what we were seeing,” Updike said, in part because it also explained why P granules had evaded biochemical purification for over two decades. “You can purify a granule, but purifying something more similar to an oil droplet is much more of a challenge.”
As ever more scientific papers back up the concept of phase separation as a cellular mechanism, the number of skeptics keeps on dropping, according to Updike and Brangwynne. Questions still remain, though.
When we discovered that [the P granules] were liquids, a number of quantitative measurements that we had been taking suddenly made perfect sense.
Clifford Brangwynne, Princeton University
“One of the criticisms is that some people say every protein can do this,” Alberti said. It’s common knowledge in science that concentrating proteins under various conditions can sometimes make them solidify or liquefy. “But there was never this idea that this could actually be used by cells, that evolution would actually act and use this ability of biomolecules to achieve a functional change such as down-regulating metabolism.”
Susan Wegmann, a biologist at the German Center for Neurodegenerative Diseases (DZNE), said, “So far it has not been shown that phase separation of proteins actually occurs in a living multicellular organism.” The relevance of phase separation in cells to complex problems in neuroscience and other areas is therefore uncertain. “We and others are trying to make that link, but it is of course very difficult and technically challenging. And if it turns out that protein condensation is linked to human diseases such as neurodegeneration, then we have to find smart ways to interfere in a specific manner with it.”
Tim Mitchison, a professor of systems biology at Harvard Medical School, is skeptical about whether phase separation is a generally important concept in biology. “I haven’t seen much evidence for phase separation in the cytoplasm of cells except for a few specific examples, like stress granules,” he said. The concept has seemingly not found much of an audience outside of cell biology: Many researchers either have not yet heard of phase separation or are ignoring the research.
 “Maybe [they’re] waiting until there is more functional evidence,” Mitchison said. He noted that with enough of the right solvent, almost any protein or RNA can be made to phase separate. “But it’s not clear how much of this is physiologically relevant. I’m totally convinced phase separation is a thing, perhaps especially in RNA-protein biology,” he said. “I’m less clear how general it is.”
Brangwynne seems unperturbed by that reservation. He thinks that some skeptics “are asking very valid questions about what this all means for cell function and dysfunction, which is still not well understood.” Others might still be warming up to the idea of predictive quantitative models, he said, “but that is the future of biology.”