Immune Cell Assassins Reveal Their Nurturing Side

Immune Cell Assassins Reveal Their Nurturing Side

Don’t be misled by the bloodthirsty names of immune cells. Mounting research shows that the cells also fine-tune tissues and help the body heal.

[[Everything is always much more complicated than we thought.]]

https://www.quantamagazine.org/immune-cell-assassins-reveal-their-nurturing-side-20200211/

Macrophages and other cells of the immune system are known as destroyers of bacteria and other pathogens. But research is finding that they also have important jobs in healing and molding the body.

Monique Brouillette

Contributing Writer

Quanta Magazine 

---

February 11, 2020

---

After a heart attack, patients are increasingly often offered the option of stem cell therapy, in which stem cells from their bone marrow are injected into the heart to help it heal. Skeptics, however, point out that solid evidence of the therapy’s benefits is lacking: It’s worked modestly in some animal studies, but its effectiveness is uncertain, and scientists have only been able to guess at how it helps if it does.

Last November, a team of cardiologists set out to provide some clarity on this controversial treatment. Instead, their work found evidence that some immune system cells play a nurturing, healing role that is far removed from their familiar calling as bloodthirsty protectors of the body.

Scientists and doctors from Cincinnati Children’s Hospital led by Jeffery Molkentin first injected stem cells into mice whose hearts had been temporarily deprived of oxygen to mimic a heart attack. Their hearts showed some transient inflammation from the injections, but the mice healed mildly better than those that received a placebo. Still, it was possible that the inflammation, rather than the stem cells, contributed to the improvement: “Any good immunologist will tell you, you need an inflammatory response to get healing,” said Molkentin.

To find out, the team injected a second set of heart-damaged mice with zymosan, a chemical that induces inflammation, instead of stem cells — and they saw the same improvement in heart function. Finally, they injected only bits and pieces of dead cells, which would do nothing more than prompt the immune system to infiltrate the tissue and clean up the debris. Even this, they found, improved heart function.

The protective benefit of the treatment didn’t come from a regenerative effect of the stem cells, the researchers realized. It came instead from the inflammatory immune response, which seemed to set up what Molkentin calls “a second wave of healing.”

Molkentin’s study is the latest in an avalanche of papers over the last decade showing that certain immune cells moonlight in roles unrelated to fighting disease. The phenomenon is not limited to the heart. These immune cells, many of which reside permanently in specific tissues, have been identified as participants in a range of biological activities, including heartbeat regulation, the stabilization of pregnancy, and even brain development.

More Than Elite Assassins

Immune system nomenclature is rife with cell labels suitable for fierce, battle-ready warriors. The Greek name “macrophage,” for example, translates as “big eater” and evokes images of ravenous, rotund cells gobbling up the bits of debris floating around them. “Natural killer” (NK) lymphocytes sound like elite assassins sailing through the bloodstream, breezily picking off disease-causing cells.

“When the names were given to immune cells, it was always in the context of what they did to protect us,” said Muzlifah Haniffa, an immunologist and single-cell genomics researcher at Newcastle University. Haniffa recently published an atlas of the developing blood production system in the human fetus as part of the Human Cell Atlas project, which aims to develop a comprehensive map that catalogs every type of cell in the human body. She believes that the names we gave immune cells may have pigeonholed them and prevented us from understanding their full range of abilities.

Muzlifah Haniffa, an immunologist and single-cell genomics researcher at Newcastle University, found evidence of immune cells’ versatility while she was working on the Human Cell Atlas project. Here, she is isolating immune cells from human blood.

Jooney Woodward, Wellcome CC-BY

Consider the macrophage. It is a type of phagocyte — literally an “eating cell” — described and named in 1882 by the Russian biologist Elie Metchnikoff. Metchnikoff had a hunch that starfish could rid themselves of foreign bodies, so as an experiment, he inserted a rose thorn into a transparent starfish larva. Peering through the primitive microscope on his desk, he watched as hungry phagocytic cells lumbered toward the thorn, surrounded it and gobbled it up.

Metchnikoff didn’t immediately assume that these phagocytes are specialized for disease fighting and pathogen removal alone. Trained as an evolutionary biologist, he knew that simple organisms generally had relatively unspecialized cells. He therefore hypothesized that phagocytes performed a variety of other basic biological jobs that molded and maintained the healthy function of normal tissues for the animal.

But immunology was a highly contentious field in those days, and Metchnikoff, who was considered fiery and difficult, wasn’t taken seriously at first by his peers. Many of them believed instead that antibodies and other substances in the blood plasma, not cells, were the primary agents of immunity. It was years before subsequent research substantiated Metchnikoff’s cellular immunology concepts and he was recognized for his work on the macrophage, which quickly became one of the immune system’s star players. (In 1908 he and Paul Ehrlich shared a Nobel Prize for their separate studies of the basis of immunity.)

The next century brought some of the greatest advances in medicine and immunology, and amid the exuberant fanfare for these discoveries, the nonimmunological roles that Metchnikoff had suggested for the macrophage faded into the background. But now, because of advances in immunology and single-cell RNA sequencing, these roles are coming back into focus.

The Heart of the Matter

Metchnikoff would probably have found Molkentin’s heart study validating. The cells that delivered the healing boost to the hearts of the mice are a subset of what are called tissue-resident macrophages.

Unlike the macrophages that circulate in the blood and look for pathogens, these cells migrate into the heart during embryonic development and remain there for the rest of their lives. Over the past decade or so, evidence has accumulated that they perform a variety of tasks, such as aiding in the maturation of coronary vasculature and maintaining a proper heartbeat.

“They’re doing activities that are not normally associated with immunology, such as helping tissues reshape and change in response to stresses, or repair and regenerate, or even conduct electricity,” said Kory Lavine, an assistant professor of medicine at the Washington University School of Medicine in St. Louis.

Lavine gained some of the first insights into the origins of tissue-resident macrophages in the heart while studying sex-mismatched heart transplants — cases in which the heart of a female donor went to a male recipient or vice versa. In biopsied tissues, he was able to see that the macrophages in the heart were from the original donor, which meant that they stayed in the heart for the lifetime of the organ.

Lucy Reading-Ikkanda/Quanta Magazine

In 2014, Lavine published a paper showing that when an embryonic heart is damaged, these cells can repair and regenerate the tissue. Then in 2016, his group presented evidence that CCR macrophages in the heart actively sculpt the mature layout of the organ’s blood vessels. During embryonic development, blood vessels are laid down in the heart before the blood begins circulating. Once blood flow starts, however, vessels are weeded out so that only the best routes are maintained. Lavine found that CCR macrophages are integral to this process.

A few years ago, research was published showing that macrophages are abundant throughout an electrically conductive region of the heart known as the atrioventricular (AV) node, which connects the heart chambers called the atria and ventricles in mice and humans. The macrophages in the AV are elongated, with projections that extend their reach. When scientists bred mice that lacked these cells, they found significant delays in the conduction of electrical signals through the AV node. When they chemically blocked the activity of these macrophages, they witnessed “AV block,” an impairment of the electrical signal traveling from the atria to the ventricles.

How the macrophages aid conduction is still unclear, but it appears that their presence primes the heart cells’ firing signals to travel more quickly. The finding has scientists now looking into whether abnormalities in heart macrophages can lead to arrhythmias in humans.

The heart is not unique. In fact, most tissues and organs in the body have their own cache of tissue-resident macrophages. They have been found to carry out key functions, as if they were a part of the organ in which they reside. In the brain, for example, they remove axons and aid in the pruning of synapses during development. Those in adipose tissue help to regulate body heat. Macrophages have even been found to aid in the recycling of iron in the spleen and liver.

From Killers to Builders

If macrophages are the greatest multitaskers in the immune system, then natural killer cells are the most poorly named. NK cells were first identified for their ability to destroy tumor cells on contact by blasting them with chemicals that induce apoptosis or cellular suicide. They are powerful players in the immune system’s defensive arsenal.

But almost from the time of their discovery, scientists have noted that subpopulations of these NK cells reside full time in the liver, skin, kidney and uterus. And unlike their deadly cousins, these cells don’t kill.

Two natural killer (NK) cells (yellow) attack a cancer cell (red) in this artificially colored micrograph. NK cells took their name from how avidly they attacked abnormal and infected cells, but some of them also help to ensure the blood supply to the uterus during pregnancy.

Eye of Science/Science Source

In the uterus, NK cells make up 70% of the white blood cells during the first half of pregnancy. Early experiments in mice showed that when these uterine NK cells were isolated and pitted against mouse lymphoma cells — a natural adversary — they lacked the cancer-fighting powers of their immune system brethren. This revelation prompted scientists to ask what, exactly, the NK cells were doing there.

Early work by the pioneering scientist Anne Croy of Queen’s University pointed to an answer. The Canadian scientist, who was trained as a veterinarian, studied pregnancy and the immune system in mice. She noticed that these cells tended to congregate at the very edge of the maternal-fetal interface in pregnant mice, where the placenta meets up with the lining of the uterus. That fact led her to hypothesize that NK cells were involved in the remodeling of blood vessels in the uterus.

Any good immunologist will tell you, you need an inflammatory response to get healing.

Jeffery Molkentin, Cincinnati Children’s Hospital

During pregnancy, fetal cells “remodel” maternal arteries in the uterus so that they will no longer respond to the mother’s fight-or-flight signals. Imagine a pregnant mouse being chased by a cat (or a pregnant woman fleeing a tiger): The rush of adrenaline she experiences makes the blood vessels to her organs shrink and shunts blood to her muscles to aid her escape. But those changes could be detrimental and possibly lethal for a fetus in her uterus by depriving it of blood and the oxygen and nutrients it delivers. Evolution has invented this remodeling mechanism as protection against that physiological response to a crisis.

In a set of landmark experiments, Croy showed that uterine NK cells control the vascular changes that happen during pregnancy by means of substances they secrete from their granules. In NK cells that circulate throughout the body, similar granules are normally filled with an assassin’s cocktail of toxins, but in the uterine NK cells, they carry growth factors and chemokines (messenger molecules) that attract other cells. Once released, these molecules attract endothelial cells and trophoblasts, which are fetal cells from the placenta that can also remodel the blood vessels in the uterus.

“Instead of being killers, they are really builders,” Francesco Colucci, an immunologist at the University of Cambridge, said of the NK cells. Colucci published research showing that uterine NK cells regulate the extent to which fetal cells can invade the uterus, and he is now using RNA sequencing techniques to characterize different types of uterine NK cells (as described in a paper he published on this in Nature Communications in late January).

“Natural killer cells are actually playing a role in supporting healthy pregnancies, but it has got nothing to do with killing,” said Haniffa. In 2018, Haniffa and colleagues published a map of the maternal-fetal interface with single-cell resolution that revealed the gene activity of these NK cells, further elucidating their dexterity.

Mapping Out a Theory

Natural killers and macrophages are some of the best-characterized examples of multitasking immune cells, but there are many more. Regulatory T cells, or Tregs, a subset of the T lymphocytes, modulate the immune response. But they have been shown to be involved in other processes as diverse as hair growth in the skin and insulin regulation in fat tissue. Innate lymphoid cells — lymphocytes that do not express the same antigen receptors as B and T cells — are involved in metabolism and even the healthy function of the nervous system. Also, combinations of these cells have been observed in crosstalk with stem cells, helping to maintain the regeneration of tissues that constantly turn over like the skin and the intestinal lining.

When the names were given to immune cells, it was always in the context of what they did to protect us.

Muzlifah Haniffa, Newcastle University

“For a long time, people thought of the immune system as basically what’s in your blood,” Haniffa said. “Then they realized that your immune system doesn’t just exist in your blood, it exists in every tissue.” Moreover, the immune system cells embedded in tissues and even among your microbiota are in communication. The cells in the brain called microglia have traditionally not been recognized as part of the immune system, but they consume cellular debris like macrophages. They have also been shown to respond to signals from gut microbiota. “We should view the immune system as a bit like a matrix that exists in the entire body,” Haniffa said.

Aviv Regev, a computational biologist at the Broad Institute who helped launch the Human Cell Atlas, echoes these thoughts. You can think of immune cells as one of the major sensing systems in the body along with the nervous system, she said: “We often thought of [immune cells] in narrower functional terms, but we increasingly realize that their roles are broader.”

Haniffa wants to explore the immune system’s role in embryonic development. Last October, she and her colleagues published a study in Nature that detailed the gene activity in individual cells from the developing blood system and immune system of a human embryo. They profiled more than 200,000 cells from the embryonic yolk sac, liver, skin and kidneys at various points between the seventh and 17th weeks of development. The work was a milestone because it was the first effort to map the development of the human immune and blood systems, including red and white blood cells, with single-cell resolution.

According to Shruti Naik, a stem cell biologist and single-cell researcher at New York University, “this paper has huge implications” for our “understanding of not just human gestation but inborn errors in immunity and developmental disorders.”

Haniffa found that a trove of immune cells was present very early in human development, which she thinks could signify that the cells have an important part to play in the development of tissues. She points out that mast cells, which are traditionally involved in allergic reactions, show up in the yolk sac during the first trimester. Why would they be there when allergy is not typically an issue for embryos? But mast cells have been also implicated in blood vessel development in cancer, so Haniffa wonders whether they might have something to do with healthy blood vessel formation too.

Regev notes that more research is still needed to elucidate the functions of mast cells at various stages of development. But to her, “the possibility that the cells that arise early have more diverse functions in developing tissue is a very compelling hypothesis.”

Wise Oysters, Galloping Sea Stars, and More

Wise Oysters, Galloping Sea Stars, and More: Biological Marvels Keep Coming

Evolution News | @DiscoveryCSC

January 28, 2020, 12:34 PM

https://evolutionnews.org/2020/01/wise-oysters-galloping-sea-stars-and-more-biological-marvels-keep-coming/

Strong theories in science require fewer auxiliary hypotheses when new discoveries come to light. Design advocates can gain confidence when discoveries continue to illustrate the core principles of intelligent design, like irreducible complexity, meaningful information, and hierarchical design, while undermining the blind, gradualistic principles of Darwinian evolution. Here are some recent illustrations.

“Pearls of Wisdom”

That’s the headline on news from the Okinawa Institute of Science and Technology, where the only thing said about evolution is that “From a genetic and evolutionary perspective, scientists have known little about the source of these pearls” in the Japanese pearl oyster, Pinctada fucata. By implication, don’t look for pearls of wisdom from evolutionary theory. The research published in Evolutionary Applications only concerns genetic variations within the species and the geographic distributions of isolated populations. If it helps conserve these oysters with their magnificent mother-of-pearl nacre — the envy of materials scientists — well, it’s wise to keep jewelry makers in business. Design scores as evolution fumbles.

Flight Feathers

Another level of design has been uncovered in bird feathers. In Science Magazine, Matloff et al. discuss “How flight feathers stick together to form a continuous morphing wing.” Pigeon and dove wing feathers spread out from their folded position into beautiful fans, as most people know. But how do birds prevent gaps from opening up between individual wing feathers? The team found a combination of factors at work. 

Birds can dynamically alter the shape of their wings during flight, although how this is accomplished is poorly understood. Matloff et al. found that two mechanisms control the movement of the individual feathers. Whenever the skeleton moves, the feathers are redistributed passively through compliance of the elastic connective tissue at the feather base. To prevent the feathers from spreading too far apart, hook-shaped microstructures on adjacent feathers form a directional fastener that locks adjacent feathers.

Notice that the muscles, bones, and connective tissue inside the skin work in synergy with the exterior hooks on the wings. Using a robot mimic, the team found that (1) the muscles for each feather keep the angle just right to spread them into a fan arrangement, and (2) the barbules snap together quickly to create a lightweight, flexible surface without breaks. The barbules can quickly detach like the hook-and-loop materials we are all familiar with.

This clarifies the function of the thousands of fastening barbules on the underlapping flight feathers; they lock probabilistically with the tens to hundreds of hooked rami of the overlapping flight feather and form a feather-separation end stop. The emergent properties of the interfeather fastener are not only probabilistic like bur fruit hooks, which inspired Velcro, but also highly directional like gecko feet setae — a combination that has not been observed before.

Rapid opening and closing of wings makes a little bit of noise a bit like Velcro does, explaining the din when a flock of geese takes off. Interestingly, the researchers found that night flyers like owls, which need silent wings as they hunt, “lack the lobate cilia and hooked rami in regions of feather overlap and instead have modified barbules with elongated, thin, velvety pennualue” that produce relatively little noise. Otherwise, this amazing complex mechanism works at scales all the way from a tiny 40-gram Cassin’s hummingbird to the 9000-gram California condor. What’s an evolutionist going to say about this ingenious mechanism? Once upon a time, a dinosaur leaped out of a tree and… died.

Distributed Running

Sea stars, seen in time-lapse videos, appear to “run” across the sea floor, bouncing as they go:

Scientists at the University of Southern California wondered how the echinoderms do it without a brain or centralized nervous system. The undersides of sea stars are composed of hundreds of “tube feet” which can move autonomously. How do they engage in coordinated motion? 

The answer, from researchers at the USC Viterbi School of Engineering, was recently published in the Journal of the Royal Society Interface: sea star[s] couple a global directionality command from a “dominant arm” with individual, localized responses to stimuli to achieve coordinated locomotion. In other words, once the sea star provides an instruction on which way to move, the individual feet figure out how to achieve this on their own, without further communication.

That would be a cool strategy for robots, the engineers figure. In fact, they built a model based on sea star motion, and show both the animal and robot movement side by side in the video above. No other animal movement seems to use this strategy. 

“In the case of the sea star, the nervous system seems to rely on the physics of the interaction between the body and the environment to control locomotion. All of the tube feet are attached structurally to the sea star and thus, to each other.”

In this way, there is a mechanism for “information” to be communicated mechanically between tube feet. 

Even though one of the team members was a “professor of ecology and evolutionary biology,” he seemed to rely more on the engineers than on Darwin. 

Understanding how a distributed nervous system, like that of a sea star, achieves complex, coordinated motions could lead to advancements in areas such as robotics. In robotics systems, it is relatively straightforward to program a robot to perform repetitive tasks. However, in more complex situations where customization is required, robots face difficulties. How can robots be engineered to apply the same benefits to a more complex problem or environment?

The answer might lie in the sea star model, [Eva] Kanso said. “Using the example of a sea star, we can design controllers so that learning can happen hierarchically. There is a decentralized component for both decision-making and for communicating to a global authority. This could be useful for designing control algorithms for systems with multiple actuators, where we are delegating a lot of the control to the physics of the system — mechanical coupling — versus the input or intervention of a central controller.”

Once again, the search to understand a design in nature propels further research that can aid in the design of products for human flourishing.

Quickies:

Grasshoppers don’t faint when they leap. Why? Arizona State wants to know how the insects keep their heads while taking off and landing in all kinds of different orientations. Gravity should be making the blood slosh around, causing dizziness and disorientation, but it doesn’t. Apparently it has something to do with the distribution of air sacs that automatically adjust to gravity, keeping the hemolymph (insect blood) from rapidly moving about in the head and body. “Thus, similar to vertebrates, grasshoppers have mechanisms to adjust to gravitational effects on their blood,” they say.

Cows know more than their blank stares indicate. Articles from Fox News and the New York Post had fun with a “shocking study” about “cowmoooonication” published in Nature’s open-access journal Scientific Reports. Experiments with 13 Holstein heifers seem to indicate that they all know each other’s names, and can learn where food is located, and more, from each other’s “individual moos.” They regularly share “cues in certain situations and express different emotions, including excitement, arousal, engagement and distress.” Other scientists are praising young researcher Ali Green, whose 333 recordings and voice analysis studies of moooosic is like “building a Google translate for cows.”

Design appears everywhere scientists look when they take their Darwin glasses off. For quality research that actually does some good for people, join the Uprising.

Photo credit: Japanese pearl oyster, Pinctada fuc

The Real Butterfly Effect

The Real Butterfly Effect

Posted by Sabine Hossenfelder at 1:02 PM

http://backreaction.blogspot.com/2020/01/the-real-butterfly-effect.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+blogspot%2Fermku+%28Backreaction%29

If a butterfly flaps its wings in China today, it may cause a tornado in America next week. Most of you will be familiar with this “Butterfly Effect” that is frequently used to illustrate a typical behavior of chaotic systems: Even smallest disturbances can grow and have big consequences.

 The name “Butterfly Effect” was popularized by James Gleick in his 1987 book “Chaos” and is usually attributed to the meteorologist Edward Lorenz. But I recently learned that this is not what Lorenz actually meant by Butterfly Effect.

I learned this from a paper by Tim Palmer, Andreas Döring, and Gregory Seregin called “The Real Butterfly Effect” and that led me to dig up Lorenz’ original paper from 1969.

Lorenz, in this paper, does not write about butterfly wings. He instead refers to a sea gull’s wings, but then attributes that to a meteorologist whose name he can’t recall. The reference to a butterfly seems to have come from a talk that Lorenz gave in 1972, which was titled “Does the Flap of a Butterfly’s Wings in Brazil set off a Tornado in Texas?”

The title of this talk was actually suggested by the session chair, a meteorologist by name Phil Merilees. In any case, it was the butterfly that stuck instead of the sea gull. And what was the butterfly talk about? It was a summary of Lorentz 1969 paper. So what’s in that paper?

In that paper, Lorenz made a much stronger claim than that a chaotic system is sensitive to the initial conditions. The usual butterfly effect says that any small inaccuracy in the knowledge that you have about the initial state of the system will eventually blow up and make a large difference. But if you did precisely know the initial state, then you could precisely predict the outcome, and if only you had good enough data you could make predictions as far ahead as you like. It’s chaos, alright, but it’s still deterministic.

Now, in the 1969 paper, Lorenz looks at a system that has an even worse behavior. He talks about weather, so the system he considers is the Earth, but that doesn’t really matter, it could be anything. He says, let us divide up the system into pieces of equal size. In each piece we put a detector that makes a measurement of some quantity. That quantity is what you need as input to make a prediction. Say, air pressure and temperature. He further assumes that these measurements are arbitrarily accurate. Clearly unrealistic, but that’s just to make a point.

How well can you make predictions using the data from your measurements? You have data on that finite grid. But that does not mean you can generally make a good prediction on the scale of that grid, because errors will creep into your prediction from scales smaller than the grid. You expect that to happen of course because that’s chaos; the non-linearity couples all the different scales together and the error on the small scales doesn’t stay on the small scales.

But you can try to combat this error by making the grid smaller and putting in more measurement devices. For example, Lorenz says, if you have a typical grid of some thousand kilometers, you can make a prediction that’s good for, say, 5 days. After these 5 days, the errors from smaller distances screw you up. So then you go and decrease your grid length by a factor of two.

Now you have many more measurements and much more data. But, and here comes the important point: Lorenz says this may only increase the time for which you can make a good prediction by half of the original time. So now you have 5 days plus 2 and a half days. Then you can go and make your grid finer again. And again you will gain half of the time. So now you have 5 days plus 2 and half plus 1 and a quarter. And so on.

Most of you will know that if you sum up this series all the way to infinity it will converge to a finite value, in this case that’s 10 days. This means that even if you have an arbitrarily fine grid and you know the initial condition precisely, you will only be able to make predictions for a finite amount of time.

And this is the real butterfly effect. That a chaotic system may be deterministic and yet still be non-predictable beyond a finite amount of time .

This of course raises the question whether there actually is any system that has such properties. There are differential equations which have such a behavior. But whether the real butterfly effect occurs for any equation that describes nature is unclear. The Navier-Stokes equation, which Lorenz was talking about may or may not suffer from the “real” butterfly effect. No one knows. This is presently one of the big unsolved problems in mathematics.

However, the Navier-Stokes equation, and really any other equation for macroscopic systems, is strictly speaking only an approximation. On the most fundamental level it’s all particle physics and, ultimately, quantum mechanics. And the equations of quantum mechanics do not have butterfly effects because they are linear. Then again, no one would use quantum mechanics to predict the weather, so that’s a rather theoretical answer.

The brief summary is that even in a deterministic system predictions may only be possible for a finite amount of time and that is what Lorenz really meant by “Butterfly Effect.”

Glial Brain Cells Reveal Hidden Powers

Glial Brain Cells, Long in Neurons’ Shadow, Reveal Hidden Powers

Elena Renken

https://www.quantamagazine.org/glial-brain-cells-long-in-neurons-shadow-reveal-hidden-powers-20200127/

[[Gee - scientists are still studying E. elegans with 302 neurons and  have not explained all of its function. And our brains have approximately 80b [80,000,000,000] neurons, so understanding the human brain seems to be just a  little beyond our present reach. But there are another 80b glial cells in the brain and they too have a wide variety of functions. So now it is 160b to 302. Maybe it will take a little longer than we thought to figure out how our brains work....]]

The sting of a paper cut or the throb of a dog bite is perceived through the skin, where cells react to mechanical forces and send an electrical message to the brain. These signals were believed to originate in the naked endings of neurons that extend into the skin. But a few months ago, scientists came to the surprising realization that some of the cells essential for sensing this type of pain aren’t neurons at all. It’s a previously overlooked type of specialized glial cell that intertwines with nerve endings to form a mesh in the outer layers of the skin. The information the glial cells send to neurons is what initiates the “ouch”: When researchers stimulated only the glial cells, mice pulled back their paws or guarded them while licking or shaking — responses specific to pain.

This discovery is only one of many recent findings showing that glia, the motley collection of cells in the nervous system that aren’t neurons, are far more important than researchers expected. Glia were long presumed to be housekeepers that only nourished, protected and swept up after the neurons, whose more obvious role of channeling electric signals through the brain and body kept them in the spotlight for centuries. But over the last couple of decades, research into glia has increased dramatically.

“In the human brain, glial cells are as abundant as neurons are. Yet we know orders of magnitude less about what they do than we know about the neurons,” said Shai Shaham, a professor of cell biology at the Rockefeller University who focuses on glia. As more scientists turn their attention to glia, findings have been piling up to reveal a family of diverse cells that are unexpectedly crucial to vital processes.

It turns out that glia perform a staggering number of functions. They help process memories. Some serve as immune system agents and ward off infection, while some communicate with neurons. Others are essential to brain development. Far from being mere valets to neurons, glia often take leading roles in protecting the brain’s health and directing its development. “Pick any question in the nervous system, and glial cells will be involved,” Shaham said.

More Than Just ‘Glue’

Glia take many forms to perform their specialized functions: Some are sheathlike, while others are spindly, bushy or star-shaped. Many tangle around neurons and form a network so dense that individual cells are hard to distinguish. To some early observers, they didn’t even look like cells — they were considered a supportive matrix within the skull. This prompted the 19th-century researcher Rudolph Virchow to dub this non-neuronal material “neuroglia,” drawing on the Greek word for glue.

In this magnified image of brain tissue, neurons (blue) are surrounded by large numbers of glial cells, including astrocytes (red) and oligodendrocytes (green).

One reason glia were given such short shrift was that when researchers first began staining nervous system tissue, their methods revealed the convoluted shapes of neurons but rendered only select glia visible. Santiago Ramón y Cajal, who is credited with the discovery of neurons and widely regarded as the founder of neuroscience, illustrated one subtype of glia but lumped the rest together as “the third element.” His focus on neurons set the stage for the burgeoning field of euroscience but shoved the glia behind the curtains.

In addition, some glia are challenging to study because their fates are so entwined with those of neurons that it’s hard to learn about them separately. If researchers try to learn about the glia’s functions by knocking them out and observing the effects, the neurons they support will die along with them.

But the revolution in cell biology techniques in recent decades has generated an arsenal of tools offering greater access to glia, Shaham said. Advances in live imaging, fluorescent labeling and genetic manipulation are revealing the breadth of glia’s forms and functions.

Microglia Reveal Their Versatility

Several cell types are contained within the umbrella category of glia, with varied functions that are still coming to light. Oligodendrocytes and Schwann cells wrap around nerve fibers and insulate them in fatty myelin sheaths, which help to confine the electrical signals moving through neurons and speed their passage. Astrocytes, with their complex branching shapes, direct the flow of fluid in the brain, reshape the synaptic connections between neurons, and recycle the released neurotransmitter molecules that enable neurons to communicate, among other jobs.

The highly versatile microglia seem to serve a variety of functions in the brain, such as removing cellular debris and determining which synapses between neurons are unnecessary.

But the cells that have been the subjects of an especially strong spike in interest over the last decade or so are the ones called microglia.

Microglia were originally defined in four papers published in 1919 by Pío del Río-Hortega, but the study of them then stalled for decades, until finally picking up in the 1980s. Microglia research is now growing exponentially, said Amanda Sierra, a group leader at the Achucarro Basque Center for Neuroscience. The work is exposing how microglia respond to brain trauma and other injuries, how they suppress inflammation, and how they behave in the presence of neurodegenerative diseases. The cells “really are at the edge between immunology and neuroscience,” Sierra said.

Guy Brown, a professor of biochemistry at the University of Cambridge, was first drawn to microglia by their star shapes and dynamic movements, but it was their behavior that held his attention. In recent years, microglia have been found to mimic the macrophages of the immune system by engulfing threats to the brain such as cellular debris and microbes. Microglia also seem to go after obsolete synapses. “If you live-image them, you can see them eating neurons,” Brown said.

Some of these active functions are shared with other types of glia as well. Astrocytes and Schwann cells, for example, may also prune synaptic connections. But despite the commonalities among different subsets of glia, researchers are starting to realize that there’s little to unify glial cells as a group. In fact, in a 2017 article, scientists argued for discarding the general term “glia” altogether. “They don’t have an enormous amount in common, different glial cells,” Brown said. “I don’t think there’s much future to glia as a label.”

---

Ben Barres, a neuroscientist who championed glia research and passed away in 2017, considered deeper investigations of glia essential to the advance of neurobiology as a field. Others have taken up that cause as well. To them, the historical emphasis on neurons made sense at one time: “They are the ones who process the information from the outside world into our memories, our thinking, our processing,” Sierra said. “They are us.” But now the importance of glia is clear.

Neurons and glia cannot function independently: Their interactions are vital to the survival of the nervous system and the memories, thoughts and emotions it generates. But the nature of their partnership is still mysterious, notes Staci Bilbo, a professor of psychology and neuroscience at Duke University. Glia are gaining a reputation for the complexity long attributed to neurons, but it’s still unclear whether one cell type primarily directs the other. “The big unknown in the field is: Who is driving the response?” she said.