Fourteen years ago, I was paralyzed with Guillain-Barre syndrome, a rare autoimmune disease that left me unable to walk for nearly a year. Mine was an unusual case in its severity but the pathology of the condition is well understood: As in all autoimmune diseases, my immune system was behaving like an army gone rogue. Instead of judiciously protecting my body, my white blood cells were mistakenly destroying the myelin sheaths that coat my nerves, causing the nerve-muscle interconnections that I needed to stand and walk, or simply wriggle my feet, to go dark.
Excerpted from The Angel and the Assassin: The Tiny Brain Cell That Changed the Course of Medicine by Donna Jackson Nakazawa. Buy on Amazon.
I began to think of these overactive immune cells as being like Pac-Men: 1980s video game characters crazily eating away at the crucial nerve connections that made my physical body mine—strong, capable, dependable me. My neurologist hoped that regular intravenous therapies would help to reboot my immune system so that my overvigilant white blood cells would cease their attack and my nerves would begin to regenerate on their own—perhaps not all of them, but enough to allow me to live a good life. In time, he turned out to be right. The human body can be miraculous that way.
Still, I had questions that my medical team could not answer. After losing the use of my legs, I’d also experienced some distinct and disquieting cognitive changes. For one thing, although I’d always been pretty even-keeled, I found myself facing a black-dog depression. The feeling was at times so oppressive that when I read Harry Potter aloud to my young children, I felt as if I’d been attacked by the “dementors,” those dark, sky-drifting ghouls who introduce a cloud of despair that steals a person’s happy thoughts and replaces them with bad ones.
Then, there were the memory problems. My six-year-old daughter would ask for help with first-grade math and I’d find my brain stuttering just to add seven and eight. Or I’d reach down to tie her shoes and find myself staring dumbly at the laces, struggling to remember how, exactly, it was done. My mood, memory, clarity of mind, word recall were different—my brain did not feel like my own. I could not shake the feeling that, just as my body had been altered, something physical had also shifted in my brain.
I was not, of course, the only patient with inflammation in my body who also complained of a change in mental well-being. Such patient stories had even led some epidemiologists to begin to associate inflammatory diseases to brain-related symptoms. In 2008, researchers reported that patients with multiple sclerosis were several times more likely to suffer from depression and bipolar disorder. A 2010 analysis of 17 studies showed that 56 percent of patients with lupus—which manifests in inflammation in the organs of the body—reported cognitive or psychiatric symptoms. Patients recently hospitalized with bacterial infections were 62 percent more likely to develop depression, bipolar disorder, and memory issues.
Several case studies in the scientific literature showed a curious link between disorders in the bone marrow—where most of our body’s immune cells are “born”—and schizophrenia. In one case study, a patient who received a bone marrow transplant from his brother, who suffered from schizophrenia, also developed schizophrenia a few weeks after the transplant. In another, a young man with schizophrenia and acute myeloid leukemia received a bone marrow transplant from a healthy donor, and both his cancer and his schizophrenia resolved.
Yet, as compelling as this research was, it just did not make scientific sense at that time that being sick in the body could be connected to, much less cause, illness in the brain. The philosopher Descartes first put forth this concept known as mind-body dualism—the idea that the workings of the brain are divorced from the mechanisms of the body—during the Enlightenment. This ruling out of a biological link between immune health and brain function was due, however, more to the work of 19th-century scientists than early philosophers. At the base of the brain sits a dense constellation of cells known as the blood-brain barrier. These cells are so tightly packed around the blood vessels that lead to the brain that they block immune cells from the bloodstream from ever rising into the brain. The inviolate nature of the blood-brain barrier has long been seen as ample proof that the brain is off-limits to the body’s immune system—or “immune-privileged.” Since the first modern day med school textbooks were penned, they’ve taught a simple anatomical fact: The immune system rules every bodily organ except the brain, and physicians have operated under the assumption that body and brain function as church and state entities.
But a novel understanding of the form and function of a long-overlooked cell in the brain, called microglia, has recently challenged that assumption.
Beth Stevens had been curious about microglial cells, if only tangentially, since starting her career. In 1993, Stevens worked for a researcher named R. Douglas Fields at the National Institutes of Health, who was studying the firing pattern of neurons in the brain, and how that affected development. Neurons, at the time, were the undisputed flashy darlings of the scientific world; seen as the A-team players of our mood, our mental health, our memory, responsible for creating the trillions of synaptic connections needed for us to think, feel, remember, learn, and love, for all of our intuitions and perceptions. The small family of four glial cells—astrocytes, Schwann cells, oligodendrocytes and microglia—made up the B-team; they catered to the needs of neurons the way an entourage caters to the whims of a movie star.
One of Stevens’ frustrations in her first lab job had to do with the fact that microglial cells would contaminate her petri dishes. “Microglia ruined my experiments,” she says. “They’d get in my cultures when I was trying to look at other cells. And I’d be groaning to myself, ‘Oh no no no, here are these annoying little microglia again.’” But Stevens was struck by the fact that these annoying little cells also made up a really big part of the brain’s population—as much as one-tenth of our brain cells. “It was such a mysterious part of neuroscience.”
First noted and named in the 1920s by Pio del Rio-Hortega, microglia were tiny (hence the “micro” in their name) and seemed to have one simple job: If a neuron died, microglia carted it away. They were dubbed as the “housekeeper cells” of the brain.
Stevens did her post doc at Stanford, in the lab of Ben Barres, arguably the leading glial researcher in the world, between 2004 and 2008. In 2005, fellow researcher at Barres’s lab, Axel Nimmerjahn, gave a talk during which he showed one of the first imaging studies that offered high resolution images of microglial cells, enlarging them to gigantic visual projections in real time.
“Suddenly we had this new visual tool that allowed us to watch microglia in action,” Stevens tells me when I visit her in her lab in Boston, Massachusetts. (She’s now an associate professor of neurology at Boston Children’s Hospital and Harvard.) She gets up from her desk and scoots her chair closer to a computer terminal to pull up early footage of microglia. She leans forward and points to the images of swirling microglia dancing in the brain with the eraser end of her pencil. The images remind me of those I’ve seen of the Milky Way—if all the stars were glowing green and whirling in large, purposeful clusters swimming against a black sky.
“The first time I saw this I sat there stunned,” Stevens says. “I could see all these bright green microglial cells that almost appeared to be moving through the brain. I kept thinking, Whoa, what are these little cells doing? They’re so dynamic! They’re everywhere! No other cell in the brain can move like this. How could we have ignored these cells for so long? I’d never seen another cell move so purposefully. Microglia were constantly surveying every area of the brain, just checking things out: How is that neuron doing? How is that synapse doing? How’s that circuit? Oh shoot, something is going on there—let’s head over and see what’s happening!”
When enlarged under a high-resolution microscope, microglia resemble elegant tree branches with many slender limbs. As they pass by neurons, microglia extend and retract their tiny arm-like protrusions, tapping on each neuron as if to inquire, Are we good here? All okay? Or not okay?—as a doctor might palpate a patient’s abdomen, or check reflexes by tapping on knees and elbows.
Back in 2004, Barres and Stevens were examining how synapses originally come to be pruned to form a healthy brain during early, normal development. They’d recently discovered that immune molecules known as complement were sending out “eat me” signals from some brain synapses, and these synapses—tagged with a kind of “kiss of death” signage—were destroyed. Think of the way you click and tag emails that you want deleted from your inbox. Your email server’s software recognizes those tags, and when you click on the Trash icon, bing, they’re gone. That’s similar to what Stevens and Barres were seeing happen to brain synapses that were tagged by complement. They disappeared.
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What they described happening in the brain, which they reported in the journal Cell in 2007, echoed a similar process that was well-understood to happen in the body. When a cell dies in a bodily organ, or if the body’s immune system senses a threatening pathogen, complement molecules tag those unwanted cells and invaders for removal. Then, a type of white blood cell known as macrophages—Greek for “big eaters”—recognizes the tag, engulfs the cell or pathogen, and destroys it. In the body, macrophages play a role in inflammation as well as in autoimmune diseases like rheumatoid arthritis and Guillain Barre. When activated, they can mistakenly go too far in their effort to engulf and destroy pathogens and spew forth a slew of inflammatory chemicals that begin to do harm to the body’s own tissue.
Stevens and Barres weren’t sure what was eating away at these tagged synapses, causing them to disappear in the brain, but Stevens had a hunch that it might have something to do with microglia.
“We could see that when microglia sensed even the smallest damage or change to a neuron, they headed, spider-like, in that neuron’s direction, then they drew in their limbs and morphed into small, amoeba-like blobs,” Stevens says. Soon after, those same synapses disappeared. Poof.
Could microglia be the culprit at the center of it all, the macrophage corollary in the brain, responding to “eat me” signals and pruning the brain’s circuitry during development? “And what if this process was not only taking place in utero?” Stevens wondered, when she first saw microglia behaving this way. “What if it was also being mistakenly turned back on again later in life, during the teen years, or in adulthood—only now it’s a bad thing and microglia are sometimes mistakenly engulfing and destroying healthy brain synapses too?”
“You can imagine how you could have too many synapses, or not enough synapse connectivity,” Stevens says, her hands spreading wide with excitement. “And you can imagine, given how our brain works, if that connectivity is even slightly off, that could potentially underlie a range of neuropsychiatric and cognitive disorders.”
When she landed at Harvard, Stevens and her postdoc, Dori Schafer, tried to get a closer look at what microglia were up to in the brain. Schafer injected dye into the eyes of mice, which she then traced down from the neurons in the eye nerves and into the brain. This made the brain’s synapses glow bright fluorescent red. Microglia were stained fluorescent green. If they saw structures—the synapses—glowing like red, fluorescent lit-up dots inside the bellies of the green microglia, they would know that microglia were eating synapses.
Six months into their efforts, Schafer came running into Stevens’s office with photo images flapping in her hand. “They’re in there!” she told Stevens. “The synapses are inside the microglia! We can see it!” “It was such a high-five moment,” Stevens recalls. “Microglia were like tiny little Pac-Men in the brain—and brain synapses were in the belly of the Pac-Men! We felt we were on to something really wonderful, really novel. This was deeply important in terms of looking ahead to microglia’s role in disease.”
Stevens’s and Schafer’s study, which was reported in the journal Neuron in 2012, helped address a decades-old mystery. In many different neurological, neuropsychiatric and neurodegenerative diseases, healthy synapses disappeared. Suddenly it made sense that inflammation in the body was correlated with cognitive decline, depression, mood disorders, and a loss of synaptic connectivity in the brain. Just like white blood cells in the body, microglia were trying to protect the brain from immune hits, and constantly responding to cues from the environment. When they detected that something was off—an over influx of stress hormones, an infiltrating virus, chemical, or pathogen on the scene—they sometimes went too far, removing healthy, needed, brain synapses, the same way macrophages sometimes went too far in the body.
Others in the field were adding new revelations about microglia cells, too. Researchers at Mount Sinai School of Medicine in New York discovered in 2010 that microglia—unlike the other three glial cells, which emerged from the same family of stem cells that went on to develop into nerve cells and neurons – had an entirely different origin. Microglia emerged from the same family of stem cells that developed into the immune system’s white blood cells and macrophages. But instead of staying in the body like white blood cells, on the seventh day of gestation, microglia traveled up through the bloodstream and into the brain—where they settled and stayed throughout a person’s lifetime. Microglia were immune cells—part of the immune system’s arsenal. It was true that white blood cells didn’t have access to the brain—but they didn’t need to, because their cousins, microglia, were already policing the neighborhood.
But how were microglia getting their instructions? Work by Jonathan Kipnis might hold some clues as to the answer. Kipnis, the director of the Center for Brain Immunology and Glia and chairman of the department of neuroscience at the University of Virginia, was curious, for much of the last decade, as to whether the body’s immune system might somehow be in dialogue with the brain, and microglia, in ways that could influence neurological and psychiatric conditions. His discovery, in 2015, that lymphatic vessels lie hidden inside the layers of membranes that wrap around the brain just beneath the skull (known as the meningeal spaces) brought him one step closer to demonstrating a possible connection. Lymphatic vessels course through your body the way the earth’s underground springs run through and beneath the land. If you skin your knee, T-cells send white blood cells marching into the tissue around your knee in order to protect your body from bacteria, fungi, and microbes. This immune brigade circulates to the precise site of your wound through this intricate, waterway-like system of lymphatic vessels. Since the days of early anatomists, physicians had agreed that there were no immune vessels interacting with the brain. Kipnis’s discovery showed the brain, like every other organ in the body, is connected to the peripheral immune system via this lymphatic system. It also raises mechanistic questions, one of which has to do with microglia: Is the lymphatic system somehow triggering immune cells in the brain—microglia—to carry out an overactive immune response, creating neuroinflammation, or triggering microglia to eat away at synapses? At the moment, there are details at the edges of our understanding that scientists are still grappling with. What we do know, Kipnis says, is that the meningeal spaces house immune cells from the body that can release cytokines, which in turn influence brain circuitry.
In 2018, Stevens was named a Howard Hughes Medical Institute Investigator, and received generous funding to follow the breadcrumbs to further learn how microglia might be contributing to a range of cognitive and psychiatric diseases.
Perhaps no aspect of our world is as mysterious as the question of why mental health disorders become intractable in one person and non-existent in another. Runaway microglial inflammation, triggered by environmental exposures, life experiences, and genetics—a combination unique to each individual—could well provide the answer. When microglia go on a full-throttle attack, they take out crucial synapses in the brain that we need to process thoughts, manage complex emotions, and make decisions. We may feel it keenly. Important parts of the brain that should be talking to each other can’t communicate well. Synapses misfire. Perhaps when something seemingly small happens we overreact. We feel despair. We can’t concentrate or remember things. We act out. We may feel elated one moment and devastated the next. Or we feel anxious all the time. It’s a little different for everyone. And so we give it a hundred different names: OCD, ADHD, anxiety, depression, bipolar disorder, memory loss.
Researchers have shown that patients experiencing major depressive episodes have significantly higher levels of activated microglia, as do patients with OCD and Parkinson’s. Many of the most difficult to treat brain-related diseases of our century, which plague humankind from womb to grave, and many of which appear to be on the rise, share a common denominator: Immune-triggered microglia appear to be wreaking havoc with the brain in response to the same triggers that spark inflammation in the body.
There is hope here, I think, especially in an era in which psychiatry hasn’t lived up to its promise. Survival and recovery rates have improved for heart disease and cancer over the past half a century, but rates of mental health disorders continue to rise while recovery rates are lackluster. And part of this stagnancy in progress is because the language we use to describe disorders of the brain has become so dangerously outdated. Understanding that psychiatric and neurodegenerative disorders are also disorders of microgliopathy and the immune system matters in if we are to catalyze new approaches and answers.
Our new understanding that microglial cells are the empress cells of the brain, constantly on the lookout for possible new threats, and always in an intricate dance with the environment—and that myriad triggers can cause them to remodel our synapses in suboptimal ways—tells us that our brain is responding to the world we live in with what Kipnis calls our “seventh sense.” Our emotional and physical capacities cannot be separated; this tiny cell plays some role in every story of human suffering—or in what we might think of as the making and unmaking of the self—and in the remaking of the self. If we can influence microglia in positive ways, we can create a new set of possibilities for those mired in a sense of hopelessness.
From the book THE ANGEL AND THE ASSASSIN: The Tiny Brain Cell That Changed the Course of Medicine by Donna Jackson Nakazawa. Copyright © 2020 by Donna Jackson Nakazawa. Published by Ballantine Books, an imprint of Random House, a division of Penguin Random House LLC. All rights reserved.
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