The Angel and the Assassin

Prologue:
When the Body Attacks the Brain 

My interest in the mystery surrounding the link between physical disease, the immune system, and brain-based disorders began more than a decade ago, when I developed a rare autoimmune disease that left me unable to walk. Over the course of a five-year span, between 2001 and 2006, I spent, all told, a year in bed or in a wheelchair. My doctor, a neuroscientist at Johns Hopkins, was studying my disease, Guillain-Barré syndrome. My case was unusual in that I had been felled and paralyzed not once, but twice by the disease—rare but not entirely unheard of.

My doctor, who knew I was a science journalist, and I talked at length about what was happening repeatedly to my body, and how he hoped to reverse my paralysis. He explained that in my disorder, as in all autoimmune diseases, my immune system’s white blood cells were behaving erratically, like an army gone rogue. Instead of judiciously protecting my body from invading pathogens, my white blood cells were mistakenly attacking and destroying the protective myelin sheaths that coated my body’s nerves, causing the nerve-muscle interconnections that I needed to stand and walk, or simply wriggle my feet, to go dark.

I began to think of these overactive immune cells as being like Pac- Men—those 1980s video game characters—crazily gobbling up and destroying my good nerve cells, eating away at the crucial nerve connections that made my physical body mine—strong, capable, dependable me. Regular intravenous therapies would, my neurologist hoped, reboot my immune system so that my white blood cells would stop overreacting and behave normally. If this approach worked, and we could get my overvigilant immune cells to back off from their attack, my nerves would hopefully start to regenerate on their own. The nerves that had gone dark would light up again, regrowing enough neuromuscular connections that I might even be able to walk once more.

Many months later, it would turn out that my neurologist was right. In the end, my immune system’s overexcited cells did back off. I did get much better. Not all of my nerves regenerated, but enough did so that I could walk again, and the significant gains I made have allowed me to live a good life. The human body can be miraculous that way. 

I had one question for my medical team during that time, however, that they could not answer. After losing the use of my legs, I’d also experienced what seemed to be 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 human being’s happy thoughts and replaces them with bad ones. It almost seemed, I told my primary care physician, whom I was also seeing at the time, “like someone has inhabited my brain.” 

I’d also always had a stellar memory and could recall conversations that had taken place weeks, months, even years earlier, word for word. Now, though, I was having to write simple things down, such as what time the physical therapist was coming the next day. No big deal, I thought. That’s new for me, but it happens to lots of people. 

But there were other, more worrisome “glitches.” It was, for instance, taking me a disturbingly long time to recall the names of people I’d lived with and loved all my life. At Thanksgiving dinner in 2005—when I’d graduated from being bedridden to getting around, albeit in a limited fashion, with a walker or cane—it became a source of good-natured amusement for my extended family to watch me struggle to come up with a person’s name. Everyone smiled patiently as I called out a string of names across our long table, one after the other, until I landed on the right one: “Sam! Christian! Zen! Don! Jay! Cody!”—the dog’s name— “Chip! Could you please pass the salt?” 

Even that could be seen, I told myself, as almost humorous; at least my brain was able to distinguish between male and female names. But some things weren’t at all funny. My six-year-old daughter would ask for help with simple first-grade math and I found my brain stuttering just to add seven and eight. Or I’d reach down to tie her shoes, something I’d done for years, and find myself staring dumbly at the laces, struggling to re- member how, exactly, it was done. I can still recall cutting up slices of watermelon, putting them in a bowl, and staring down, thinking, What is this again? I knew, but I could not remember the word. I’d cover my lapse by bringing the bowl to the table and waiting for my children to call out, “Yay! Watermelon!” And I’d think, Yes, watermelon, of course it is. 

My rife anxiety was less surprising, given that I’d been plunged, practically overnight, into almost complete physical paralysis and hospitalized for several weeks at a time, more than once. In the process, as my body’s nerves had demyelinated, I’d endured excruciating muscle spasms, and undergone repeated spinal tap and electrical conduction tests in which technicians shocked nerves in my arms and legs to see which ones were not responding. For a time, I’d lost use of the muscles needed to swallow solids. In the hospital, I’d blacked out after an allergic reaction to an IV therapy and come back to consciousness to find a team of ashen-faced doctors hovering over me with a crash cart, and a nurse uttering prayers under her breath. And then there were the endless weeks I’d spent in physical rehabilitation centers, learning to balance myself and push a walker across a room on numb legs that were nevertheless riddled with shooting pains. 

But this omnipresent anxiety felt like a separate disease in and of itself. My memory, clarity of mind, word recall were different—my brain did not feel like my own.

I sometimes commiserated on the phone with a friend of mine, Lila, who had Crohn’s disease and was having similar cognitive concerns. She told me that one day when she’d dropped off her older son at kindergarten, she’d left her two-year-old son (he’d clambered down out of her arms to play at the sand table while she chatted with the teacher) in the class- room too, by mistake. The teacher had followed her out of the class, with the toddler shrieking in her arms. “I forgot my own son!” Lila said, sobbing. Her doctor had sent her to a psychiatrist, who was prescribing anti- depressants for anxiety and obsessive-compulsive disorder and Ritalin for ADD. But, she wept, “I never needed Zoloft or Ritalin before I had Crohn’s.” 

I empathized with Lila; her concerns mirrored my own. The next time I saw my primary care physician, I confided to her, “It’s like a part of my brain has gone dark too, along with my legs and feet.” It reminded me of people I’d known who’d had a mini stroke. “What’s going on with that?” I asked, hoping to learn more about my own situation. 

I had not had a mini stroke, my internist assured me. She reminded me that my life had been much changed, and what had happened to me had been traumatic. It made sense that my mental state would be deeply affected. My neurologist, meanwhile, encouraged me, cheered me on in my recovery, and reassured me that as time went by I would continue to heal. 

And so I did. Still, a number of my cognitive symptoms lingered. And I could not shake the feeling that just as my body had been altered, something physical had also shifted in my brain. 

I began to wonder whether any immunologists, who studied the immune system’s effect on all the other systems and organs of the body, suspected there might be biological links between physical immune dysfunction and brain-related or psychiatric illness. I began to dig a little deeper. 

During this same time, between 2007 and 2010, I was also enormously busy writing books, lecturing, managing my illness, and raising a young family. But I kept doing sideline research on the topic. And it turned out that a handful of researchers in labs around the world were setting forth to examine this precise link. I collected every peer-reviewed study that documented patients whose immune systems were overactive— thus causing inflammation and disease in their body—who also reported considerable cognitive and mood issues. 

In 2008, research revealed that patients with MS also experienced changes in their ability to remember things and were several times more likely to suffer from depression and bipolar disorder than individuals without MS. 

In 2010, an analysis of seventeen different studies showed that having lupus, which often manifests in systemic inflammation in the organs of the body, was associated with a much greater likelihood of suffering from depression, and even psychosis. Shockingly, as many as 56 percent of patients with lupus reported cognitive or psychiatric symptoms, including trouble concentrating, mood disorders, depression, generalized anxiety, and learning issues. Having lupus is also associated with early dementia. 

And, that same year, researchers found, after looking at thirty years of health data on three million people, that individuals who’d recently been 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 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 just a few weeks after receiving the bone marrow. In another case study, 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 were cured. 

Yet, as compelling as all this research was, at the time that many of these studies were coming to light, it just did not make any scientific sense that being sick in the body could be connected to, much less cause, physical sickness in the brain. In 2009, the majority of the scientific community believed (as one research review put it) that it was “an undisputed anatomical fact” that the brain was the only major organ lacking a direct connection to the body’s immune system.

Let’s take a minute and step back to remember high school biology basics about how your immune system functions. Your white blood cells— the army of the immune system—constantly circulate in your body, scanning for invaders, germs, pathogens, and environmental toxins you can’t see or smell. In the time it will take you to read just this sentence, your immune system will respond to thousands of unseen threats to your well-being. The germ cloud from the person sitting next to you on the bus who just sneezed. The minute bacteria in the dirt still clinging to the organic salad you had for lunch. The fungus that’s growing in your office building’s HVAC system. The chemicals coming off the new plastic bins you bought to file away this year’s tax receipts. Your white blood cells are there to snuff out an endless parade of invaders, 24-7. 

If you cut your thumb while slicing onions, your immune system’s white blood cells rush in like a SWAT team to battle any infiltrating bacteria while also mending damaged tissue. Your thumb swells up and becomes inflamed—red, hot, swollen, and painful—while your white blood cells congregate to do the necessary repair work. While red, hot, swollen, and painful might seem problematic, this is actually your immune system doing its job, and doing it well. 

But inflammation occurs in ways that can be harmful too. If your body happens to be overtaxed by too many environmental triggers, your army of white blood cells can become overwhelmed and go into over- drive, mistakenly attacking your own tissues, joints, organs, and nerves, leading to autoimmune diseases such as rheumatoid arthritis, lupus, MS, and type 1 diabetes.

Inflammation and autoimmune disease can both arise in virtually any organ or system in the body. White blood cells have to get it just right. If they don’t battle hard enough, infection and pathogens can spread and shut down organs, and you can die of sepsis. If white blood cells overdo it, they may protect you from outside invaders, but in the process mistakenly launch an inflammatory hyperattack on your body too, giving you a new illness you didn’t previously have. (In my case, when I fell ill, I’d originally had stomach virus. My white blood cells knocked out the infection—but went too far and knocked out the myelin sheaths around my nerves too, which resulted in Guillain-Barré syndrome.) 

There is only one organ in the human body that scientists have categorically believed for over a century was not affected by the body’s immune system. 

That organ is your brain. 

And, it follows, if your immune system can’t reach—and doesn’t rule—your brain, then your brain cannot be touched by inflammation or become inflamed. 

When my internist and I talked about the cognitive changes that occurred during flare-ups of my physical disease, we assumed these symptoms had to be purely emotional in nature because for decades, textbooks had declared that when a disease was attacking the human body, the brain was off limits. The prevailing idea in neuroscience, long taught in medical schools, was that the brain was “immune-privileged.” Scientists unilaterally believed that, for better or for worse, the immune system had access to every single organ in your body except your brain. Inflammation in the brain could occur only if there was an external event—head trauma, or an infection known to directly target brain tissue, such as meningitis. Other than that, the brain simply could not generate inflammation. 

This theory made sense for anatomical reasons. After all, if your inflamed thumb swells up—even to twice its normal size—your skin can expand (albeit painfully) to accommodate the internal swelling. But if your brain expands, it has nowhere to go—it’s trapped inside your skull. If too much pressure builds up, the brain—and you—can’t survive. In extreme instances, when there is a major head trauma such as in a car crash, brain tissue can swell—and pressure has to be relieved by surgeons drilling into the skull. So early anatomists had very good reason for assuming the brain was simply not an immune organ.*

But by 2011, an increasing number of researchers were starting to doubt that dogma. Neuroscientists and immunologists were beginning to wonder: Could the brain be affected by inflammatory processes—and if so, how? 

But these questions had no answers. 

Occasionally, I’d mention what I called my “Brain Flame project” to my literary agent. She’d play devil’s advocate, asking, “But if we don’t know how or why the brain could be affected by the body’s physical immune system, how can you say that having an overactive immune system can result in brain-based illness?” 

To be honest, at that time—around 2011 and 2012, prior to the groundbreaking discoveries I’ll detail in the following pages—I could not prove that the brain was affected by disorders of the body. No one understood the exact way in which immune dysfunction in the body could lead to brain-related psychiatric or neurodegenerative disorders, or cognitive decline. The brain was immune-privileged, and that was that. 

And yet, even as my agent and I had that conversation, the scientific community was on the verge of exploding with surprising answers to the questions that had haunted me for more than five years. Newly under- stood scientific links between physical immune health and brain health were emerging at a rapid pace. 

And all of these discoveries revolved around one type of tiny cell that had, for over a century, been largely overlooked in human health. These deceptively minuscule cells, called microglia, had never been seen as significant in determining mental and cognitive health. Then, in 2012, groundbreaking research showed that, contrary to scientific dogma, these microglial cells held enormous power to protect, repair, and repopulate the brain’s billions of neurons and trillions of synapses, or to cripple and destroy them, leaving wildfire-like devastation in their wake.* Unbeknownst to researchers, microglial cells had long been functioning as the white blood cells of the brain, governing the brain’s health. 

In fact, the five-year span between 2012 and 2017 was a watershed time for neuroscience and immunology, during which the discovery of microglia’s true role in brain health would cause the two fields to be- come one. 

During these same years, scientists also unveiled that these microglia cells in the brain were chatting with the body’s immune cells in direct and indirect ways: If there was inflammation in the body, there would almost inevitably be immune changes within the brain. Moreover, these immune changes in the brain could manifest themselves as cognitive or neuropsychiatric disorders. 

These immune changes could affect the brain’s synapses and neural connections even when there were no signs of physical illness in the body itself. 

And this meant that we could begin to understand the interior health of the brain in ways that had been unimaginable just a few years earlier. The discovery of microglia’s ability to both build and break down the brain provided researchers with an entirely new organizing principle for deciphering brain health and brain illnesses. 

Still, it was clear that even as this research rocked the scientific world, patients were not learning about what scientists now knew, or why this information was so vital to their well-being. 

As a science journalist, I had often seen that it took many years for research to trickle down to the patients who needed answers most. My goal as a writer was simple: report on findings that could ease suffering, in order to close the gap between what science knew and what patients needed to know in order to live their best, healthiest lives. 

And so I set out to do a journalistic investigation, delving into, analyzing, synthesizing, and connecting the dots between the stunning new stories of research emerging on microglia and their role in helping to cause, but also to reverse, brain-based illness. This book tells the story of the birth, exploration, and promise of one of the most paradigm-shifting and powerful stories in the history of medicine—the story of these tiny microglial cells in brain health. In the pages that follow, we’ll see how these cells hold the potential to trans- form human health by helping us to repair the brain in ways that we have previously only dreamed of. I’ll take you on a journey of discovery, detailing the most exciting promise for healing that I’ve ever reported on in my thirty-some-year career as a science journalist. 

I believe that you will come to see, as I have, how and why this ground- breaking revelation about microglia has forever overturned many of the longstanding and powerful assumptions we have made about the mind- body-brain connection—including why it tells us, categorically, that the brain is indeed an immune organ, ruled by these powerful, enigmatic immune cells. Along the way, we’ll follow the progress of a few patients whose lives have been transformed by our new understanding that this cell serves as both the angel and the assassin of the mind. 

Perhaps most important, we’ll learn about cutting-edge new approaches that help reboot and redirect the activity of microglia so that these little immune cells stop their attack, thus allowing the brain’s neurons and synapses to regrow and heal. 

We’ll peer too inside top research labs across the country and see how the work of a small band of fearless and dedicated neurobiologists, who discovered the extraordinary power of microglia, have changed the future of human health forever. 

Including, quite possibly, yours. 

* This longstanding belief that the brain was immune-privileged also had to do with scientists’ understanding of the blood-brain barrier, a dense, complex constellation of cells that congregate around the blood vessels that lead to the brain. These vessels are so tightly packed together that they block particles from the bloodstream and the body, including immune cells, from reaching the brain. The inviolate nature of the blood- brain barrier has long been seen as proof that the brain is off limits to the body’s immune system—and therefore immune-privileged. 

* Synapses are the small gaps between neurons that allow electrical and chemical signals to pass from one neuron to the next.

Copyright © Donna Jackson. All rights reserved.