FAQ: The Angel and the Assassin

FAQ: The Angel and the Assassin

People often ask me why I wrote my new book, The Angel and the Assassin: The Tiny Brain Cell That Changed the Course of Medicine. Here’s why:

Over the past several years, a series of revelations about a long-overlooked brain cell, called microglia, have changed our understanding of mental illness and human suffering, including how brain disorders develop, and how we might better prevent and treat them.

For most of the past century, scientists believed the workings of the mind were separate from the body – and that the brain was our only organ that was not ruled by our body’s immune system. But new findings about the true role that microglia play in orchestrating brain health have overturned this centuries-old assumption.

Microglia, long assumed to be boring cells that simply carted away dead cells, were recently found to be powerful, swift-moving immune cells that constantly monitor the brain. And just as detecting something off kilter – emotional stressors, infections, toxins – can trigger our body’s immune system to rev into overdrive, sparking inflammation and disease, these same stressors can trigger microglia to over-prune the brain’s synapses, setting the stage for depression, anxiety, mood disorders, and Alzheimer’s. Other recent discoveries show that microglia are able to “communicate” with our body’s immune system via the vagus nerve, as well as through a network of immune vessels that travel up from the body to the brain – vessels we never knew existed before 2016. All of these developments give new meaning to the mind-body connection.

This extraordinary research wasn’t being covered, or when it was, no one was standing on the mountaintop, connecting the dots between emerging research and synthesizing what this meant for our understanding of the brain, brain-related disorders, patient well-being, and the extraordinary hope that this entirely new understanding of the brain provides for the future of medicine and psychiatry.

So I set out to follow the tale of this little cell, microglia, and bring it to life, and connect the dots between different researchers’ work and different patients’ experiences to tell  one of the most paradigm-shifting and powerful stories in the history of medicine—the tale of these tiny, powerful, enigmatic microglial cells in determining brain health, and their potential to transform human health by helping us to repair the brain in ways that we have previously only dreamed of.

As I am out on book tour, from Harvard to Indy bookstores up and down the East Coast, talking about The Angel and the Assassin, a lot of folks want to know, how did all of science miss the true role of this tiny cell—microglia, which links our physical and mental health—for so long?

Since the Enlightenment, scientists, clinicians, and patients have operated under the age-old assumption that the workings of the brain are physically divorced from mechanisms of the body. The philosopher Descartes first put forth this concept, known as mind-body dualism, in the seventeenth century, and the medical dogma that brain and body function as separate church-and-state entities has permeated the way in which we’ve viewed mental health disorders ever since.

Throughout the twentieth century, scientists categorically ruled out the idea that there might be biophysical pathways between the body’s immune system and the development of psychiatric or cognitive disorders, largely because of what’s known as the blood-brain barrier, a dense constellation of cells that surround the blood vessels that lead to the brain. These vessels are so tightly packed, they block particles from the bloodstream and the peripheral body, including immune cells, from reaching the brain. The inviolate nature of the blood-brain barrier has long been accepted as proof that the brain is off-limits to the body’s immune system, or what we call “immune-privileged.”

So, really, it was unthinkable that these tiny microglial brain cells could be functioning as the white blood cells of the brain. From the time they were first noted by neuroscientists in the 1920s, they didn’t generate much interest among the scientific community. But all that changed when Beth Stevens’ lab at Harvard revealed in 2012 (a millisecond ago in terms of scientific literature!) that microglia are capable of terrifying Jekyll-and-Hyde behavior. We now know that, when triggered (and anything that activates the immune system in the body can activate microglia) these tiny cells can morph into big Pac-Men like destroyers and take out healthy brain synapses, and stir up inflammation, in the same way that immune cells in the body can attack tissue or organs.

We also know that a loss of synapses is associated in brain scans with anxiety, depression, bipolar, schizophrenia, and Alzheimer’s Disease – often years before symptoms set in.

This gives us an entirely new understanding of mental health and cognitive disorders and offers a new picture of hope and possibility for patients.

One question I’m getting a lot as I do news interviews, podcasts, and live on-stage events talking about The Angel and the Assassin is this: how is this science a game-changer in terms of our understanding of the brain and brain-related disorders?

Our new understanding of the power of microglia sheds new light on hundreds of different disorders and diseases that have long remained the black box of psychiatry and neurology, and provide researchers with an entirely new organizing principle for approaching brain health and treating brain illnesses. I call this the Microglial Universal Theory of Disease.

Many of the big, bad, and difficult to treat brain-related diseases of our century, most of which are on the rise, share one common denominator: triggered microglia are wreaking havoc with the brain. And we missed it.

This discovery stands to rewrite psychiatric and medical texts as we know them. For decades, scientists thought that mental illness was all about chemical imbalances in the brain, but now, we’re beginning to understand that disorders of the mind are first and foremost immune disorders that reflect alterations in the brain’s immune health and in the health of the brain’s synaptic connections. Already, researchers and clinicians are developing treatments that address brain illnesses at the source, by rebooting microglia so that they return to their good role – protecting and healing the brain. This science has given us a promising new window into better understanding an array of intractable disorders of the mind, and the field in moving fast – this is science in motion. Today, in both clinical research labs and therapeutic settings, scientists are uncovering extraordinary approaches to help calm overreactive microglia so that they behave as nature intended: as the angels of the brain, rather than as blind assassins.

One of the most important questions I get from people while I’m on book tour for The Angel and the Assassin (whether I’m at Harvard or a local independent bookstore) is also the most moving for me: how does this groundbreaking science offer new hope for patients who are suffering right now? Often, people ask me this with tears in their eyes. Here’s what I try to convey to them:

Microglia act like a “light switch” in the brain. Their behavior for good or ill can help prevent, or lead to, or worsen a wide range of issues, including: depression, anxiety, OCD, bipolar disorder, cognitive decline, glaucoma, Parkinson’s, autism, schizophrenia, post-concussion syndrome, neurological autoimmune disease, and Alzheimer’s.

This research tells us that the brain is even more plastic than we previously imagined, and constantly changing. Our brain’s immune system is physically connected to, and engaged in, a constant dialogue with the body’s immune system; it’s all one system, connected by a brain-immune super highway. The long-held line in the sand between mental and physical health simply does not exist. Our brain, like our body, is always engaged in a complicated, interactive dance with our environment. The promise and the peril of this science tells us that our emotional and physical capacities cannot be separated: the emotional gradually becomes physical and the physical gradually becomes emotional.

With this new understanding that microglia are the white blood cells of the brain, and that brain-body crosstalk is constant, it makes sense that chronic inflammation in the body is correlated with cognitive decline, depression, mood disorders, and a loss of synaptic connectivity in the brain. Microglia hold enormous power to protect and repair the brain’s trillions of synapses or to cripple them, leaving wildfire-like devastation in their wake.

When microglia are overactivated – by the same triggers that can overtax or confuse our immune system – they start to target and attack healthy, needed, and necessary synapses, eating away at the synapses that give us mental stamina, hope, joy, clarity of mind. Over time, many small changes in neurocircuitry wrought by inflammation-led microglia can cause individuals to feel and behave very differently.

But because these microglia-led inflammatory changes appear differently in the brain from one person to another, we give it 100 different names: ADHD, OCD, anxiety, depression, bipolar, schizophrenia, memory loss.

But there is so much good news here, too: under the right circumstances these cells can be coaxed back into being the brain’s healers and hold promise to one day prevent or halt disease.

This science sheds new light on the link between brain function and immune function, or the mind-body connection, and rewrites our understanding of the origin story for disorders of the mind, ushering in a new era of hope for patients and families. This is really nothing less than a new window into the making and unmaking of the self.

With this past decade of brain research, we are revisiting everything that we thought that we knew about brain and immune health. The Microglial Universal Theory of Disease helps us to recognize that we are all dependent on the health of our brain’s immune system, just as we are all dependent upon the immune health of our bodies.

We’ve long known that we have five established senses—smell, touch, taste, sight, and hearing. Our sense of proprioception, or where our body is in space, is often called our sixth sense. Together, these senses constantly send our brain messages telling us whether we are safe or not. One of the defining roles of the immune system is to detect when there are threats in our environment and inform the brain about them—and our new understanding that the brain is an immune organ, ruled by microglia, tells us that – as Jony Kipnis, a leading glial researcher and professor of neuroscience at the University of Virginia once put it, “this immune response is hardwired into the brain” as well as the body. That, says Kipnis, makes our immune system’s back-and-forth dialogue with our brain our “seventh sense.” Everything that happens to us – in terms of our minute-by-minute exposures to environmental factors including relationships, infections, and chronic stressors – matters more than we might ever have imagined to our brain health and well-being, our mental stamina, our mood state, our sense of hope and joy, our clarity of mind.

It has always been a conundrum for those suffering from mental health disorders to explain the depth of their pain to those who’ve never been afflicted. And the difficulty that the medical community has had in understanding mental suffering from a biological perspective has done little to ease that burden. The Microglial Universal Theory of Disease offers patients a new understanding of their conditions, while simultaneously offering physicians and practitioners a new playbook on how to intervene and help those suffering to reclaim wellbeing. Of course as with all new therapies, we much proceed with an abundance of caution.

This science is giving birth to new treatment options and also lending new credence to a range of already existing interventions that, it turns out, help patients by helping to calm the behavior of overexcited microglia. Transcranial magnetic stimulation, neurofeedback, gamma light flicker therapy, novel concussion protocols, anti-inflammatory medications, ketamine, and fasting diets are just a few of the ways that scientists hope to restore microglia to their good, angelic function: keeping synapses healthy and thus improving the quality of patients’ lives. These treatments work by addressing symptoms at their source: helping to reboot microglia to a healthy state, and bring them into homeostasis, to keep neuroinflammation in check and nurture robust synaptic health.

A lot of people are asking me how I hope my new book, The Angel and the Assassin, will make a difference in the world.  

Over the past thirty years, we’ve seen progress in almost every area of medicine—heart disease, cancer, etc.—but we’ve made very little headway, comparatively, in psychiatry. In fact, rates of treatment-resistant mental health disorders are rising. My hope in writing The Angel and the Assassin is to catalyze the emerging science around microglia and our understanding that the brain is an immune organ, involved in an intricate and intimate dance with our environment, and to underscore that just as our body’s immune system is affected by so many factors in our environment, so is our brain health. I would love to see the book help to forward this conversation in the fields of medicine and psychiatry, so that the fields can evolve with this research, and more patients can benefit from new treatment options to find the healing they long for and deserve.

Time is obviously of the essence: While survival and recovery rates for serious medical conditions, including heart disease and cancer, have improved greatly in the past fifty years, recovery rates for mental illness have barely budged. More than a third of the 300 million people around the world with major depressive disorder don’t respond to any antidepressant treatments, and some who do respond find that medications stop working for them over time.

I’d like to travel forward twenty-ish years, to a time when patients with mental health and brain-related disorders can enjoy the promise that I lay forth The Angel and The Assassin. I’d like to see patients benefiting—in their local psychiatrist or physician’s office—from this revelatory science in their daily lives. For instance, we will soon have early, non-invasive blood tests that allow doctors to see if early synapse loss is occurring, by measuring factors released by microglia when they are over-pruning synapses. These tests can be done in the early teens years, before mood disorders develop in adolescence or young adulthood and derail a life, a future, a family. Imagine if a teenager who is facing trauma and who has a family history of a mood disorder were given a simple blood test at the age of eleven, and a pediatrician were to say, “Hey, there are signs of some early microglial over-activation and synapse loss, let’s start some neurofeedback and other therapies prophylactically.” A similar scenario applies to Alzheimer’s Disease. Over time, a physician or psychiatrist will be able to scan the brain and do blood tests to see what emerging microglia-based treatments—gamma light flicker therapy, TMS, anti-inflammatories, special diets, neurofeedback, vagal stimulation—are working or not working in almost real time. Of course we have to proceed carefully and first do no harm. But a sea change is coming in psychiatry. I want to witness this new era of medicine, and see lives restored by the promise of this science.

Some folks are asking me whether I have any personal connection to the science in my new book, The Angel and the Assassin. The answer is yes.

I myself face a neurological autoimmune disease, and there are several women in my extended family who face genetic mental health disorders, women I love and admire deeply. Many of my readers, over the years, have reached out to tell me that they suffer from mental health or autoimmune concerns, or both. In my writing, I am always trying to close the gap between the latest neuroscience emerging from the world’s most innovative research labs and what patients need to know in order to find healing and relief. I often thought of all of these women as I wrote this book.

But more broadly, I often approach my writing from a female perspective. We know that statistically, women are struck by most of these illnesses—depression, bipolar, Alzheimer’s, autoimmune disease—at three times the rate of men. (This has to do with complex aspects of the female immune response. In one chapter of The Angel and the Assassin, I write about how the female immune system functions slightly differently in response to our environment, leading to higher rates of depression in girls.) So, I also see this book from a feminist perspective. I’m on a mission to sound a clarion call to change how we view and approach mental health disorders as a society and in medicine, and I’m conscious that many of those who are suffering are women.

Sometimes I get a curveball question while I’m on book tour for The Angel and the Assassin – and this is one of my favorites: Why did I become a writer? The question has caused me to think about that…

I suppose I ended up being a science writer for two reasons. The first is that it’s in my DNA—my grandfather was an early founder of the National Institutes of Medicine (NIH) and an award-winning researcher. We had many scientists on my mother’s side of the family. My father’s side of the family were in the newspaper business and ran a small chain of newspapers in Maryland. I grew up running around the editorial offices of my dad’s newspaper in Annapolis, the Capital Gazette. A bit of both the science-gene and the writing-gene landed in my DNA.

But the other reason, I suspect, is that many members of my family have suffered from rare autoimmune disorders, several of them genetic. My father died when I was twelve from a combination of genetic autoimmune disorders and a physician’s error on an operating table, and later, I was diagnosed with a similar set of disorders. I know what it means to be a revolving-door patient, with your heart in your mouth, hoping for a seemingly impossible recovery. My children have also faced some of these issues. Perhaps on some unconscious level, the child within me wishes I could have helped my father avoid an unnecessary death, and that, I think, has also led me to want to help have the science they need to help achieve the best possible outcome.

I’m getting this question a lot from younger writers – what advice would I give to those starting out, as I look back over a 30 year career as a science journalist (six books, hundreds of magazines and news articles…)

There’s an old saying, “Writing is easy, all you have to do is lean over the typewriter and wait for drops of blood to form on your forehead.” Sometimes it feels like that; at other times, ideas pour forth and it can feel as if you can’t get your fingers to move fast enough to type all the thoughts in your mind (such days are as magical as they are rare). Either way, you will throw away or re-write most of what you write many times before it appears in print. Just keep going. Focus on bringing meaning to areas of our shared human experience that are hard to give words to. By so doing, perhaps you heal something in yourself, too. But more than anything, it’s all about putting your butt in the chair, day after day. Writing long-form means building on each day’s work; it’s not unlike building a house. You achieve your goal little by little, until your vision for what you set out to build slowly, painstakingly, emerges in front of you. Keep reading everything that interests you. After writing six books, I’ve learned that writing is less about raw talent and more about the desire to say the unsaid, and approaching the process with curiosity, discipline, and endurance. In terms of how one’s writing is received your words will be both criticized and appreciated. (Social media takes this dichotomy to a whole new level.) Some articles will get millions of “hits” and others will go unnoticed. It’s not about how things are received; it’s about setting out to say what you have to say with an open-mindedness toward the ideas of others, a realistic sense of the hard work that is entailed, while staying rooted in intellectual humility, and motivated by our shared humanity.


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