An Elegant Defense

by Matt Richtel

  “Is Matthew there?”

  “This is he?”

  The guy introduced himself as the assistant to the dean of Columbia School of Journalism.

  “School started yesterday and a spot opened up. I’ll be honest, Matthew, you were far down on the waiting list. But the dean saw your postcard and thinks you’re funny. Would you like to come to Columbia?”

  Pause to make sure it wasn’t a high school buddy playing a prank.

  Sure, yeah.

  Fuck.

  At Columbia, I exhibited a devil-may-care exterior. Outwardly, I still thought of myself as belonging to that too-cool-for-school club Jason had christened the Concerned Fellows League. But I was petrified, the youngest, most inexperienced member of the class. The terror went deeper than that. As I look back, I realize that this was the moment when I subconsciously decided it was time for me to become something great, whatever that meant. My childhood aspirations had come home to roost. I could be the Jason of journalists. The thing is, a sizable part of that emotion wasn’t authentic interest—I didn’t yet understand what it means to be a journalist or a writer. I just knew I wanted to succeed. This terrible disconnect helped explain the fear; I knew, on some level, I had only generic goals, not ones true to me.

  Why tell you all this?

  Because it explains why I stopped sleeping. I don’t mean just restless nights. I hardly slept at all. I would go full weeks, largely tossing and turning, sleeping only a few hours at a time, trying to figure out how to tackle stories I didn’t understand or attack classes that I wasn’t sure I found interesting. Or maintain a facade of calm that had no existence in reality.

  After I realized something was wrong, I spent three intense years learning a lot about myself and this sickness, and that’s exactly what it is—a disorder. In practical terms, its toll on my behaviors ranged from spending days sweating from exhaustion to struggling to focus on work to making stupid social choices and, more than any of that, to setting the stage for severe anxiety and depression, letting my adrenaline run wild to keep me functioning without good rest. When I took on this book, I went back and learned that what overwhelmed me then had very much to do with the immune system and its relationship to sleep and stress, even though it looks like a matter of “mere” psychology. There was some of that too.

  In the course of researching this book, I described my situation at that time to Dr. William Malarkey, a professor emeritus at Ohio State University and an expert in how the body’s stress and neurological systems relate to immune function. He’s worked closely with Janice Kiecolt-Glaser and Ron Glaser, and is an expert in the causes and impacts of stress.

  “You were going through a search for a mission and meaning,” he said. “At some point, you took this incredible long shot”—meaning applying to Columbia—“that you hadn’t thought out. You happened to hit a home run. Suddenly you think, ‘I have to be Babe Ruth. Now I’m among major league players.’”

  Then he switched to biological terms. He said that fight or flight took over as if “I’d been thrown into a lion’s den, or with a pack of bears.”

  This, he said, was obviously not true. But that’s how I perceived it, and I and many others tend to make the same mistake. “What happens today is that many people are living with imaginary bears at every step of their lives—something in the news or around the bend is going to get them.” What followed was what he called a “norepinephrine high.”

  It was a survival mechanism, in the short term. But in the long term, it was dangerous, even deadly.

  As I discussed earlier, norepinephrine is one of two major neurotransmitters or hormones—a signal secreted from the nerve endings or the adrenal glands—that are released immediately as part of a fight-or-flight response. The other major hormone is called epinephrine, or adrenaline. When we perceive a dangerous situation or any kind of threat, these get secreted and start to impact other cells in the body. “You get thrown into the lion’s den or surrounded by bears, and you begin to be alert to everything that’s going on around you.”

  Immune cells are among those impacted. In fact, according to Dr. Malarkey, the connection between the immune system and the adrenal system may be so intimate that it’s difficult to separate the two.

  I told Dr. Malarkey that norepinephrine and epinephrine sound much like interleukins in that they are sending signals that impact immune cells. He just laughed. “Exactly!” he said. “I’ve been saying it for years. The difference is they were discovered by people in different fields. If they’d been discovered by immunologists, they would’ve been called IL-1 or IL-6 or something.”

  Leaving semantics and returning to substance, he said that norepinephrine and epinephrine can start to feel, perversely, exciting. “You get addicted to it. You need it. Suddenly it’s going on all the time. The brain is driving it. Now you get all the disruptions of excess. You get dis-regulation of the immune system.”

  Dr. Irwin, the sleep expert from UCLA, explained that what followed was “a sickness syndrome, sickness behaviors, driven by inflammation.” Feelings of depression, social isolation, withdrawal, fatigue.

  That’s exactly what happened next.

  For that period in the mid- to late 1990s, I battled to discover myself. I realize this is an overused phrase, somewhat trite. Here I’ll defend it as central to health. I wasn’t going to stop until I had a better understanding of what was consistent with me. I had long moved past questions like what I wanted to be. Quickly, that stupid idea dissolved into much more basic questions: What was comfortable to me? What activities and circumstances felt right?

  The need to answer those questions was amplified greatly by insomnia. The level of sympathetic response that I was experiencing on a daily basis, still having trouble sleeping, was clearly impacting my health, my well-being, my level of anxiety. I can fairly say that I was experiencing a kind of addiction to that adrenaline, the norepinephrine and epinephrine. It felt like excitement. But it was betrayal.

  I solved it by backing into the science. I started meditating. I can’t remember how or why, beyond the obvious idea that the concept was out there.

  I can still picture one night when I was lying in bed, breathing deeply, and I kept meditating. An hour, more than an hour. I felt my jaw go slack. I felt my body calm. I fell asleep. I woke up in the morning rested—genuinely rested. Feeling different than I had in a long, long time. I kept doing it. Many nights, it would take an hour or more, maybe two.

  Now that I have learned the science, I know I was shutting off my sympathetic immune system. I was short-circuiting the dangerous cycle that Dr. Irwin had described in which my central nervous system had dosed my body with adrenaline, further intensifying the fight-or-flight response, inflaming swelling and the immune system, leading to further adrenal responses. I don’t know what toll that period took on my longevity, but I wouldn’t trade anything for what it taught me.

  Simultaneously, I’d drained my psychological tank dry. Sat on a shrink’s couch and sobbed. I accrued an unpayable debt to my parents, my girlfriend, and a buddy I’d met in journalism school at Columbia named Bob Tedeschi, who had become a brother. I mention these people not for the sake of merely giving thanks, but because the science bears out that the ability to find connection during times of sickness, including anxiety and depression, is instrumental in healing. It helps the immune system find balance, and this makes sense from an evolutionary perspective; the idea that you are part of a community is powerful incentive and motivation for your body’s machinery to seek harmony. Left alone, you might recede further.

  During this period, I scoured every corner of my brain and began to realize the wisdom of the old adage that there is little to fear except fear itself. Looking back, I can see a close association between the end of my psychological probing and the beginning of my period of meditation and relaxation. I had, in plain terms, given myself permission to relax. I’d become somewhat comfortable, and then eventually, I had nothing to prove. I’d learne
d, the hard way, to let myself listen to me, first and foremost, and to suppress the voices of others.

  It is also impossible to overstate, as it speaks to my health and, I suspect, the health of many. I emerged as someone with a sense of confidence to trust myself, which in turn allowed me to listen to the parts of life that excited and motivated me, the kinds of environments and friends that made me comfortable, and the things that I needed to shed as inauthentic. I’d found self.

  The best example I can offer about the value to health of hearing and following my own voice, and not chasing generic external validation, took place for me in the late 1990s. I was freelancing for the New York Times. It was going well. I loved the aspects of journalism that I’d suspected I would all along, writing and exploring and being curious. But I also was thrilled to be freelancing. I was working more on my own terms. This wasn’t about the grades anymore, or the approval of the boss. I worked and I liked it and I got paid and I’d stopped aspiring to rise in any ranks.

  Then the New York Times offered me a job. It was a dream opportunity for a still-young journalist. The only catch was that I had to move to New York instead of remaining in San Francisco, where I had moved after college.

  The idea scared the hell out of me. I knew in my heart that I didn’t belong in that city, where I’d suffered at Columbia, and in an environment where I feared I might lose track of my priorities—days spent in a hypercompetitive world with the feeling of people looking over my shoulder. I pictured myself getting caught in the spiral of adrenaline, enduring long days in an office with people more able to sustain that than I was, or more willing to. I turned down the job.

  Remarkably, the Times relented. They’d hire me, they said, and I could stay in San Francisco. Two years later, the paper changed its mind. I was told I’d have to move back to New York. “That’s what everyone does,” an editor told me. It was nothing personal.

  I flew back to New York and made my case to be allowed to stay in San Francisco. I told them they seemed happy and I was happy and nothing was broken. An editor told me: “This isn’t about being happy. It’s about doing the drill everyone has done.”

  That idea, I’d discovered, was anathema to me.

  I was given a date: October 1, 2001—move to New York or be fired. By then I’d started dating Meredith (not Merredith Branscombe, but another fellow Coloradan named Meredith Barad), the amazing woman who would become my wife. On October 1, I woke up and went to my desk and waited for the phone to ring. I worked and I waited. The next call, any call, could be the one telling me was I fired.

  It didn’t come, not for a week, then not for a month, and then not for more months. I kept writing and living and doing my thing, and more and more I trusted my voice, my muse. I married Meredith, and I started writing books, and they were foremost for me, stories I told myself, that poured out, all kinds of songs, using a voice so far from the one I’d parroted for a long time. One day, the Times relented. They were happy and I was happy.

  Again, this is not an aside. And, again, the value of that cannot be overstated as a lesson of the immune system. The more consistent I became with myself, the more I jettisoned what was alien, the healthier I got. I also tell this story because it allowed Jason and me to become real friends, on a much more honest footing than we’d shared as kids.

  Jason, meantime, had been following his own muse. It led him to come up with one business idea after the next, selling, schmoozing, spinning yarns of the power of the gadgets and ideas he truly believed were new and different—from mobile phone minutes to power juice blenders and on and on until he’d settled on his latest venture, casino trinkets.

  That night in the spring of 2011, the contours of a new relationship took shape. We talked about life, and we talked about cancer.

  “I need to beat this thing,” Jason told me, “and then I can figure out what to do next.”

  “So how’s that going?” Cancer.

  “I’m not going to lie to you, Rick, it fucking sucks.”

  He told me about the chemo, and how it wrecked his body, and about how he had to take a steroid to keep the inflammation down, and that kept him up at night. “It’s the sickest I’ve ever felt, times a thousand. I just sit there, starving for sleep. I hurt all over and I’m lying there and I can’t even read or watch TV. It’s brutal. I wouldn’t wish this on my worst enemy.”

  I guess I’d have wanted to miss a few chemo appointments too.

  Jason had failed his first treatment. There were other options in the chemotherapy realm and he was headed for them.

  In the background, though, a new field of medicine was taking shape that built on all those years of hard-hat immunology work. It was called immunotherapy. The science behind it blows the mind.

  38

  The Lazarus Mouse

  A substantial part of the immune system revolves around the way information is communicated. Molecules send and receive signals, urging immune cells to attack, do further surveillance, withdraw, implode, lurk, help new tissue grow. In the broadest sense, this information is transmitted in two different formats, or media.

  Some of the communications are known as soluble, or fluid-like, and involve interleukins. These molecules are released and can travel around and infuse other cells with instructions.

  The second type, which I’ve already also described and will elaborate on here, involves molecules or proteins that appear on the surface of cells and that connect, or bind, to a molecule or protein on another cell. These are like antibodies. They travel the body not in fluid form but attached to a cell, and then they connect to another cell at an extremely specific spot. These are mates in a puzzle that require physical proximity.

  The concept is important because it helped save Jason’s life. To show how, I need to delve a little more deeply into the science.

  Typically, one piece of the puzzle is called a ligand, and the other is a receptor. (Ligand comes from the Latin ligare, meaning to bind.) A ligand binds to a receptor.

  Through the 1980s and the 1990s, immunologists did a lot of looking for molecules on the surface of immune cells—basic archaeology—and then tried to find their mates. One reason they would hunt for these pairs was in hopes of finding a match that would help explain what each molecule was doing on the cell surface in the first place. What did the individual pieces of the puzzle do, and what happened when you put them together?

  “Every piece builds a story. It’s like getting to know a friend. Same thing through a series of encounters through molecules,” said Matthew “Max” Krummel, an immunologist who was there at the moment of one of the twentieth century’s major scientific moments—when CD80 and CD86 met their mates.

  This is the story.

  In the late 1980s, work had been done that identified two ligands that are expressed on the surface of two major immune system cells, B cells and dendritic cells. Scientists had discovered that these ligands bind to specific molecules on the surface of T cells.

  As these various immune cells circulated in the festival of our lives, they would bump into one another. If the surface of a B cell had the right ligand and the surface of the T cell had the right receptor, the two molecules would bind to each other. This would set off a reaction.

  Okay, fine, but so what? What was the reaction?

  So we’re trying to cure cancer here, give it a sec, will you? Stick with me.

  In plainer English still:

  T cells can attack invaders and organize attacks. Researchers discovered molecules on the surface of T cells that connect to molecules from other parts of the immune system, namely B cells and dendritic cells. In other words, scientists had found pieces of a puzzle that fit together but without knowing what the puzzle looked like—or exactly what that puzzle meant. They discovered that one of the key molecules on the surface of the T cell was called CTLA-4. Another was CD28.

  One more bit of deep trivia that is not at all trivial: CTLA-4 and CD28 both bind to ligands called B7-1 and B7-2—also kno
wn as CD80 and CD86.

  Okay, so then what?

  Around 1989, CTLA-4 was being explored jointly by two eventual all-star academics in the immune sciences, James Allison, who was at Berkeley at the time, and Jeffrey Bluestone, who was at the University of Chicago and eventually the University of California at San Francisco. There was a third researcher named Peter Linsley, from Bristol-Myers Squibb, a pharmaceutical company, doing related work.

  Bluestone and Allison weren’t particularly interested in cancer, or rather, that wasn’t their central focus. They were concerned with the immune system overall.

  At Berkeley, a PhD student in Allison’s lab performed an experiment that entailed taking a tumor from a mouse, putting it into a test tube, and then injecting it with foreign genes. The impact of injecting these genes was to cause the tumor cells to present the molecule called B7-1, the ligand that binds to receptors on T cells called CTLA-4 and CD28. The researchers then injected T cells into the test tube, and lo and behold, the T cells attacked the tumor in force, attracted by B7-1, and they wiped out the malignancy.

  One more time, gently, for good measure. Researchers figured out how to display a puzzle piece that attracted another puzzle piece and this stimulated an immune system response to wipe out a tumor.

  Good news, right?

  Two T cells (right) attack a cancer cell. (NCI/NIH)

  Yes, a huge step in the right direction. But this wasn’t yet the Holy Grail. The steps were too artificial, like tailor-making a tumor by putting foreign genes into it so that it could be targeted. Plus, this whole thing had happened in a test tube. This wasn’t yet a solution to allow manipulation of the human immune system. But it was a powerful indication that such a solution was possible.